Spinocerebellar Degenerations

Spinal Cord Image Denoising Using Dncnn Algorithm

Background: Spinal image denoising plays a vital role in the accurate diagnosis of disc herniation (DH).

Objective: Traditional denoising algorithms perform less due Limited Directional Selectivity problem and do not adequately capture directional information in pixels. Traditional algorithms' edge representation and texture details are insufficient for the earlier detection of DH. Limited Directional Selectivity leads to inaccurate diagnosis and classification of Disc Herniation (DH) stages. The DH stages are (i) Degeneration (ii) Prolapse (iii) Extrusion and (iv) Sequestration. Moreover, detection of DH size below 2mm using MR image is the major problem.

Methods: To solve the above problem, spinal cord MR images fed to the proposed Parrot optimization tuned Denoising Convolutional Neural Network (Po- DnCNN) algorithm for perspective enhancement of nucleus pulposus region in the spinal cord, vertebrae. The perspective enhancement of Spinal cord image led to the accurate classification of stages and earlier detection of DH by using the proposed Hippopotamus optimization- Fast Hybrid Vision Transformer (Ho–FastViT) algorithm. For this study, spinal cord MR images are obtained from the Grand Challenge website – SPIDER dataset.

Results: The proposed Po-DnCNN method and Ho-FastViT results are analysed quantitatively and qualitatively based on the edge, contrast, classification of the stage, and enhancement of the projected nucleus pulposus region in the spinal cord and vertebrae. The predicted DH results using the proposed method are compared with the manual Pfirrman Grade value of the spinal card method.

Conclusion: Proposed method is better than traditional methods for earlier detection of DH. Po-DnCNN and Ho-FastViat methods give high accuracy of about 98% and 97% compared to traditional methods.

BDNF and Cerebellar Ataxia

Brain-derived neurotrophic factor (BDNF) has been proposed as a treatment for neurodegeneration, including diseases of the cerebellum, where BDNF levels or those of its main receptor, TrkB, are often diminished relative to controls, thereby serving as replacement therapy. Experimental evidence indicates that BDNF signaling countered cerebellar degeneration, sensorimotor deficits, or both, in transgenic ATXN1 mice mutated for ataxin-1, Cacna1a knock-in mice mutated for ataxin-6, mice injected with lentivectors encoding RNA sequences against human FXN into the cerebellar cortex, Kcnj6^Wv (Weaver) mutant mice with granule cell degeneration, and rats with olivocerebellar transaction, similar to a BDNF-overexpressing transgenic line interbred with Cacng2^stg mutant mice. In this regard, this study discusses whether BDNF is effective in cerebellar pathologies where BDNF levels are normal and whether it is effective in cases with combined cerebellar and basal ganglia damage.

An Update on Parkinson’s Disease and its Neurodegenerative Counterparts

Introduction: Neurodegenerative disorders are a group of diseases that cause nerve cell degeneration in the brain, resulting in a variety of symptoms and are not treatable with drugs. Parkinson's disease (PD), prion disease, motor neuron disease (MND), Huntington's disease (HD), spinal cerebral dyskinesia (SCA), spinal muscle atrophy (SMA), multiple system atrophy, Alzheimer's disease (AD), spinocerebellar ataxia (SCA) (ALS), pantothenate kinase-related neurodegeneration, and TDP-43 protein disorder are examples of neurodegenerative diseases. Dementia is caused by the loss of brain and spinal cord nerve cells in neurodegenerative diseases.

Background: Even though environmental and genetic predispositions have also been involved in the process, redox metal abuse plays a crucial role in neurodegeneration since the preponderance of symptoms originates from abnormal metal metabolism.

Method: Hence, this review investigates several neurodegenerative diseases that may occur symptoms similar to Parkinson's disease to understand the differences and similarities between Parkinson's disease and other neurodegenerative disorders based on reviewing previously published papers.

Results: Based on the findings, the aggregation of alpha-synuclein occurs in Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies. Other neurodegenerative diseases occur with different protein aggregation or mutations.

Conclusion: We can conclude that Parkinson's disease, Multiple system atrophy, and Dementia with Lewy bodies are closely related. Therefore, researchers must distinguish among the three diseases to avoid misdiagnosis of Multiple System Atrophy and Dementia with Lewy bodies with Parkinson's disease symptoms.

In silico Strategy: A Promising Implement in the Development of Multitarget Drugs against Neurodegenerative Diseases

Multi-target drug development (MTDD) is the demand of the recent era, especially in the case of multi-factorial conditions such as cancer, depression, neurodegenerative diseases (NDs), etc. The MTDD approaches have many advantages; avoidance of drug-drug interactions, predictable pharmacokinetic profile, and less drug resistance. The wet lab practice in MTDD is very challenging for the researchers, and the chances of late-stage failure are obvious. Identification of an appropriate target (Target fishing) is another challenging task in the development of multi-target drugs. The in silico tools will be one of the promising tools in the MTDD for the NDs. Therefore the outlook of the review comprises a short description of NDs, target associated with different NDs, in silico studies so far done for MTDD for various NDs. The main thrust of this review is to explore the present and future aspects of in silico tools used in MTDD for different NDs in combating the challenge of drug development and the application of various in silico tools to solve the problem of target fishing.

A Review of Current and Prospective Treatments for Channelopathies, with a Focus on Gene and Protein Therapy

Reduced cell surface expression or the malfunctioning of ion channels gives rise to a group of disorders known as channelopathies. To treat the underlying cause, the delivery and/or expression of a functional ion channel into the cell membrane of the cell of interest is required. Unfortunately, for most channelopathies, current treatment options are only symptomatic and treatments that rectify the underlying damage are still lacking. Within this context, approaches that rely on gene and protein therapy are required. Gene therapy would allow the expression of a functional protein, provided that the cellular machinery in the diseased cell could correctly fold and traffic the protein to the cell membrane. Whereas protein therapy would allow the direct delivery of a functional protein, provided that the purification process does not affect protein function and a suitable delivery vehicle for targeted delivery is used. In this review, we provide an overview of channelopathies and available symptomatic treatments. The current state of gene therapy approaches mainly using viral vectors is discussed, which is followed by the role of nanomedicine in protein therapy and how nanomedicine could be exploited for the delivery of functional ion channels to diseased cells.

Therapeutic Peptides: Unravelling Conformational Dynamics by Systematic Application of Biophysical Techniques

Peptide therapeutics represents one of the fastest-growing sectors in the pharmaceutical drugs pipeline, with an increasing number of regulatory approvals every year. Their pharmacological diversity, biocompatibility, high degree of potency and selectivity make them an attractive choice in several therapeutic areas, such as diabetes, cancer, immune, metabolic, cardiovascular and infectious diseases. However, the development of peptides as drugs presents its own set of challenges, necessitating extensive property optimization aimed at improving their drug-like properties and stability in biological environments. The discovery and development of innovative peptide therapeutic platforms entail the employment of several biophysical techniques, which monitor the structural as well as the functional integrity of peptides. Small structural changes of the bioactive peptides in response to the presence of various excipients can have a major impact on their pharmaceutical prowess, necessitating the use of analytical techniques for efficient quality control during development. Here we present some widely used methods, such as circular dichroism, fluorescence spectroscopy and multi-dimensional homo and heteronuclear nuclear magnetic resonance spectroscopy that form an integral part of therapeutic peptides development. The application of combination biophysical platforms ensures the maintenance of the appropriate folded structure, which is a prerequisite for the safety and efficacy of peptide pharmaceuticals.

Neurodegenerative Disorders and the Current State, Pathophysiology, and Management of Parkinson’s Disease

In the last few decades, major knowledge has been gained about pathophysiological aspects and molecular pathways behind Parkinson’s Disease (PD). Based on neurotoxicological studies and postmortem investigations, there is a general concept of how environmental toxicants (neurotoxins, pesticides, insecticides) and genetic factors (genetic mutations in PD-associated proteins) cause depletion of dopamine from substantia nigra pars compacta region of the midbrain and modulate cellular processes leading to the pathogenesis of PD. α-Synuclein, a neuronal protein accumulation in oligomeric form, called protofibrils, is associated with cellular dysfunction and neuronal death, thus possibly contributing to PD propagation. With advances made in identifying loci that contribute to PD, molecular pathways involved in disease pathogenesis are now clear, and introducing therapeutic strategy at the right time may delay the progression. Biomarkers for PD have helped monitor PD progression; therefore, personalized therapeutic strategies can be facilitated. In order to further improve PD diagnostic and prognostic accuracy, independent validation of biomarkers is required.

Mechanisms Involved in Neuroprotective Effects of Transcranial Magnetic Stimulation

Transcranial Magnetic Stimulation (TMS) is widely used in neurophysiology to study cortical excitability. Research over the last few decades has highlighted its added value as a potential therapeutic tool in the treatment of a broad range of psychiatric disorders. More recently, a number of studies have reported beneficial and therapeutic effects for TMS in neurodegenerative conditions and strokes. Yet, despite its recognised clinical applications and considerable research using animal models, the molecular and physiological mechanisms through which TMS exerts its beneficial and therapeutic effects remain unclear. They are thought to involve biochemical-molecular events affecting membrane potential and gene expression. In this aspect, the dopaminergic system plays a special role. This is the most directly and selectively modulated neurotransmitter system, producing an increase in the flux of dopamine (DA) in various areas of the brain after the application of repetitive TMS (rTMS). Other neurotransmitters, such as glutamate and gamma-aminobutyric acid (GABA) have shown a paradoxical response to rTMS. In this way, their levels increased in the hippocampus and striatum but decreased in the hypothalamus and remained unchanged in the mesencephalon. Similarly, there are sufficient evidence that TMS up-regulates the gene expression of BDNF (one of the main brain neurotrophins). Something similar occurs with the expression of genes such as c-Fos and zif268 that encode trophic and regenerative action neuropeptides. Consequently, the application of TMS can promote the release of molecules involved in neuronal genesis and maintenance. This capacity may mean that TMS becomes a useful therapeutic resource to antagonize processes that underlie the previously mentioned neurodegenerative conditions.

SynB3 Conjugated QBP1 Passes Blood-Brain Barrier Models and Inhibits PolyQ Protein Aggregation

Background: Polyglutamine diseases are degenerative diseases in the central nervous system caused by CAG trinucleotide repeat expansion which encodes polyglutamine tracts, leading to the misfolding of pathological proteins. Small peptides can be designed to prevent polyglutamine diseases by inhibiting the polyglutamine protein aggregation, for example, polyglutamine binding peptide 1(QBP1). However, the transportation capability of polyglutamine binding peptide 1 across the blood-brain barrier is less efficient. We hypothesized whether its therapeutic effect could be improved by increasing the rate of membrane penetration.

Objective: The objective of the study was to explore whether polyglutamine binding peptide 1 conjugated cell-penetrating peptides could pass through the blood-brain barrier and inhibit the aggregation of polyglutamine proteins.

Methods: In order to investigate the toxic effects, we constructed a novel stable inducible PC12 cells to express Huntington protein that either has 11 glutamine repeats or 63 glutamine repeats to mimic wild type and polyglutamine expand Huntington protein, respectively. Both SynB3 and TAT conjugated polyglutamine binding peptide 1 was synthesized, respectively. We tested their capabilities to pass through a Trans-well system and subsequently studied the counteractive effects on polyglutamine protein aggregation.

Results: The conjugation of cell-penetrating peptides to SynB3 and TAT enhanced the transportation of polyglutamine binding peptide 1 across the mono-cell layer and ameliorated polyglutamine-- expanded Huntington protein aggregation; moreover, SynB3 showed better delivery efficiency than TAT. Interestingly, it has been observed that polyglutamine binding peptide 1 specifically inhibited polyglutamine-expanded protein aggregation rather than affected other amyloidosis proteins, for example, β-Amyloid.

Conclusion: Our study indicated that SynB3 could be an effective carrier for polyglutamine binding peptide 1 distribution through the blood-brain barrier model and ameliorate the formation of polyglutamine inclusions; thus SynB3 conjugated polyglutamine binding peptide 1 could be considered as a therapeutic candidate for polyglutamine diseases.

Role of Adenosine Receptors in Rare Neurodegenerative Diseases with Motor Symptoms

The approval of istradefylline, an adenosine 2A receptor (A2AR) antagonist, as an addon treatment in adult patients with Parkinson’s disease by the Food and Drug Administration (FDA) and European Medicines Agency (EMA), is the latest proof of the importance of the adenosinergic system in the nervous system. Adenosine is an endogenous purine nucleoside with a role as a modulator of both neurotransmission and the inflammatory response. As such, the expression pattern of the 4 adenosine receptors (A1R, A2AR, A2BR and A3R) and the extracellular adenosine levels have attracted great interest in the pathogenesis and possible treatment of rare neurodegenerative diseases with motor symptoms. These include Huntington’s Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Restless Legs Syndrome (RLS) and Machado-Joseph Disease (MJD, also known as spinocerebellar ataxia type 3, SCA3). In this review, we shall focus on the role of the different adenosine receptor subtypes in the development and possible treatment of the aforementioned rare neurodegenerative diseases with motor symptoms using the currently available data. The last section discusses the possibility of a role for the adenosine receptors in the treatment of other rare diseases based on the available molecular pathology knowledge.

C-terminus of Hsp70 Interacting Protein (CHIP) and Neurodegeneration: Lessons from the Bench and Bedside

Neurodegenerative diseases are characterized by the increasing dysfunction and death of neurons, resulting in progressive impairment of a person’s mobility and/or cognition. Protein misfolding and aggregation are commonly hypothesized to cause neurotoxicity and, eventually, neuronal degeneration that are associated with these diseases. Emerging experimental evidence, as well as recent findings from human studies, reveal that the C-terminus of Hsp70 Interacting Protein (CHIP), or STIP1 Homology and U-box containing Protein 1 (STUB1), is a quality control protein involved in neurodegeneration. Here, we review evidence that CHIP interacts with and plays a role in regulating proteins implicated in the pathogenesis of Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and polyglutamine diseases, including Huntington’s disease and spinocerebellar ataxias. We also review clinical findings identifying mutations in STUB1 as a cause of both autosomal recessive and autosomal dominant forms of cerebellar ataxia. We propose that CHIP modulation may have therapeutic potential for the treatment of multiple neurodegenerative diseases.

Role of Hydrogen Sulfide and Polysulfides in Neurological Diseases: Focus on Protein S-Persulfidation

Hydrogen sulfide (H2S) and hydrogen polysulfides are recognized as important signaling molecules that are generated physiologically in the body, including the central nervous system (CNS). Studies have shown that these two molecules are involved in cytoprotection against oxidative stress and inflammatory response. In the brain system, H2S and polysulfides exert multiple functions in both health and diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington's disease (HD), memory decline, and glioma. Mechanistically, S-Persulfidation (also known as S-sulfuration or S-sulfhydration) of target proteins is believed to be a fundamental mechanism that underlies H2S-regulated signaling pathways. Cysteine S-Persulfidation is an important paradigm of post translational protein modification in the process of H2S signaling. This model is established as a critical redox mechanism to regulate numerous biological functions, especially in H2S-mediated neuroprotection and neurogenesis. Although the current research of S-Persulfidation is still in its infancy, accumulative evidence suggests that protein S-Persulfidation may share similar characteristics with protein S-nitrosylation. In this review, we will provide a comprehensive insight into the S-Persulfidation biology of H2S and polysulfides in neurological ailments and presume potential avenues for therapeutic development in these disorders based on S-Persulfidation of target proteins.

Purines and Pyrimidines: Metabolism, Function and Potential as Therapeutic Options in Neurodegenerative Diseases

Various neurodegenerative disorders have various molecular origins but some common molecular mechanisms. In the current scenario, there are very few treatment regimens present for advanced neurodegenerative diseases. In this context, there is an urgent need for alternate options in the form of natural compounds with an ameliorating effect on patients. There have been individual scattered experiments trying to identify potential values of various intracellular metabolites. Purines and Pyrimidines, which are vital molecules governing various aspects of cellular biochemical reactions, have been long sought as crucial candidates for the same, but there are still many questions that go unanswered. Some critical functions of these molecules associated with neuromodulation activities have been identified. They are also known to play a role in foetal neurodevelopment, but there is a lacuna in understanding their mechanisms. In this review, we have tried to assemble and identify the importance of purines and pyrimidines, connecting them with the prevalence of neurodegenerative diseases. The leading cause of this class of diseases is protein misfolding and the formation of amyloids. A direct correlation between loss of balance in cellular homeostasis and amyloidosis is yet an unexplored area. This review aims at bringing the current literature available under one umbrella serving as a foundation for further extensive research in this field of drug development in neurodegenerative diseases.

Therapeutic Applications of Mesenchymal Stem Cells: A Comprehensive Review

Mesenchymal Stem Cells (MSCs) are one of the most promising tools for cell therapy, that are isolated from bone marrow and many other adult tissues such as liver, cord blood, placenta, dental pulp and adipose tissue. Due to the lack of MHC class II expression on the surface of MSCs, they can also be used as a potent cell source for tissue regeneration in non-autologous cell therapy applications. Many advantages of MSCs such as their self-renewal, in vitro proliferation, rapid cell doubling capacity, anti-fibrotic, anti-apoptotic, anti-inflammatory, immunomodulatory and immunosuppressive effects, and also paracrine nature have been demonstrated in various pre-- clinical studies and clinical evidence. The ability of MSCs to differentiate into multiple cell lineages, as well as the lack of ethical issues in comparison with embryonic and induced Pluripotent Stem Cells (iPSCs), has introduced them as a suitable candidate for cell therapy. This review provides a comprehensive overview of various clinical trials based on MSCs for the treatment of a variety of diseases, demonstrating their capability in the treatment of dermatological, musculoskeletal, neurological, cardiovascular, respiratory, renal, gastroenterological and urological conditions, etc.

Mannitol Reduces Spinal Cord Edema in Rats with Acute Traumatic Spinal Cord Injury

Background: The research about anti-edema effects of mannitol on acute traumatic spinal cord injury (SCI) in rats is rare.

Objective: This study aimed to explore the effect of mannitol on spinal cord edema after SCI in rats.

Methods: Seventy-eight adult female rats were assigned to three groups randomly: a sham control group (n = 18), a contusion and normal saline contrast group (n=30), and a contusion and mannitol treatment group (n=30). We used the open-field test to estimate the functional recovery of rats weekly. Spinal cord water content was measured to determine the spinal cord edema. The ultrastructure features of the injured dorsolateral spinal cord were determined on the 7th day after SCI by HE staining.

Results: The mannitol group had greatly improved Basso-Beattie-Bresnahan (BBB) scores when compared with the saline contrast group. The spinal cord water content was increased significantly after SCI, and there was no significant difference in the water content between the NaCl and mannitol groups 1 day after SCI. The water content at 3 and 7 days after SCI was significantly lower in the mannitol group than in the NaCl group (p < 0.05). Mannitol can reduce spinal cord edema by increasing the number of red blood cells in the injured spinal cord and decrease the ratio (dorsoventral diameter/ mediolateral diameter) of spinal cord 7 days post-SCI.

Conclusion: Mannitol increases recovery of motor function in rats, reduces spinal cord edema and increases the number of red blood cells in the injured spinal cord, decreasing the ratio of spinal cord to reduce pressure.

Excitotoxicity as a Target Against Neurodegenerative Processes

The global burden of neurodegenerative diseases is alarmingly increasing in parallel to the aging of population. Although the molecular mechanisms leading to neurodegeneration are not completely understood, excitotoxicity, defined as the injury and death of neurons due to excessive or prolonged exposure to excitatory amino acids, has been shown to play a pivotal role. The increased release and/or decreased uptake of glutamate results in dysregulation of neuronal calcium homeostasis, leading to oxidative stress, mitochondrial dysfunctions, disturbances in protein turn-over and neuroinflammation.

Despite the anti-excitotoxic drug memantine has shown modest beneficial effects in some patients with dementia, to date, there is no effective treatment capable of halting or curing neurodegenerative diseases such as Alzheimer’s disease, Parkinson disease, Huntington’s disease or amyotrophic lateral sclerosis. This has led to a growing body of research focusing on understanding the mechanisms associated with the excitotoxic insult and on uncovering potential therapeutic strategies targeting these mechanisms.

In the present review, we examine the molecular mechanisms related to excitotoxic cell death. Moreover, we provide a comprehensive and updated state of the art of preclinical and clinical investigations targeting excitotoxic- related mechanisms in order to provide an effective treatment against neurodegeneration.

Emerging Potential of Naturally Occurring Autophagy Modulators Against Neurodegeneration

Background: Naturally-occurring products derived from living organisms have been shown to modulate various pharmacological and biological activities. Natural products protect against various diseases, which could be used for therapeutic assistance. Autophagy, a lysosome-mediated self-digestion pathway, has been implicated in a range of pathophysiological conditions and has recently gained attention for its role in several neurodegenerative diseases.

Methods: In this current review, we emphasized the recent progress made in our understanding of the molecular mechanism of autophagy in different cellular and mouse models using naturally-occurring autophagy modulators for the management of several neurodegenerative diseases.

Results: Accumulating evidence has revealed that a wide variety of natural compounds such as alkaloids, polyphenols, terpenoids, xanthonoids, flavonoids, lignans, disaccharides, glycolipoproteins, and saponins are involved in the modulation of the autophagy signaling pathway. These natural products have been used to treat various neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, spinocerebellar ataxia, neuroblastoma, and glioblastoma. Although a number of synthetic autophagy regulators have been recognized as encouraging neurodegenerative therapeutic candidates, natural autophagy- regulating compounds have been of further interest as potential disease therapeutics, as they cause insignificant side effects.

Conclusion: Existing in vitro and in vivo data are promising and highlight that naturally-occurring autophagyregulating compounds play an important role in the prevention and treatment of neurodegenerative disorders.

The Application of Neural Stem/Progenitor Cells for Regenerative Therapy of Spinal Cord Injury

Spinal cord injury (SCI) is a devastating event, and there are still no effective therapies currently available. Neural stem cells (NSCs) have gained increasing attention as promising regenerative therapy of SCI. NSCs based therapies of various neural diseases in animal models and clinical trials have been widely investigated. In this review we aim to summarize the development and recent progress in the application of NSCs in cell transplantation therapy for SCI. After brief introduction on sequential genetic steps regulating spinal cord development in vivo, we describe current experimental approaches for neural induction of NSCs in vitro. In particular, we focus on NSCs induced from pluripotent stem cells (PSCs). Finally, we highlight recent progress on the NSCs, which show great promise in the application to regeneration therapy for SCI.

Clinical Characteristics and Possible Drug Targets in Autosomal Dominant Spinocerebellar Ataxias

Background & Objective: The autosomal dominant spinocerebellar ataxias (SCAs) belong to a large and expanding group of neurodegenerative disorders. SCAs comprise more than 40 subtypes characterized by progressive ataxia as a common feature. The most prevalent diseases among SCAs are caused by CAG repeat expansions in the coding-region of the causative gene resulting in polyglutamine (polyQ) tract formation in the encoded protein. Unfortunately, there is no approved therapy to treat cerebellar motor dysfunction in SCA patients. In recent years, several studies have been conducted to recognize the clinical and pathophysiological aspects of the polyQ SCAs more accurately. This scientific progress has provided new opportunities to develop promising gene therapies, including RNA interference and antisense oligonucleotides.

Conclusion: The aim of the current work is to give a brief summary of the clinical features of SCAs and to review the cardinal points of pathomechanisms of the most common polyQ SCAs. In addition, we review the last few year’s promising gene suppression therapies of the most frequent polyQ SCAs in animal models, on the basis of which human trials may be initiated in the near future.

The Impact of Natural Compounds on the Treatment of Neurodegenerative Diseases

Neurodegenerative diseases (NDDs) are characterized by a progressive deterioration of the motor and/or cognitive function, that are often accompanied by psychiatric disorders, caused by a selective loss of neurons in the central nervous system. Among the NDDs we can mention Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia 3 (SCA3), spinal and bulbar muscular atrophy (SBMA) and Creutzfeldt-Jakob disease (CJD). AD and HD are characterized mainly by massive neuronal loss. PD, ALS, SCA3 and SBMA are agerelated diseases which have characteristic motor symptoms. CJD is an NDD caused by prion proteins. With increasing life expectancy, elderly populations tend to have more health problems, such as chronic diseases related to age and disability. Therefore, the development of therapeutic strategies to treat or prevent multiple pathophysiological conditions in the elderly can improve the expectation and quality of life. The attention of researchers has been focused on bioactive natural compounds that represent important resources in the discovery and development of drug candidates against NDDs. In this review, we discuss the pathogenesis, symptoms, potential targets, treatment and natural compounds effective in the treatment of AD, PD, HD, ALS, SCA3, SBMA and CJD.

Transcranial Direct Current Stimulation for Treatment of Alzheimer’s Disease: A Systematic Review of Randomized Clinical Trial

Introduction: Alzheimer’s disease (AD) is a neurodegenerative pathology manifested by cognitive impairment and behavioral derangement. Transcranial Direct Current Stimulation (tDCS) as non-invasive and safe neuromodulation technique has shown promising effects in different neuropsychiatric disorders. Similarly, tDCS has recently shown potential therapeutic outcomes in AD. The present study aims to systematically review the therapeutic efficacy of tDCS in patients with AD.

Method: The databases of PubMed (1970-2017), Web of Sciences (1970-2017), and Google Scholar (1980-2017) were searched using the set terms "tDCS" OR "transcranial direct current stimulation" AND "Alzheimer’s disease" OR "AD" AND "treatment". The search engine Trip Database was used and the date of last search was August 30, 2017. The retrieved records were reviewed Independently by two authors.

Results: Seven studies were obtained with a total of 185 patients who met the inclusion criteria. Evaluating the results, 4 studies supported the possible efficacy of the therapy versus 3 that did not find statistically significant differences compared with the placebo groups. Anodal tDCS over frontal cortex, particularly left dorsolateral prefrontal cortex and temporal cortex, showed therapeutic efficacy in AD.

Conclusion: Further studies are needed to determine effective protocols and clinical efficacy of tDCS for AD treatment. However, the current evidence from clinical trials encourages further research to investigate anodal tDCS as an adjuvant treatment for patients with AD.

Immune-mediated Cerebellar Ataxias: Practical Guidelines and Therapeutic Challenges

Immune-mediated cerebellar ataxias (IMCAs), a clinical entity reported for the first time in the 1980s, include gluten ataxia (GA), paraneoplastic cerebellar degenerations (PCDs), antiglutamate decarboxylase 65 (GAD) antibody-associated cerebellar ataxia, post-infectious cerebellitis, and opsoclonus myoclonus syndrome (OMS). These IMCAs share common features with regard to therapeutic approaches. When certain factors trigger immune processes, elimination of the antigen( s) becomes a priority: e.g., gluten-free diet in GA and surgical excision of the primary tumor in PCDs. Furthermore, various immunotherapeutic modalities (e.g., steroids, immunoglobulins, plasmapheresis, immunosuppressants, rituximab) should be considered alone or in combination to prevent the progression of the IMCAs. There is no evidence of significant differences in terms of response and prognosis among the various types of immunotherapies. Treatment introduced at an early stage, when CAs or cerebellar atrophy is mild, is associated with better prognosis. Preservation of the “cerebellar reserve” is necessary for the improvement of CAs and resilience of the cerebellar networks. In this regard, we emphasize the therapeutic principle of “Time is Cerebellum” in IMCAs.

Aminopyridines and Acetyl-DL-leucine: New Therapies in Cerebellar Disorders

Cerebellar ataxia is a frequent and often disabling syndrome severely impairing motor functioning and quality of life. Patients suffer from reduced mobility, and restricted autonomy, experiencing an even lower quality of life than, e.g., stroke survivors. Aminopyridines have been demonstrated viable for the symptomatic treatment of certain forms of cerebellar ataxia. This article will give an outline of the present pharmacotherapy of different cerebellar disorders. As a current key-therapy for the treatment of downbeat nystagmus 4-aminopyridine (4-AP) is suggested for the treatment of downbeat nystagmus (5–10 mg Twice a day [TID]), a frequent type of persisting nystagmus, due to a compromise of the vestibulo-cerebellum. Studies with animals have demonstrated, that a nonselective blockage of voltage-gated potassium channels (mainly Kv1.5) increases Purkinje- cell (PC) excitability. In episodic ataxia type 2 (EA2), which is frequently caused by mutations of the PQ-calcium channel, the efficacy of 4-AP (5–10 mg TID) has been shown in a randomized controlled trial (RCT). 4-AP was well tolerated in the recommended dosages. 4-AP was also effective in elevating symptoms in cerebellar gait ataxia of different etiologies (2 case series).

A new treatment option for cerebellar disease is the amino-acid acetyl-DL-leucine, which has significantly improved cerebellar symptoms in three case series. There are on-going randomized controlled trials for cerebellar ataxia (acetyl-DL-leucine vs placebo; ALCAT), cerebellar gait disorders (SR-form of 4-AP vs placebo; FACEG) and EA2 (sustained-release/SR-form of 4-AP vs acetazolamide vs placebo; EAT2TREAT), which will provide new insights into the pharmacological treatment of cerebellar disorders.

Noninvasive Cerebellar Stimulation as a Complement Tool to Pharmacotherapy

Background: Cerebellar ataxias represent a wide and heterogeneous group of diseases characterized by balance and coordination disturbance, dysarthria, dyssynergia and adyadococinesia, caused by a dysfunction in the cerebellum. In recent years there has been growing interest in discovering therapeutical strategy for specific forms of cerebellar ataxia. Together with pharmacological studies, there has been growing interest in non-invasive cerebellar stimulation techniques to improve ataxia and limb coordination. Both transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are non-invasive techniques to modulate cerebro and cerebellar cortex excitability using magnetic or electric fields.

Methods: Here we aim to review the most relevant studies regarding the application of TMS and tDCS for the treatment of cerebellar ataxia.

Conclusion: As pharmacological strategies were shown to be effective in specific forms of cerebellar ataxia and are not devoid of collateral effects, non-invasive stimulation may represent a promising strategy to improve residual cerebellar circuits functioning and a complement tool to pharmacotherapy.

Anti-Oxidant Drugs: Novelties and Clinical Implications in Cerebellar Ataxias

Background: Hereditary cerebellar ataxias are a group of disorders characterized by heterogeneous clinical manifestations, progressive clinical course, and diverse genetic causes. No disease modifying treatments are yet available for many of these disorders. Oxidative stress has been recurrently identified in different progressive cerebellar diseases, and it represents a widely investigated target for treatment.

Objective: To review the main aspects and new perspectives of antioxidant therapy in cerebellar ataxias ranging from bench to bedside.

Method: This article is a summary of the state-of-the-art on the use of antioxidant molecules in cerebellar ataxia treatments. It also briefly summarizes aspects of oxidative stress production and general characteristics of antioxidant compounds.

Results: Antioxidants represent a vast category of compounds; old drugs have been extensively studied and modified in order to achieve better biological effects. Despite the vast body of literature present on the use of antioxidants in cerebellar ataxias, for the majority of these disorders conclusive results on the efficacy are still missing.

Conclusion: Antioxidant therapy in cerebellar ataxias is a promising field of investigations. To achieve the success in identifying the correct treatment more work needs to be done. In particular, a combined effort is needed by basic scientists in developing more efficient molecules, and by clinical researchers together with patients communities, to run clinical trials in order to identify conclusive treatments strategies.

Models of Parkinson’s Disease with Special Emphasis on Drosophila melanogaster

Background & Objective: Parkinson’s disease is the second most common neurodegenerative disorder affecting more than 1% of the population averaged 60 years of age. The majority of PD cases are sporadic and are probably caused by a combination of risk factors but 5-10% of the PD cases are familial. Due to the high degree of the gene, conservation in humans, mice and insects using an animal model system is a valuable approach to further elucidate the roles of the genes in PD.

Conclusion: The present review highlights the models used to study PD symptoms with special emphasis on Drosophila.

Current and Promising Therapies in Autosomal Recessive Ataxias

Background & Objective: Ataxia is clinically characterized by unsteady gait and imbalance. Cerebellar disorders may arise from many causes such as metabolic diseases, stroke or genetic mutations. The genetic causes are classified by mode of inheritance and include autosomal dominant, X-linked and autosomal recessive ataxias. Many years have passed since the description of the Friedreich's ataxia, the most common autosomal recessive ataxia, and mutations in many other genes have now been described. The genetic mutations mostly result in the accumulation of toxic metabolites which causes Purkinje neuron lost and eventual cerebellar dysfunction. Unfortunately, the recessive ataxias remain a poorly known group of diseases and most of them are yet untreatable.

Conclusion: The aim of this review is to provide a comprehensive clinical profile and to review the currently available therapies. We overview the physiopathology, neurological features and diagnostic approach of the common recessive ataxias. The emphasis is also made on potential drugs currently or soon-to-be in clinical trials. For instance, promising gene therapies raise the possibility of treating differently Friedreich's ataxia, Ataxia-telangiectasia, Wilson's disease and Niemann-Pick disease in the next few years.

Neurotransplantation Therapy and Cerebellar Reserve

Background & Objective: Neurotransplantation has been recently the focus of interest as a promising therapy to substitute lost cerebellar neurons and improve cerebellar ataxias. However, since cell differentiation and synaptic formation are required to obtain a functional circuitry, highly integrated reproduction of cerebellar anatomy is not a simple process. Rather than a genuine replacement, recent studies have shown that grafted cells rescue surviving cells from neurodegeneration by exerting trophic effects, supporting mitochondrial function, modulating neuroinflammation, stimulating endogenous regenerative processes, and facilitating cerebellar compensatory properties thanks to neural plasticity. On the other hand, accumulating clinical evidence suggests that the self-recovery capacity is still preserved even if the cerebellum is affected by a diffuse and progressive pathology. We put forward the period with intact recovery capacity as “restorable stage” and the notion of reversal capacity as “cerebellar reserve”.

Conclusion: The concept of cerebellar reserve is particularly relevant, both theoretically and practically, to target recovery of cerebellar deficits by neurotransplantation. Reinforcing the cerebellar reserve and prolonging the restorable stage can be envisioned as future endpoints of neurotransplantation.

In Silico Studies in Drug Research Against Neurodegenerative Diseases

Background: Neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis, Parkinson's disease (PD), spinal cerebellar ataxias, and spinal and bulbar muscular atrophy are described by slow and selective degeneration of neurons and axons in the central nervous system (CNS) and constitute one of the major challenges of modern medicine. Computeraided or in silico drug design methods have matured into powerful tools for reducing the number of ligands that should be screened in experimental assays.

Methods: In the present review, the authors provide a basic background about neurodegenerative diseases and in silico techniques in the drug research. Furthermore, they review the various in silico studies reported against various targets in neurodegenerative diseases, including homology modeling, molecular docking, virtual high-throughput screening, quantitative structure activity relationship (QSAR), hologram quantitative structure activity relationship (HQSAR), 3D pharmacophore mapping, proteochemometrics modeling (PCM), fingerprints, fragment-based drug discovery, Monte Carlo simulation, molecular dynamic (MD) simulation, quantum-mechanical methods for drug design, support vector machines, and machine learning approaches.

Results: Detailed analysis of the recently reported case studies revealed that the majority of them use a sequential combination of ligand and structure-based virtual screening techniques, with particular focus on pharmacophore models and the docking approach.

Conclusion: Neurodegenerative diseases have a multifactorial pathoetiological origin, so scientists have become persuaded that a multi-target therapeutic strategy aimed at the simultaneous targeting of multiple proteins (and therefore etiologies) involved in the development of a disease is recommended in future.

Coumarin Compounds in Medicinal Chemistry: Some Important Examples from the Last Years

Coumarins are natural products characterized as 1,2 benzopyrones widely distributed in plants, as well as, in many species of fungi and bacteria. Nowadays, many synthetic procedures allow the discovery of coumarins with expanded chemical space. The ability to exert noncovalent interactions with many enzymes and receptors in live organisms lead the coumarins to exhibit a wide range of biological activities and applications. Then, this manuscript provides an overview of the use of coumarins compounds in medicinal chemistry in treating many diseases. Important examples of the last years have been selected concerning the activities of coumarins as anticoagulant, anticancer, antioxidant, antiviral, anti-diabetics, anti-inflammatory, antibacterial, antifungal and anti-neurodegerative agents. Additionally, it also includes applications of coumarins as fluorescent sensors for biological systems. Thus, this work aims to contribute to the development of new rational research projects for the treatment and diagnosis of pathologies using coumarin derivatives.

Structure-function Evaluation of Stem Cell Therapies for Spinal Cord Injury

Background: Spinal cord injuries (SCI) are prevalent, devastating for quality and expectancy of life, and cause heavy economic burdens. Stem cell therapies hold promise in complete structural and functional restoration of SCI.

Objective: This review focuses on the methods currently used to evaluate the stem cell therapies for SCI.

Results: Various kinds of stem cells involving embryonic stem cells (ESCs), bone marrow stromal cells (BMSCs), neural stem cells (NSCs) and induced pluripotent stem cells (iPSCs) are extensively used in regenerative research of SCI. For evaluation, the survival and integration of transplanted cells, spinal cord reconstruction and functional recovery all should be considered. Histological and histochemistrical, microscopic, and colorimetric assays, and real-time RT-PCR techniques are applied to determine the outcome. From the three main aspects-transplanted cells, spinal cord structure, and functional recovery-we summarize and discuss these methods with certain instances of applications in SCI models. Importantly, for the evaluations of function, neuronal transmitting, electrophysiological analysis and behavioral score are included.

Conclusion: Wider conjunction of established technologies, as well as the further development of nondestructive methods might make a big difference in testing stem cell therapies.

Calcium Signaling, PKC Gamma, IP3R1 and CAR8 Link Spinocerebellar Ataxias and Purkinje Cell Dendritic Development

Background: Spinocerebellar ataxias (SCAs) are a group of cerebellar diseases characterized by progressive ataxia and cerebellar atrophy. Several forms of SCAs are caused by missense mutations or deletions in genes related to calcium signaling in Purkinje cells. Among them, spinocerebellar ataxia type 14 (SCA14) is caused by missense mutations in PRKCG gene which encodes protein kinase C gamma (PKCγ). It is remarkable that in several cases in which SCA is caused by point mutations in an individual gene, the affected genes are involved in the PKCγ signaling pathway and calcium signaling which is not only crucial for proper Purkinje cell function but is also involved in the control of Purkinje cell dendritic development. In this review, we will focus on the PKCγ signaling related genes and calcium signaling related genes then discuss their role for both Purkinje cell dendritic development and cerebellar ataxia.

Methods: Research related to SCAs and Purkinje cell dendritic development is reviewed.

Results: PKCγ dysregulation causes abnormal Purkinje cell dendritic development and SCA14. Carbonic anhydrase related protein 8 (Car8) encoding CAR8 and Itpr1 encoding IP3R1were identified as upregulated genes in one of SCA14 mouse model. IP3R1, CAR8 and PKCγ proteins are strongly and specifically expressed in Purkinje cells. The common function among them is that they are involved in the regulation of calcium homeostasis in Purkinje cells and their dysfunction causes ataxia in mouse and human. Furthermore, disruption of intracellular calcium homeostasis caused by mutations in some calcium channels in Purkinje cells links to abnormal Purkinje cell dendritic development and the pathogenesis of several SCAs.

Conclusion: Once PKCγ signaling related genes and calcium signaling related genes are disturbed, the normal dendritic development of Purkinje cells is impaired as well as the integration of signals from other neurons, resulting in abnormal development, cerebellar dysfunction and eventually Purkinje cell loss.

Commonalities in Biological Pathways, Genetics, and Cellular Mechanism between Alzheimer Disease and Other Neurodegenerative Diseases: An In Silico-Updated Overview

Background: Alzheimer's disease (AD) is the most common and well-studied neurodegenerative disease (ND). Biological pathways, pathophysiology and genetics of AD show commonalities with other NDs viz. Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Prion disease and Dentatorubral-pallidoluysian atrophy (DRPLA). Many of the NDs, sharing the common features and molecular mechanisms suggest that pathology may be directly comparable and be implicated in disease prevention and development of highly effective therapies.

Method: In this review, a brief description of pathophysiology, clinical symptoms and available treatment of various NDs have been explored with special emphasis on AD. Commonalities in these fatal NDs provide support for therapeutic advancements and enhance the understanding of disease manifestation.

Conclusion: The studies concentrating on the commonalities in biological pathways, cellular mechanisms and genetics may provide the scope to researchers to identify few novel common target(s) for disease prevention and development of effective common drugs for multi-neurodegenerative diseases.

Aging as an Epigenetic Phenomenon

Introduction: Hypermethylation of genes associated with promoter CpG islands, and hypomethylation of CpG poor genes, repeat sequences, transposable elements and intergenic genome sections occur during aging in mammals. Methylation levels of certain CpG sites display strict correlation to age and could be used as “epigenetic clock” to predict biological age. Multi-substrate deacetylases SIRT1 and SIRT6 affect aging via locus-specific modulations of chromatin structure and activity of multiple regulatory proteins involved in aging. Random errors in DNA methylation and other epigenetic marks during aging increase the transcriptional noise, and thus lead to enhanced phenotypic variation between cells of the same tissue. Such variation could cause progressive organ dysfunction observed in aged individuals. Multiple experimental data show that induction of NF-κB regulated gene sets occurs in various tissues of aged mammals. Upregulation of multiple miRNAs occurs at mid age leading to downregulation of enzymes and regulatory proteins involved in basic cellular functions, such as DNA repair, oxidative phosphorylation, intermediate metabolism, and others.

Conclusion: Strong evidence shows that all epigenetic systems contribute to the lifespan control in various organisms. Similar to other cell systems, epigenome is prone to gradual degradation due to the genome damage, stressful agents, and other aging factors. But unlike mutations and other kinds of the genome damage, age-related epigenetic changes could be fully or partially reversed to a “young” state.

Nano-medicine Improving the Bioavailability of Small Molecules for the Prevention of Neurodegenerative Diseases

Neurodegenerative diseases, including Parkinson’s and Alzheimer’s, are a heterogeneous group of brain disorders characterized by the progressive degeneration of the structure and function of the central or peripheral nervous system. It is thought that the number of people affected by these pathologies will increase in future decades, particularly in the more economically developed countries, where the populations are experiencing a demographic shift towards older ages. For many of these pathologies, and in particular for Alzheimer’s disease, no effective treatments are available, and the consequent economic and social costs are very high. Scientific progress in recent decades has provided a better understanding of the genetic and biological mechanisms responsible for these neurodegenerative diseases, and offers the hope for new therapeutic approaches in the near future. Meanwhile, the lack of effective therapies for these diseases has caused researchers to focus attention on the powerful opportunity of prevention, seen on the one hand as a series of healthcare measures and patient behaviors, and on the other hand as treatments exploiting several molecules or compounds with the potential to slow down the appearance of the first signs of pathology or even to prevent these diseases. Among these, curcumin, flavonoids, such as quercetin, Gingko biloba, and folic acid have attracted the attention of scientists, and ways are being explored to increase their effectiveness and bioavailability in the site of action. Most molecules suffer from problems of solubility, or bioavailability, or the ability to cross the blood brain barrier, and one solution to this limitation being explored is nanomedicine. Polymeric nanoparticles, as well as liposomes, and functionalized nanosystems may overcome several bioavailability limits of active molecules and increase their effectiveness in the brain. This review offers an overview of small molecules that may prove effective in preventing neurodegenerative diseases, and describes the strategies in nanomedicine that are being studied to improve their bioavailability.

Other Proteins Involved in Parkinson's Disease and Related Disorders

In order to explain the molecular causes of Parkinson’s Disease (PD) it is important to understand the effect that mutations described as causative of the disease have at the functional level. In this special issue, several authors have been reviewing the effects in PD and other parkinsonisms of mutations described in LRRK2, α-synuclein, PINK1-Parkin-DJ-1, UCHL1, ATP13A2, GBA, VPS35, FBOX7 and HTRA2. In this review, we compile the knowledge about other proteins with a more general role in neurodegenerative diseases (MAPT) or for which less data is available due to its recent discovery (EIF4G1, DNAJC13), the lack of structural or functional data (as for PLA2G6 or DNAJC6), or even their doubtful association with the disease (as for GIGYF2, SYNJ1 and SPR). Also the cellular pathways involved in this disease are reviewed, with the goal of having an overview of the effects on the proteins and its possible role in the disease. This knowledge could also serve as the basis for designing tools that may potentially be used as a treatment for the disease, such as inhibitory or activating molecules, as well as other involved in regulating the half-life of the proteins involved.

Heat Shock Proteins: Old and Novel Roles in Neurodegenerative Diseases in the Central Nervous System

Heat shock proteins (HSPs) are families of molecular chaperones that play important homeostatic functions in the central nervous system (CNS) by preventing protein misfolding, promoting degradation of improperly folded proteins, and protecting against apoptosis and inflammatory damage especially during hyperthermia, hypoxia, or oxidative stress. Under stress conditions, HSPs are upregulated to protect cells from damage that accumulates during ageing as well as pathological conditions. An important, yet frequently overlooked function of some HSPs is their ability to function as extracellular messengers (also termed chaperokines) that modulate immune responses within the CNS. Given the strong association between protein aggregation, innate immune cell activation and neurodegeneration, the expression and roles of HSPs in the CNS is attracting attention in many neurodegenerative disorders including inflammatory diseases such as multiple sclerosis, protein folding diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis, and genetic white matter diseases. This is especially so since several studies show that HSPs act therapeutically by modulating innate immune activation and may thus serve as neuroprotective agents.

Here we review the evidence linking HSPs with neurodegenerative disorders in humans and the experimental animal models of these disorders. We discuss the mechanisms by which HSPs protect cells, and how the knowledge of their endogenous functions can be exploited to treat disorders of the CNS.

Secondary Metabolites from Acremonium Fungi: Diverse Structures and Bioactivities

Background: Acremonium fungi have been isolated from various sources, such as soil, plants, and marine organisms.

Method: The species in Acremonium have been proved to be rich sources of novel and bioactive secondary metabolites. Up to now, 356 metabolites belonging to steroids (6 compounds), terpenoids (86), meroterpenoids (66), polyketides (89), alkaloids (28), peptides (75), and miscellaneous types (6) have been isolated from Acremonium fungi. These metabolites displayed a wide range of biological activities including antimicrobial, cytotoxic, antitumor, immunosuppressive, antioxidant, antiinflammatory, antimalarial, phytotoxic, tremorgenic, antiviral, neuritogenic, insecticidal and enzymesinhibiting activities.

Conclusion: This review highlights the structures and bioactivities of the secondary metabolites from Acremonium fungi reported until July 2016.

SUMOylation in Neurological Diseases

Since the discovery of SUMOs (small ubiquitin-like modifiers) over 20 years ago, sumoylation has recently emerged as an important posttranslational modification involved in almost all aspects of cellular physiology. In neurons, sumoylation dynamically modulates protein function and consequently plays an important role in neuronal maturation, synapse formation and plasticity. Thus, the dysfunction of sumoylation pathway is associated with many different neurological disorders. Hundreds of different proteins implicated in the pathogenesis of neurological disorders are SUMO-modified, indicating the importance of sumoylation involved in the neurological diseases. In this review, we summarize the growing findings on protein sumoylation in neuronal function and dysfunction. It is essential to have a thorough understanding on the mechanism how sumoylation contributes to neurological diseases in developing efficient therapy for these diseases.

Possible Targets of Herbals for Type 3 Diabetes: A Review

There is substantial evidence for the formation of Aβ and their conversion into toxic species under hyperglycemic condition. So, we can say that brain is one of the most important sites for diabetic end organ damage and AZ can be considered as a type of Diabetes. Till date we don’t have proper therapy for successful prevention of neuronal cell death in neurodegenerative diseases and research focuses to bring drugs that can either slow down disease progression or provide prophylaxis. However, Ayurveda that has numerous plants which can execute amazing and outstanding properties with (few) actions of herbs that are quite new to the conventional medicine. Polyphenolic compounds, found in various types of plant parts, that are antioxidant by nature having useful prophylactic properties for the treatment of excitotoxicity and oxidative cell death. Plants become source material for the development of drugs, as herbs have recently become attractive for targeting different pathologies as health-beneficial foods (physiologically functional foods). As an addition to various potent reviews that provided the therapeutic effect/efficacy information about various herbals as better neuro modulators, herein we have given up to date information of various phytoconstituents, polyherbal formulations and extracts which were found effective in the treatment of AZ. Although there are several herbals that have been proved to increase cognitive abilities, here we mentioned the herbals that were tested against various AZ insults.

Neurodegeneration with Dementia: From Fundamentals of Pathology to Clinical Imaging by MRI and SPECT.

The increasing incidence of neurodegenerative disorders with dementia (NDD) requires structural and functional imaging methods which are easily available in the clinical setting. The diagnostic work-up for patients who have NDD includes magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), and positron emission tomography (PET). Both, MRI and SPECT can show characteristic findings of NDD. However, the interpretation of these findings has to be done in the context of clinical data, which includes biochemical and histological examinations. In this article, we review recent advances in pathology and the impact of these advances on MRI and SPECT studies interpretations. We present a literature review describing typical MRI and SPECT findings and the diagnostic accuracies reported for NDD. Combining MRI and SPECT examinations with quantitative evaluation of clinical data further improves the diagnostic potential of these imaging procedures for NDD.

Spinal Cord Injury Changes Cytokine Transport

Here we summarize three aspects of our understanding of the interactions of cytokines and neurotrophic peptides/proteins with the blood-brain and bloodspinal cord barriers (BBB): (a) pharmacokinetic analysis that has been reported for native cytokines and neurotrophic peptides/proteins; (b) landmark work on conjugated proteins to enhance their delivery across the normal BBB; and (c) regulatory changes under pathophysiological conditions in rodents, particularly after spinal cord injury (SCI). First, though the BBB restricts the permeation of large proteins, some cytokines and neurotrophic peptides/proteins in the periphery can reach the central nervous system (CNS) by specific transport systems. Moreover, SCI and some other disease processes may regulate these transport systems. The significance of studies of the transport systems is obvious because of the biological impact of these molecules on the CNS in health and disease. We have characterized the pharmacokinetic characteristics of some stable cytokines and neurotrophic peptides/proteins in mice after intravenous administration and also in the setting of in situ brain perfusion. In the particular case of SCI, there are time- and regionspecific changes of BBB permeability and transport systems. Tumor necrosis factor-α, a cytokine with dual actions in regeneration of the spinal cord, has a slow basal influx into the brain and spinal cord. After SCI, the increase in the entry of tumor necrosis factor-α to the CNS differs from leakage after BBB disruption and is related to upregulation of the transport system in a unique temporal and regional pattern. Overall, the permeation of cytokines across the BBB can be mediated by specific transport systems. The regulation of transport in pathophysiological conditions affects the extent of neuroinflammation and is implicated in neuroregeneration.

Dichotomous Life of DNA Binding High Mobility Group Box1 Protein in Human Health and Disease

The High mobility group box 1 (HMGB1) protein is an extremely versatile, highly conserved nuclear protein, with its unique intracellular and extracellular functions mediated by its relatively simple domain structure. Within the nucleus, HMGB1 binds to DNA minor groove in a nonspecific manner and causes bends in the double helix thus helps in recruiting a number of DNA binding protein and transcription factors, to facilitate transcription of various genes. HMGB1 also helps in DNA repair, chromatin remodeling, V (D) J recombination, and assembly of nucleosome on the chromatin. On contrary, under pathological conditions HMGB1 displays inflammatory response by interaction with specific cell surface receptors like RAGE, TLR-4, TLR9, and TLR2 and activates NF-kB downstream signaling pathways. The upregulation of HMGB1 is directly associated with the pathogenesis of cancer, sepsis, ischemia, hemorrhagic shock, anorexia, rheumatic disease, periodontal disease etc. Therefore, HMGB1 has been considered as a promising target in the treatment of various human diseases. The interest in HMGB1 is evident and reflected in the exponential increase in the recent publications, and therefore there is a need for an update on the understanding of the role of HMGB1 in pathogenesis and its potential application of HMGB1 as a therapeutic target in a number of human diseases.

Current Progress of Reelin in Development, Inflammation and Tissue Remodeling: From Nervous to Visual Systems

Reelin is a matrix glycoprotein that plays a pivotal role for the positioning of neurons throughout brain development. In the early developing cortex Reelin regulates radial migration of cortical neurons while later in development, Reelin promotes maturation of dendrites and dendritic spines. Low Reelin levels characterize healthy adult brain while increased Reelin levels have been associated with cellular events underlying response to injury.

Reelin has been detected in structural and immune cells outside brain (liver, gut/colon tracts, kidney, testis, ovary, lung, retina and cornea). In the Visual system, Reelin was first described in the retina and thereafter in the cornea. Increased Reelin levels were observed during retinogenesis, low levels were found in adulthood and a significant increase was detected upon injury. Insult-driven Reelin changes occur after upregulation of adhesion molecules, cytokines, neurotrophins, growth factors, neuropeptides and other mediators as well as their receptors. These soluble factors contribute to the development of nervous and visual system and promote survival/recovery of neurons/accessory cells populating the injured visual system. Likewise, Reelin might modulate these factors by driving different multiple effects on homeostasis/plasticity, inflammation, healing and remodeling at different physiopathological levels. Very low-density lipoprotein receptor, apolipoprotein E receptor 2, integrins and the adaptor molecule Disabled 1 trigger Reelin pathway.

Recent advances highlight some Reelin activities during inflammation and tissue remodeling and point out to a crucial Reelin activity in the visual system. A better understanding of Reelin function in retinal development might open to new attractive perspective for counteracting retina degeneration.

Pharmacological Properties and Therapeutic Potential of Naringenin: A Citrus Flavonoid of Pharmaceutical Promise

Naringenin chemically known as 5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one is a common dietary polyphenolic constituent of the citrus fruits. It has received considerable attention for pharmaceutical and nutritional development due to potent pharmacological activities and therapeutic potential. Accruing evidence from both in vitro and in vivo studies have unraveled numerous biological targets along with complex underlying mechanisms suggesting possible therapeutic applications of naringenin in various neurological, cardiovascular, gastrointestinal, rheumatological, metabolic and malignant disorders. Functionally, this ameliorative effect of naringenin is primarily attributed to its antiinflammatory (via inhibiting recruitment of cytokines and inflammatory transcription factors) and anti-oxidant (via scavenging of free radicals, bolstering of endogenous antioxidant defense system and metal ion chelation) effects. The present article provides a comprehensive review of the various studies that have evaluated the therapeutic potential of naringenin and its actions at the molecular level. It also summarizes the pharmacokinetic data and issues and challenges involved in pharmaceutical development and suggest that it may be a potential agent for further exploration as well as may be useful as a dietary adjunct in treatment of various human ailments.

The Brainstem Tau Cytoskeletal Pathology of Alzheimer’s Disease: A Brief Historical Overview and Description of its Anatomical Distribution Pattern, Evolutional Features, Pathogenetic and Clinical Relevance

The human brainstem is involved in the regulation of the sleep/waking cycle and normal sleep architectonics and is crucial for the performance of a variety of somatomotor, vital autonomic, oculomotor, vestibular, auditory, ingestive and somatosensory functions. It harbors the origins of the ascending dopaminergic, cholinergic, noradrenergic, serotonergic systems, as well the home base of the descending serotonergic system. In contrast to the cerebral cortex the affection of the brainstem in Alzheimer’s disease (AD) by the neurofibrillary or tau cytoskeletal pathology was recognized only approximately fourty years ago in initial brainstem studies. Detailed pathoanatomical investigations of silver stained or tau immunostained brainstem tissue sections revealed nerve cell loss and prominent ADrelated cytoskeletal changes in the raphe nuclei, locus coeruleus, and in the compact parts of the substantia nigra and pedunculopontine nucleus. An additional conspicuous AD-related cytoskeletal pathology was also detected in the auditory brainstem system of AD patients (i.e. inferior colliculus, superior olive, dorsal cochlear nucleus), in the oculomotor brainstem network (i.e. rostral interstitial nucleus of the medial longitudinal fascicle, Edinger-Westphal nucleus, reticulotegmental nucleus of pons), autonomic system (i.e. central and periaqueductal grays, parabrachial nuclei, gigantocellular reticular nucleus, dorsal motor vagal and solitary nuclei, intermediate reticular zone). The alterations in these brainstem nuclei offered for the first time adequate explanations for a variety of less understood disease symptoms of AD patients: Parkinsonian extrapyramidal motor signs, depression, hallucinations, dysfunctions of the sleep/wake cycle, changes in sleeping patterns, attentional deficits, exaggerated pupil dilatation, autonomic dysfunctions, impairments of horizontal and vertical saccades, dysfunctional smooth pursuits. The very early occurrence of the AD-related cytoskeletal pathology in some of these brainstem nuclei points to a major and strategic role of the brainstem in the induction and brain spread of the AD-related cytoskeletal pathology.

Neuropsychiatric Disturbances in Alzheimer’s Disease: What Have We Learned from Neuropathological Studies?

Neuropsychiatric symptoms (NPS) are an integral part of the dementia syndrome and were therefore recently included in the core diagnostic criteria of dementia. The near universal prevalence of NPS in Alzheimer’s disease (AD), combined with their disabling effects on patients and caregivers, is contrasted by the fact that few effective and safe treatments exist, which is in part to be attributed to our incomplete understanding of the neurobiology of NPS. In this review, we describe the pathological alterations typical for AD, including spreading and evolution of burden, effect on the molecular and cellular integrity, functional consequences and atrophy of NPS-relevant brain regions and circuits in correlation with specific NPS assessments. It is thereby clearly established that NPS are fundamental expressions of the underlying neurodegenerative brain disease and not simply reflect the patients’ secondary response to their illness. Neuropathological studies, moreover, include a majority of end-stage patient samples, which may not correctly represent the pathophysiological environment responsible for particular NPS that may already be present in an early stage, or even prior to AD diagnosis. The burdensome nature and high prevalence of NPS, in combination with the absence of effective and safe pharmacotherapies, provide a strong incentive to continue neuropathological and neurochemical, as well as imaging and other relevant approaches to further improve our apprehension of the neurobiology of NPS.

Brain Magnetic Stimulation in Animal Models: A Valuable Lesson for Clinical Applications

Transcranial magnetic stimulation (TMS) is more than a mere tool for clinical non-invasive approaches to stimulate and synchronize the neuronal activity in the brain. Electromagnetic stimulation through TMS has recently emerged as a therapeutic alternative for the treatment of different neurological disorders. Among the many properties recently discovered for TMS, its action as an accounting factor for neuroplasticity and neurogenesis is among its most promising features. Translational studies in animal models offer various advantages and also bridge this knowledge gap due to their direct assessment of the brain stimulation impact at the neural level. These profiles have been obtained through the study of animal models, which, in turn, have served for the establishment of the action mechanisms of this method. In this review, we revise and discuss evidence collected on the promising properties of TMS after visiting the different animal models developed so far, and provide a practical perspective of its possible application for clinical purposes.

The Impact of Small Heat Shock Proteins (HspBs) in Alzheimer’s and Other Neurological Diseases

Background: Heat shock proteins are powerful endogenous cytoprotective proteins which help cells to survive recurrent cellular stress events. Identifying the underlying molecular mechanisms and molecular targets is especially interesting since it may help to develop new therapeutic strategies for the treatment of diseases. Objective: This review will focus on the group of small heat shock proteins, also named HspBs. HspBs play an important role in various neurological diseases. Most neurodegenerative diseases are characterized by a distinct pathology with accumulation and aggregation of misfolded proteins, such as deposits of amyloid plaques or neurofibrillary tangles in Alzheimer`s disease. Such pathological protein aggregates are thought to lead to cellular dysfunction and finally to cell death. HspBs display chaperone-like functions and are able to prevent protein aggregation by which they may slow down progression of these diseases. However, HspBs have multiple additional functions which also may contribute to neuroprotection.

Results/Conclusions: In this review we will first give an overview of the HspB protein family, their structure, functions and expression pattern. Then we will highlight their impact in the brain, in neurodegenerative diseases and especially in Alzheimer`s disease and try to unravel their multifactorial effects in several aspects of the disease pathologies.

Alzheimer’s Disease and Molecular Chaperones: Current Knowledge and the Future of Chaperonotherapy

Background: Alzheimer’s disease (AD) is a dementia, a neurodegenerative condition, and a protein-misfolding disease or proteinopathy, characterized by protein deposits, extracellular plaques and intracellular neurofibrillary tangles, which contain the AD’s typical pathological proteins, abnormal β-amyloid and hyperphosphorylated tau, respectively, and are located predominantly in the cortex of the frontal, parietal, and temporal brain lobes. What is the role of molecular chaperones in AD? Data indicate that molecular chaperones, also known as Hsp, are involved in AD, probably displaying protective roles and/or acting as pathogenic factors as it occurs in chaperonopathies in which case AD would be suitable to chaperonotherapy. Hsp60, Hsp70, and Hsp90 can be augmented and overexpressed or diminished and downregulated in various situations in AD affected tissues and cells, indicating they are active during disease development and progression. Question: What is the role of molecular chaperones in AD? Data indicate that molecular chaperones, also known as Hsp, are involved in AD, probably displaying protective roles and/or acting as pathogenic factors as it occurs in chaperonopathies in which case AD would be suitable to chaperonotherapy. Objective: Investigate the role of Hsp in AD, focusing on Hsp60, Hsp70, and Hsp90. Method: Critical examination of published data. Results: Hsp60, Hsp70, and Hsp90 can be augmented and overexpressed or diminished and downregulated in various situations in AD affected tissues and cells, indicating they are active during disease development and progression. Conclusion and Perspectives: Notwithstanding that the roles and mechanisms of action of chaperones in AD are still incompletely understood, there is already enough evidence to encourage the development of therapeutic strategies targeting them, either to block their activity in case they promote disease progression or to boost their performance when they are protective. The latter is an example of positive chaperonotherapy, which also includes chaperone replacement via gene or protein administration. On the contrary, if a chaperone is found to help the disease, it has to be blocked or eliminated, which constitute modalities of negative chaperonotherapy.

Lithium, a Therapy for AD: Current Evidence from Clinical Trials of Neurodegenerative Disorders

Background: Preclinical studies have shown that lithium modifies pathological cascades implicated in certain neurodegenerative disorders, such as Alzheimer’s disease (AD), Huntigton`s disease (HD), multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS). A critical question is whether these pharmacodynamic properties of lithium translate into neurodegenerative diseases modifying effects in human subjects. Methods: We reviewed all English controlled clinical trials published in PubMed, PsycINFO, Embase, SCOPUS, ISI-Web with the use of lithium for the treatment of neurodegenerative disorders between July 2004 and July 2014. Results: Lithium showed evidence for positive effects on cognitive functions and biomarkers in amnestic mild cognitive impairment (aMCI, 1 study) and AD (2 studies), even with doses lower than those used for mood stabilisation. Studies of Li in HD, MSA and CSI did not show benefits of lithium. However, due to methodological limitations and small sample size, these studies may be inconclusive. Studies in ALS showed consistently negative results and presented evidence against the use of lithium for the treatment of this disease. Conclusion: In absence of disease modifying treatments for any neurodegenerative disorders, the fact that at least 3 studies supported the effect of lithium in aMCI/AD is noteworthy. Future studies should focus on defining the dose range necessary for neuroprotective effects to occur.

Mitochondrial Proteases as Emerging Pharmacological Targets

The preservation of mitochondrial function and integrity is critical for cell viability. Under stress conditions, unfolded, misfolded or damaged proteins accumulate in a certain compartment of the organelle, interfering with oxidative phosphorylation and normal mitochondrial functions. In stress conditions, several mechanisms, including mitochondrial unfolded protease response (UPRmt), fusion and fission, and mitophagy are engaged to restore normal proteostasis of the organelle.

Mitochondrial proteases are a family of more than 20 enzymes that not only are involved in the UPRmt, but actively participate at multiple levels in the stress-response system. Alterations in their expression levels, or mutations that determine loss or gain of function of these proteases deeply impair mitochondrial functionality and can be associated with the onset of inherited diseases, with the development of neurodegenerative disorders and with the process of carcinogenesis. In this review, we focus our attention on six of them, namely CLPP, HTRA2 and LONP1, by analysing the current knowledge about their functions, their involvement in the pathogenesis of human diseases, and the compounds currently available for inhibiting their functions.

Regulation of Gait and Balance: The Underappreciated Role of Neuronal Nicotinic Receptor Agonists

Alterations in gait and balance are manifest in numerous neurological disorders such as the ataxias and Parkinson's disease, and may occur as a consequence of stroke, traumatic brain injury and chemical insults to the brain. Although the underlying etiology of these disorders differs, disturbances in gait and balance appear to reflect deficits in cholinergic pathways within the brain. During the past 40 years, both clinical case studies and preclinical data have provided evidence that nicotinic cholinergic activation is beneficial for alleviating gait and balance deficits in many disorders. Further, studies indicate that activation of neuronal nicotinic receptors leads to neuroprotective and neurotrophic actions. And yet, despite these findings, there hsas been no concerted effort to develop neuronal nicotinic agonists for the treatment of abnormal gait and balance. The goal of this review is to shed light on the therapeutic benefit of the cholinergic nicotinic system for the treatment of ataxia, and discuss the challenges and limitations associated with developing drugs to treat disorders involving deficits in gait and balance.

Novel Lactulose and Melibiose Targeting Autophagy to Reduce PolyQ Aggregation in Cell Models of Spinocerebellar Ataxia 3

Trehalose, a chemical chaperone and mTOR-independent autophagy enhancer, has shown promise in models of Huntington’s disease, Parkinson’s disease and tauopathies. In this study, two trehalase analogs, lactulose and melibiose, were examined for their potentials in spinocerebellar ataxia treatment. Using a SCA3 ATXN3/Q75-GFP cell model, we found that the ATXN3/Q75 aggregation was significantly prohibited by lactulose and melibiose because of their abilities to up-regulate autophagy. Meanwhile, lactulose and melibiose reduced reactive oxygen species production in ATXN3/Q75 cells. Both of them further inhibited the ATXN3/Q75 aggregation in neuronally differentiated SH-SY5Y cells. These findings suggest the therapeutic applications of novel trehalose analogs in polyglutamine aggregation-associated neurodegenerative diseases.

Novel Methods of Genetic Modification of Human Pluripotent Stem Cells

Genomic engineering has enormous potential along basic research, drug discovery and cell therapeutics. Many existing methods for targeted gene knockout mutagenesis or integration rely on homologous recombination. The low rate of spontaneous recombination in nearly all mammalian cell types, as well as the scale of screening, effort and time required to isolate the targeted events during genome modification, have hindered progress in this field. The present review has the objective to present latest improvements of technology to develop genetic modification to a clinical grade level so it can be used in human therapy.

PERK-opathies: An Endoplasmic Reticulum Stress Mechanism Underlying Neurodegeneration

The unfolded protein response (UPR) plays a vital role in maintaining cell homeostasis as a consequence of endoplasmic reticulum (ER) stress. However, prolonged UPR activity leads to cell death. This time-dependent dual functionality of the UPR represents the adaptive and cytotoxic pathways that result from ER stress. Chronic UPR activation in systemic and neurodegenerative diseases has been identified as an early sign of cellular dyshomeostasis.

The Protein Kinase R-like ER Kinase (PERK) pathway is one of three major branches in the UPR, and it is the only one to modulate protein synthesis as an adaptive response. The specific identification of prolonged PERK activity has been correlated with the progression of disorders such as diabetes, Alzheimer’s disease, and cancer, suggesting that PERK plays a role in the pathology of these disorders. For the first time, the term “PERK-opathies” is used to group these diseases in which PERK mediates detriment to the cell culminating in chronic disorders. This article reviews the literature documenting links between systemic disorders with the UPR, but with a specific emphasis on the PERK pathway. Then, articles reporting links between the UPR, and more specifically PERK, and neurodegenerative disorders are presented. Finally, a therapeutic perspective is discussed, where PERK interventions could be potential remedies for cellular dysfunction in chronic neurodegenerative disorders.

Role of Mitochondrial Protein Quality Control in Oxidative Stress-induced Neurodegenerative Diseases

Proteins are constantly exposed to environmental stressors such as free radicals and heat shock leading to their misfolding and later to aggregation. In particular mitochondrial proteins are challenged by reactive oxygen species (ROS) due to the oxidative metabolism of the organelle. Protein aggregation has been associated with a wide variety of pathological conditions called proteopathies. However, for the maintenance of protein and cellular homeostasis, mitochondria have developed an elaborate protein quality control system consisting of chaperones and ATP-dependent proteases, specifically employed to rescue this organelle from damage due to the accumulation of misfolded proteins and toxic aggregates. Aging is characterized by a general decline of mitochondrial functions, correlating with a decrease in mitochondrial protein quality control activity and an increase of free radical production. In particular in age-related diseases like neurodegeneration, a correlation between mitochondrial damage and disease onset has been established. In this review we summarize the current knowledge about mitochondrial protein quality control mechanisms in mammalian cells, with a special emphasis on the role in oxidative stress and in neurodegenerative diseases.

GABAergic Pharmacotherapy in the Treatment of Motor Disorders of the Central Nervous System

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system, and diseases that associate a deficiency in GABA might benefit from GABAergic drugs.

Cerebellar Purkinje cells employ GABA as a neurotransmitter. Cortical cerebellar atrophy (CCA) shows Purkinje cell loss, and ataxia caused by it was alleviated by gabapentin and pregabalin. Thus, CCA is proposed as a model of selective deficiency in GABA in the cerebellum, which benefits clinically from administration of GABAergic drugs, in a manner similar in which levodopa improves motor manifestations in Parkinson’s disease. Other ataxias also benefited clinically from GABAergic drugs, as adult-onset GM2 gangliosidosis, olivopontocerebellar atrophy, cerebellar ataxia with hypogonadism, spinocerebellar ataxias 1, 2 and 6, and adult-onset ataxia-telangiectasia. Complex neurochemical diseases, as multiple-system atrophy, had ataxia worsened by GABAergic drugs. Various disorders with a deficiency in GABA content had their manifestations relieved by admistration of GABAergic drugs, as one patient with progressive encephalomyelitis with rigidity, whose muscular spasms were suppressed by a combination of gabapentin and tiagabine, and another with diaphragmatic myoclonus, who required gabapentin and tiagabine for symptomatic control. On the contrary, GABAergic drugs were not effective in cervical dystonia, amyotrophic lateral sclerosis, Parkinson’s disease and progressive supranuclear palsy, presumably because a deficiency in GABA is not an essential neurochemical abnormality in these diseases. Research aimed at identifying effective therapies to treat cerebellar ataxias and other motor disorders of the central nervous system is warranted. Meanwhile, therapeutic tests with GABAergic drugs might yield clinical improvement in these diseases.

Application of Glutathione as Anti-Oxidative and Anti-Aging Drugs

Glutathione (GSH), an abundant tripeptidyl molecule, plays pivotal roles in protecting cells against oxidative stress-induced cellular damage and in detoxifying xenobiotics and drug metabolism. GSH is now entering a new era of therapeutic applications. Decreased GSH levels are associated with the common features of aging as well as of a wide range of pathological conditions, including neurodegenerative disorders. Notably, GSH depletion and/or alterations in its metabolism appear to be crucial in the onset of Parkinson’s disease. Despite the fact that GSH is required for cell survival, the molecular mechanism that links GSH depletion to cell death remains poorly understood. Recently, considerable attention has been focused on a newly defined type of cell death: irondependent cell death, also referred to as “ferroptosis”. The iron chelator deferoxamine nearly abolishes ferroptosis induced by inhibiting GSH synthesis or cystine uptake by the xCT transporter. Deferoxamine preferentially abrogates the intralysosomal accumulation of iron and inhibits oxidative stress-induced lysosomal membrane permeabilization and cell death. The use of GSH and a prodrug derived from it can be useful, since the dysfunction of the GSH redox system appears to cause a variety of diseases including neurodegenerative disorders. However, the effectiveness of GSH as a therapeutic agent is limited because of its low bioavailability. We also review trials that have been designed to cope with this difficulty; e.g. the use of precursors such as N-acetyl cysteine and chemical modification such as methylation.

siRNA Therapy, Challenges and Underlying Perspectives of Dendrimer as Delivery Vector

siRNA technology presents a helpful means of gene silencing in mammalian cells. Advancement in the field includes enhanced attentiveness in the characterization of target and off-target effects employing suitable controls and gene expression microarrays. These will permit expansion in the measurement of single and multiple target combinations and also permit comprehensive efforts to understand mammalian cell processes. Another fact is that the delivery of siRNA requires the creation of a nanoparticulate vector with controlled structural geometry and surface modalities inside the targeted cells. On the other hand, dendrimers represent the class of carrier system where massive control over size, shape and physicochemical properties makes this delivery vector exceptional and favorable in genetic transfection applications. The siRNA therapeutics may be incorporated inside the geometry of the density controlled dendrimers with the option of engineering the structure to the specific needs of the genetic material and its indication. The existing reports on the siRNA carrying and deliverance potential of dendrimers clearly suggest the significance of this novel class of polymeric architecture and certainly elevate the futuristic use of this highly branched vector as genetic material delivery system.

Nanocarriers Assisted siRNA Gene Therapy for the Management of Cardiovascular Disorders

Cardiovascular diseases (CVDs), primarily myocardial infarction (MI), atherosclerosis, hypertension and congestive heart failure symbolize the foremost cause of death in almost all parts of the world. Besides the traditional therapeutic approaches for the management of CVDs, newer innovative strategies are also emerging on the horizon. Recently, gene silencing via small interfering RNA (siRNA) is one of the hot topics amongst various strategies involved in the management of CVDs. The siRNA mechanism involves natural catalytic processes to silence pathological genes that are overexpressed in a particular disease. Also the versatility of gene expression by siRNA deciphers a prospective tactic to down-regulate diseases associated gene, protein or receptor existing on a specific disease target. This article reviews the application of siRNA against CVDs with special emphasis on gene targets in combination with delivery systems such as cationic hydrogels, polyplexes, peptides, liposomes and dendrimers.

Application of Proteomic Tools in Modern Nanotechnological Approaches Towards Effective Management of Neurodegenerative Disorders

Neurodegeneration is the progressive loss of structure or function of neurons leading to neuronal death, usually associated with ageing. Some of the common neurodegenerative disorders include Alzheimer’s disease, Parkinson’s disease, Creutzfeldt-Jakob disease, and Huntington’s disease. Due to recent advancements in highthroughput technologies in various disciplines such as genomics, epigenomics, metabolomics and proteomics, there has been a great demand for detection of specific macromolecules such as hormones, drug residues, miRNA, DNA, antibodies, peptides, proteins, pathogens and xenobiotics at nano-level concentrations for in-depth understanding of disease mechanisms as well as for the development of new therapeutic strategies. The present review focuses on the management of agerelated neurodegenerative disorders using proteomics and nanotechnological approaches. In addition, this review also highlights the metabolism and disposition of nano-drugs and nano-enabled drug delivery in neurodegenerative disorders.

Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging

Calcium (Ca²⁺) release from intracellular stores controls numerous cellular processes, including cardiac and skeletal muscle contraction, synaptic transmission and metabolism. The ryanodine receptors (RyRs: RyR1, RyR2, RyR3) and inositol 1,4,5-trisphosphate receptors (IP3Rs: IP3R1, IP3R2, IP3R3) are the major Ca²⁺ release channels (CRCs) on the endo/sarcoplasmic reticulum (ER/SR). RyRs and IP3Rs comprise macromolecular signaling complexes that include modulatory proteins which regulate channel activity in response to extracellular signals resulting in intracellular Ca²⁺ release. Here we focus on the roles of CRCs in heart, skeletal muscle, brain, metabolism, and aging.

Therapeutic Approaches for Dominant Muscle Diseases: Highlight on Myotonic Dystrophy

Myotonic Dystrophy (DM), one of the most common neuromuscular disorders in adults, comprises two genetically distinct forms triggered by unstable expanded repeats in non-coding regions. The most common DM1 is caused by expanded CTG repeats in the 3’UTR of the DMPK gene, whereas DM2 is due to large expanded CCTG repeats in the first intron of the CNBP gene. Both mutations induce a pathogenic RNA gain-of-function mechanism. Mutant RNAs containing CUG or CCUG expanded repeats, which are retained in the nuclei as aggregates alter activities of alternative splicing regulators such as MBNL proteins and CELF1. As a consequence, alternative splicing misregulations of several pre-mRNAs are associated with DM clinical symptoms. Currently, there is no available cure for this dominant neuromuscular disease. Nevertheless, promising therapeutic strategies have been developed in the last decade. Preclinical progress in DM research prompted the first DM1 clinical trial based on antisense oligonucleotides promoting a RNase-H-mediated degradation of the expanded CUG transcripts. The ongoing Phase 1/2a clinical trial will hopefully give further insights into the quest to find a bona fide cure for DM1. In this review, we will provide an overview of the different strategies that were developed to neutralize the RNA toxicity in DM1. Different approaches including antisense oligonucleotide technologies, gene therapies or small molecules have been tested and validated in cellular and animal models. Remaining challenges and additional avenues to explore will be discussed.

Trends in Mitochondrial Therapeutics for Neurological Disease

Neuronal homeostasis is critically dependent on healthy mitochondria. Mutations in mitochondrial DNA (mtDNA), in nuclear-encoded mitochondrial components, and age-dependent mitochondrial damage, have all been connected with neurological disorders. These in clude not only typical mitochondrial syndromes with neurological features such as encephalomyopathy, myoclonic epilepsy, neuropathy and ataxia; but also secondary mitochondrial involvement in neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s disease. Unravelling the molecular aetiology of mitochondrial dysfunction opens new therapeutic prospects for diseases thus far lacking effective treatments. In this review we address recent advances on preventive strategies, such as pronuclear, spindle-chromosome complex, or polar body genome transfer to replace mtDNA and avoid disease transmission to newborns; we also address experimental mitochondrial therapeutics aiming to benefit symptomatic patients and prevent disease manifestation in those at risk. Specifically, we focus on: (1) gene therapy to reduce mutant mtDNA, such as anti-replicative therapies and mitochondriatargeted nucleases allowing favourable heteroplasmic shifts; (2) allotopic expression of recoded wild-type mitochondrial genes, including targeted tRNAs and xenotopic expression of cognate genes to compensate for pathogenic mutations; (3) mitochondria targeted-peptides and lipophilic cations for in vivo delivery of antioxidants or other putative therapeutics; and (4) modulation of mitochondrial dynamics at the level of biogenesis, fission, fusion, movement and mitophagy. Further advances in therapeutic development are hindered by scarce in vivo models for mitochondrial disease, with the bulk of available data coming from cellular models. Nevertheless, wherever available, we also address data from in vivo experiments and clinical trials, focusing on neurological disease models.

Systemic Redox Biomarkers in Neurodegenerative Diseases

Neurodegenerative diseases are characterized by a gradual and selective loss of neurons. ROS overload has been proved to occur early in this heterogeneous group of disorders, indicating oxidative stress as a primer factor underlying their pathogenesis. Given the importance of a better knowledge of the cause/effect of oxidative stress in the pathogenesis and evolution of neurodegeneration, recent efforts have been focused on the identification and determination of stable markers that may reflect systemic oxidative stress. This review provides an overview of these systemic redox biomarkers and their responsiveness to antioxidant therapies. Redox biomarkers can be classified as molecules that are modified by interactions with ROS in the microenvironment and antioxidant molecules that change in response to increased oxidative stress. DNA, lipids (including phospholipids), proteins and carbohydrates are examples of molecules that can be modified by excessive ROS in vivo. Some modifications have direct effects on molecule functions (e.g. to inhibit enzyme function), but others merely reflect the degree of oxidative stress in the local environment. Testing of redox biomarkers in neurodegenerative diseases has 3 important goals: 1) to confirm the presence or absence of systemic oxidative stress; 2) to identify possible underlying (and potentially reversible) causes of neurodegeneration; and 3) to estimate the severity of the disease and the risk of progression. Reflecting pathological processes occurring in the whole body, redox biomarkers may pinpoint novel therapeutic targets and lead to diagnose diseases before they are clinically evident.

Advanced Techniques for Imaging the Human Spinal Cord: Review of Literature

Despite the high sensitivity of magnetic resonance imaging (MRI) in detecting a wide spectrum of various pathological processes, the specificity of the method to differentiate among these pathologies and its ability to predict clinical outcomes has been rather below initial expectations. The main problem arises from the fact that most of the pathologies of the spinal cord manifest with a rather nonspecific increase of water protons, reflecting local oedema or gliosis. This is a common finding in most myelopathies, which does not allow a further differential diagnostic distinction in most cases. The use of contrast media improved the specificity of the method; however, it is still challenging to differentiate types of myelopathies. Advanced imaging methodologies such as functional MRI (fMRI), diffusion-weighted and -tensor imaging (DWI/DTI), Magnetic Resonance Spectroscopy (MRS) have been used in the evaluation of neurologic diseases in the brain and have gained increased acceptance among the clinicians for improving the specificity of MR technology and for their ability to better correlate with functional disabilities and clinical symptoms thus providing predictive information about potential outcome. Preliminary results show that, quantitative parameters extracted by these techniques from the spinal cord can provide surrogate markers of disability for determining prognosis as well. In this review, we focus on implementing advanced neuroimaging methodologies (DWI/DTI, fMRI and MRS) in imaging of the human spinal cord for better clinical assessment. Additionally, we review the recent imaging literature advances in this topics and their clinical applications.

Immunotherapy Strategies for Spinal Cord Injury

Regeneration in the central nervous system (CNS) of adult mammalian after traumatic injury is limited, which often causes permanent functional motor and sensory loss. After spinal cord injury (SCI), the lack of regeneration is mainly attributed to the presence of a hostile microenvironment, glial scarring, and cavitation. Besides, inflammation has also been proved to play a crucial role in secondary degeneration following SCI. The more prominent treatment strategies in experimental models focus mainly on drugs and cell therapies, however, only a few strategies applied in clinical studies and therapies still have only limited effects on the repair of SCI. Recently, the interests in immunotherapy strategies for CNS are increasing in number and breadth. Immunotherapy strategies have made good progresses in treating many CNS degenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, and multiple sclerosis (MS). However, the strategies begin to be considered to the treatment of SCI and other neurological disorders in recent years. Besides anti-inflamatory therapy, immunization with protein vaccines and DNA vaccines has emerged as a novel therapy strategy because of the simplicity of preparation and application. An inflammatory response followed by spinal cord injury, and is controled by specific signaling molecules, such as some cytokines playing a crucial role. As a result, appropriate immunoregulation, the expression of pro-inflammatory cytokines and anti-inflammatory cytokines may be an effective therapy strategy for earlier injury of spinal cord. In addition, myelinassociated inhibitors (MAIs) in the injured spinal cord, such as Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte- myelin glycoprotein (OMgp) are known to prevent axonal regeneration through their co-receptors, and to trigger demyelinating autoimmunity through T cell-mediated harmful autoimmune response. The antagonism of the MAIs through vaccinating with protein or DNA vaccines targeting Nogo, MAG, OMgp, and their co-receptors, may be an effective strategy for the treatment of SCI. However, immunotherapy such as anti-inflammtory therapy or vaccine targeting MAIs or their receptors, accompanied with the potential in risking autoimmune diseases. As a result, in order to optimize the anti-inflammtory therapy and design of protein or DNA vaccines for their use in the future clinical application, we need to further understand the possible mechanisms of neuroprotective immunity. This review presents recent advances in the development of immunotherapy strategies for the treatment of axonal degeneration and demyelination, and improvement of motor function after SCI.

Impaired DNA Damage Repair as a Common Feature of Neurodegenerative Diseases and Psychiatric Disorders

Impaired DNA damage repair is a common pathological endophenotype of some types of neurodegenerative diseases, intellectual disabilities, and psychiatric diseases. Dysfunctional DNA repair and DNA damage, including DNA double-stranded breaks, are linked to transcriptional dysfunction and abnormal DNA methylation. Impaired DNA repair in neural stem cells leads to microcephaly or cerebellar ataxia. Furthermore, DNA repair defects and DNA damage in mature neurons lead to progressive cognitive impairment, which might be a common feature of Alzheimer's disease, Huntington’s disease, and other polyglutamine diseases. Oxidative DNA damage and altered DNA repair gene expression are observed in GABAergic neurons in schizophrenia. These findings indicate that impaired DNA repair is a common pathological endophenotype of neurological diseases, and that DNA damage might lead to diverse disease symptoms dependent on timing and the affected cell type.

MicroRNAs in CAG Trinucleotide Repeat Expansion Disorders: an Integrated Review of the Literature

MicroRNAs are small RNAs involved in gene silencing. They play important roles in transcriptional regulation and are selectively and abundantly expressed in the central nervous system. A considerable amount of the human genome is comprised of tandem repeating nucleotide streams. Several diseases are caused by above-threshold expansion of certain trinucleotide repeats occurring in a protein-coding or non-coding region. Though monogenic, CAG trinucleotide repeat expansion disorders have a complex pathogenesis, various combinations of multiple coexisting pathways resulting in one common final consequence: selective neurodegeneration. Mutant protein and mutant transcript gain of toxic function are considered to be the core pathogenic mechanisms. The profile of microRNAs in CAG trinucleotide repeat disorders is scarcely described, however microRNA dysregulation has been identified in these diseases and microRNA-related intereference with gene expression is considered to be involved in their pathogenesis. Better understanding of microRNAs functions and means of manipulation promises to offer further insights into the pathogenic pathways of CAG repeat expansion disorders, to point out new potential targets for drug intervention and to provide some of the much needed etiopathogenic therapeutic agents. A number of disease-modifying microRNA silencing strategies are under development, but several implementation impediments still have to be resolved. CAG targeting seems feasible and efficient in animal models and is an appealing approach for clinical practice. Preliminary human trials are just beginning.

A Review on Response of Immune System in Spinal Cord Injury and Therapeutic Agents useful in Treatment

Every year more than 12,000 people in US alone suffer from spinal cord injury. However, complete recovery of physical function is difficult due to multiple factors involved in disease progression. Currently available therapeutic regimens do not address all the factors concerned with the disease progression. The present review focuses mainly on the role of immune cells in progression of spinal cord injury and the drugs that target these immune cells. Literature search shows that inflammatory reactions and subsequent reactions that follow direct injury to spinal cord are sometimes responsible for the severity of the disease. Therefore, for design of proper treatment regimen a deep understanding in this area is required. Understanding the pathophysiology will help in creating delivery system that can target multiple factors involved in progression of spinal cord injury. A combination of various treatment strategies is required to reduce the disability in patients with spinal cord injury.

Single Amino Acid Repeats Connect Viruses to Neurodegeneration

We report on a high level of octapeptide matching between HCV, HIV-2, MPV, MUV, EBV, HHV-6, and CMV, and human brain antigens that, when altered, have been specifically associated with neuropathologies such as amyotrophic lateral sclerosis, spinocerebellar ataxia, frontotemporal degeneration, Huntington disease, Parkinson disease, cognitive impairment, aphasia and oculomotor apraxia. Quantitatively, the extent of the viral octapeptide sharing with neurodegeneration- associated proteins is in excess when analyzed in a stochastic expectation context. Qualitatively, two main features characterize the peptide matching: 1) many common sequences are single amino acid repeats, and 2) mostly, the shared octapeptides are part of experimentally validated epitopes, thus suggesting an immune crossreactive potential of the viral peptides shared with brain antigens involved in neurodegeneration. The present study may have relevance for peptidebased therapeutic approaches to block potential autoimmune crossreactions in neurological diseases and dysfunctional behavior.

Nanofiber Scaffolds for Treatment of Spinal Cord Injury

Spinal cord injury (SCI) is a common neurologic disorder that results in loss of sensory function and mobility. It is well documented that tissue engineering is a potential therapeutic strategy for treatment of SCI. In this connection, various biomaterials have been explored to meet the needs of SCI tissue engineering and these include natural materials, synthetic biodegradable polymers and synthetic non- degradable polymers. Nanofiber scaffolds are newly emerging biomaterials that have been widely utilized in tissue engineering recently. In comparison to the traditional biomaterials, nanofibers have advantages in topography and porosity, thus mimicking the naturally occurring extracellular matrix. Besides, they exhibit excellent biocompatibility with low immunogenicity, and furthermore they are endowed with properties that help to bridge the lesion cavity or gap, and serve as an effective delivery system for graft cells or therapeutic drugs. This review summarizes some of the unique properties of nanofiber scaffolds which are critical to their potential application in treatment of injured spinal cord.

Colloidal Supramolecular Aggregates for Therapeutic Application in Neuromedicine

Neuromedicine has recently been emerging on the research scene and presents interesting challenges in therapeutics. The range of therapies generally used to treat neurological disorders are limited in their efficacy and degree of patient compliance because of the necessity of multiple drug dosages, low drug concentration in the central nervous system and side effects. Moreover, therapeutics require standard drug dosages which cannot be personalized. The limiting obstacle in neuromedicine is still the blood-brain barrier, which prevents the accumulation of endogenous and exogenous compounds inside the brain. Various transporters located on the blood-brain barrier modulate the crossing of endogenous compounds. It has been discovered that these transporters can be used as pathways for the transport of therapeutic agents and macromolecules that pass the blood-brain barrier allowing the uptake of bioactive compounds into the central nervous system. Several attempts have recently been made to develop forms of nanomedicine capable of overcoming the limitations of conventional therapy, above all the crossing of the blood-brain barrier. An outstandingly promising option could be the use of colloidal supramolecular aggregates. These nanodrugs are safe, biodegradable, and biocompatible and can combine biomaterials useful for diagnostic and therapeutical applications. They can be modified using monoclonal antibodies, proteins, peptides and macromolecules, thus providing personalized neuromedicine, which can be used in the treatment of various neurological disorders. In this review, recent advancements of supramolecular colloidal devices as neuromedicines are discussed, with particular focus on the latest developments.

Parkinson Disease Genetics: A "Continuum" from Mendelian to Multifactorial Inheritance

Parkinson Disease (PD) is a common neurodegenerative disorder of intricate etiology, caused by progressive loss of aminergic neurons and accumulation of Lewy bodies. The predominant role of genetics in the etiology of the disease has emerged since the identification of the first pathogenetic mutation in SNCA (alpha-synuclein) gene, back in 1997. Mendelian parkinsonisms, a minority among all PD forms, have been deeply investigated, with 19 loci identified. More recently, genome wide association studies have provided convincing evidence that variants in some of these genes, as well as in other genes, may confer an increased risk for late onset, sporadic PD. Moreover, the finding that heterozygous mutations in the GBA gene (mutated in Gaucher disease) are among the strongest genetic susceptibility factors for PD, has widened the scenario of PD genetic background to enclose a number of genes previously associated to distinct disorders, such as genes causative of spinocerebellar ataxias, mitochondrial disorders and fragile X syndrome. At present, the genetic basis of PD defines a continuum from purely mendelian forms (such as those caused by autosomal recessive genes) to multifactorial inheritance, resulting from the variable interplay of many distinct genetic variants and environmental factors.

Mitochondrial Diseases in Childhood

Mitochondrial disorders are a group of heterogeneous diseases associated with abnormalities of the oxidative phosphorylation (OXPHOS), the most important source of energy for the cell. The number of mitochondrial syndromes and of identified causative genes is constantly increasing. Taken as a whole they are among the most frequent genetic diseases in humans at any age. The respiratory chain is the only metabolic pathway under double genome control and molecular genetics of these disorders is complicated by the existence of strict interactions between mitochondrial DNA and nuclear DNA. In childhood and infancy, clinical presentation differs from mitochondrial disorders with adult onset. The phenotypes are much more severe, often involving brain, frequently presenting as multisystemic disorders and seldom as isolated myopathy. Mutations in nDNA are more frequent than in adulthood.

The major phenotypes presenting in infancy are here correlated with genetic defects and biochemical data with the aim to facilitate diagnosis work-up.

Metabolic Ataxias in Adults

Metabolic ataxias are rare. They usually start in the childhood and often have autosomal recessive inheritance. They may also present in adulthood. The diagnosis is important since some patients may be successfully managed with diet and treatments.

Iron Chelating Strategies in Systemic Metal Overload, Neurodegeneration and Cancer

Iron is a trace element required for normal performance of cellular processes. Because both the deficiency and excess of this metal are dangerous, its absorption, distribution and accumulation must be tightly regulated. Disturbances of iron homeostasis and an increase in its level may lead to overload and neurodegenerative diseases. Phlebotomy was for a long time the only way of removing excess iron. But since there are many possible disadvantages of this method, chelation therapy seems to be a logical approach to remove toxic levels of iron. In clinical use, there are three drugs: desferrioxamine, deferiprone and deferasirox. FBS0701, a novel oral iron chelator, is under clinical trials with very promising results. Developing novel iron-binding chelators is an urgent matter, not only for systemic iron overload, but also for neurodegenerative disorders, such as Parkinson’s disease. Deferiprone is also used in clinical trials in Parkinson’s disease. In neurodegenerative disorders the main goal is not only to remove iron from brain tissues, but also its redistribution in system. Few chelators are tested for their potential use in neurodegeneration, such as nonhalogeneted derivatives of clioquinol. Such compounds gave promising results in animal models of neurodegenerative diseases. Drugs of possible use in neurodegeneration must meet certain criteria. Their development includes the improvement in blood brain barrier permeability, low toxicity and the ability to prevent lipid peroxidation. One of the compounds satisfying these requirements is VK28. In rat models it was able to protect neurons in very low doses without significantly changing the iron level in liver or serum. Also iron chelators able to regulate activity of monoamine oxidase were tested. Polyphenols and flavonoids are able to prevent lipid peroxidation and demonstrate neuroprotective activity. While cancer does not involve true iron overload, neoplastic cells have a higher iron requirement and are especially prone to its depletion. It was shown, that desferrioxamine and deferasirox are antiproliferative agents active in several types of cancer. Very potent compounds with possible use as anticancer drugs are thiosemicarbazones. They are able to inhibit ribonucleotide reductase, an enzyme involved in DNA synthesis. Because the relationship between the development of overload / neurodegenerative disorders, or cancer, and iron are very complex, comprehension of the mechanisms involved in the regulation of iron homeostasis is a crucial factor in the development of new pharmacological strategies based on iron chelation. In view of various factors closely involved in pathogenesis of such diseases, designing multifunctional metal-chelators seems to be the most promising approach, but it requires a lot of effort. In this perspective, the review summarizes systemic iron homeostasis, and in brain and cancer cells, iron dysregulation in neurodegenerative disease and possible chelation strategies in the treatment of metal systemic overload, neurodegeneration and cancer.

Novel In Situ Activity Assays for the Quantitative Molecular Analysis of Neurodegenerative Processes in the Retina

The mechanisms of neuronal cell death are still only poorly understood, which has hindered the advancement of therapies for many currently untreatable neurodegenerative diseases. This calls for the development of new methods which reveal critical molecular mechanisms of the celldeath machinery with both high sensitivity and cellular resolution. Using animal models for hereditary neurodegeneration in the retina, we have developed or adapted different biochemical assays to determine the enzymatic activities of calpain, poly-ADP-ribose-polymerase (PARP), and histone deacetylase (HDAC) directly and in situ. Additionally, the enzymatic activity of cGMP-dependent protein kinase (PKG) was assessed indirectly using in situ immunohistological techniques to detect PKG-activity-dependent products. Combining these assays with in situ cell death markers revealed close temporospatial correlations, suggesting causal connections between the PKG, HDAC, PARP and calpain activities and neuronal cell death. Using different pharmacological and genetic manipulations, causality could indeed be demonstrated. Surprisingly, the often dramatic rises in metabolic activities didnot match by corresponding increases in expression, highlighting the importance of analyses of protein activities at the cellular level. The above mentioned studies identified a number of metabolic processes previously unknownto be involved in inherited retinal degeneration. Comparing different animal retinal degeneration models uncovered striking similarities in enzymatic activities, suggesting a generality of the destructive pathways. Taken together, these findings provided a number of novel targets for neuroprotection and as such opened up new perspectives for the therapy of hereditary neurodegeneration in the retina and possibly other parts of the central nervous system.

Mitochondrial Biogenesis: A Therapeutic Target for Neurodevelopmental Disorders and Neurodegenerative Diseases

In the developing and mature brain, mitochondria act as central hubs for distinct but interwined pathways, necessary for neural development, survival, activity, connectivity and plasticity. In neurons, mitochondria assume diverse functions, such as energy production in the form of ATP, calcium buffering and generation of reactive oxygen species. Mitochondrial dysfunction contributes to a range of neurodevelopmental and neurodegenerative diseases, making mitochondria a potential target for pharmacological-based therapies. Pathogenesis associated with these diseases is accompanied by an increase in mitochondrial mass, a quantitative increase to overcome a qualitative deficiency due to mutated mitochondrial proteins that are either nuclear- or mitochondrial-encoded. This compensatory biological response is maladaptive, as it fails to sufficiently augment the bioenergetically functional mitochondrial mass and correct for the ATP deficit. Since regulation of neuronal mitochondrial biogenesis has been scantily investigated, our current understanding on the network of transcriptional regulators, co-activators and signaling regulators mainly derives from other cellular systems. The purpose of this review is to present the current state of our knowledge and understanding of the transcriptional and signaling cascades controlling neuronal mitochondrial biogenesis and the various therapeutic approaches to enhance the functional mitochondrial mass in the context of neurodevelopmental disorders and adult-onset neurodegenerative diseases.

The Small Heat Shock Protein HspB8: Role in Nervous System Physiology and Pathology

The accumulation and aggregation of misfolded proteins can be highly cytotoxic and may underlie several human degenerative diseases characterized by neuronal inclusions such as Alzheimer's, Parkinson's, prion-like and polyglutamine repeat diseases. In this context small heat shock proteins, molecular chaperones known to be induced by cell stress, play a fundamental role by facilitating folding of nascent polypeptides, preventing aggregation of misfolded proteins and enhancing their degradation. A recently identified member of the small heat shock protein family, HspB8, is of particular interest in the field of neurological diseases since mutations in its sequence correlate with development of distal hereditary motor neuropathy and Charcot-Marie-Tooth disease. HspB8 expression has been detected in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington disease and spinocerebellar ataxia type 3. In the latter, HspB8 appears to be involved in protecting the cell from accumulation of insoluble aggregates either by preventing aggregation or by promoting degradation of improperly folded proteins. These data propose that HspB8 may be a major player in the neuroprotective response and a promising target for the development of therapeutic strategies.

Subcellular Injuries in Alzheimer's Disease

Alzheimer’s disease (AD) is the most common form of dementia occurring in the elderly. Several hypotheses have been proposed to explain the pathophysiology of AD, including amyloidogenesis, disruption of calcium homeostasis, energetic failure, induction of oxidative stress, and hyperphosphorylation of tau protein. This review examines associations between cellular and subcellular injuries, neurodegeneration, and cell death in experimental models, clinical symptoms, and autopsy reports of AD to identify the subcellular events leading to disease onset and progression. The order in which these events occur is discussed. The first injuries reported in AD are subcellular and occur at the Golgi apparatus before any β-amyloid proteins deposit in the Golgi and endosomes. This is followed by lysosomal alterations and the inability of cells to clear β-amyloid. The next stage reveals functional changes and modifications in hippocampal synaptic transmission before structural changes are observed at the cellular level. Subsequently, an extensive intracellular inflammatory process develops in neurons and astrocytes. This inflammatory reaction begins in the nucleus, endoplasmic reticulum, endosomes and mitochondria, and is thought to lead to neurodegeneration and cell death. Finally, the neuroinflammatory response of chronically activated microglia escalates the neurodegeneration and cell death. Identifying the detailed sequence of subcellular events induced by the primum movens defect in AD may lead to the identification of novel drug targets for the treatment of the disease.

Peptide Therapeutics in Neurodegenerative Disorders

Neurodegenerative diseases are characterized by selective and progressive degeneration of neuronal population in the brain, and associated behavioural, motor, psychiatric and cognitive impairments. Aggregation of pathogenic proteins, mitochondrial dysfunction, oxidative stress, transcriptional dysfunction and apoptosis play an important role in the pathogenesis of neurodegenerative disorders such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Amyotrophic lateral sclerosis. Therefore, novel therapies that target each of these mechanisms may be effective in abating the symptoms and slow down the onset and progression of neurodegenerative disorders. This review offers insights into the tremendous utility and versatility of peptides such as neurotrophins, neurotrophic factors (NGF, BDNF and GDNF), neuropeptides, mitochondrial targeted antioxidants/peptides, MitoQ, neurturin, and β-sheet breaker peptides to address the mechanisms and pathogenesis associated with neurodegenerative disorders.

Peptide-Based Therapeutic Approaches for Treatment of the Polyglutamine Diseases

The polyglutamine (polyQ) diseases including Huntington’s disease and spinocerebellar ataxias are a group of inherited neurodegenerative diseases that are caused by an abnormal expansion of the polyQ stretch in disease-causative proteins. The expanded polyQ stretches are intrinsically unstable and are prone to form insoluble aggregates and inclusion bodies. Recent studies have revealed that the expanded polyQ proteins gain cytotoxicity during the aggregation process, which may possibly cause detrimental effects on a wide range of essential cellular functions leading to eventual neuronal degeneration. Based on the pathogenic mechanism of the polyQ diseases, several therapeutic approaches have been proposed to date. Among them, here we focus on peptide-based approaches that target either aggregate formation of the polyQ proteins or abnormal cellular processes induced by the expanded polyQ proteins. Although both approaches are effective in suppressing cytotoxicity of the abnormal polyQ proteins and the disease phenotypes of animal models, the former approach is more attractive since it targets the most upstream change occurring in the polyQ diseases, and is therefore expected to be effective against various downstream functional abnormalities in a broad range of polyQ diseases. One of the major current problems that must be overcome for development of peptide-based therapies of the polyQ diseases is the issue of brain delivery, which is also discussed in this article. We hope that in the near future effective therapies are developed, and bring hope to many patients suffering from the currently untreatable polyQ diseases.

Status Epilepticus in the Immature Rodent Brain Alters the Dynamics of Autophagy

There is considerable interest in defining the molecular pathways involved in seizure-induced neuronal death. Necrotic, apoptotic and anti-apoptotic signalling pathways are activated after status epilepticus (SE). Analyses of apoptosis and necrosis have been merely reported, however conditions of autophagic cell death with hallmarks of type 2 programmed cell death-morphology are relatively few. Autophagy is a highly regulated cellular mechanism for the bulk degradation of cytoplasmic contents which is involved in a variety of physiological and pathological conditions associated with neurological diseases. Our goal was to examine whether autophagy is implicated in the cell death machinery after SE. For this purpose, we used lithium-pilocarpine model of SE in 14-day-old rats and examined the dynamics in the expression of autophagic markers in the hippocampus in controls and in animals subjected to SE at 6, 24, and 48h after the insult. Protein levels of central components of the autophagic machinery were dramatically affected by SE with, however, altered dynamics, compared to controls. Levels of LC3, phospho-mTOR/mTOR, BAG3 and Hsp70 were significantly increased, whereas Beclin 1 levels remained unchanged after SE. The dynamics in the expression of Atg3, Atg5, Atg7, Atg14 and LAMP1 were slightly altered. The amount of SQSTM1/p62 underwent a dramatic and highly significant breakdown 48 h after the induction of SE. These results demonstrate for the first time that SE in the immature brain results in significant alterations of autophagy dynamics. There is a growing interest in the role of autophagy in neurodegeneration, and an emerging consensus that autophagy represents a double-edged sword, acting either as a prosurvival mechanism, or as part of a cell death pathway.

Novel Therapeutic Targets in Neuropsychiatric Disorders: The Neuroepigenome

The neuroepigenome, i.e., the epigenome of the nervous system, has become interesting for therapeutics in the last years due to widespread availability of dedicated drugs. A pivotal role for neuroepigenetics is certainly implied, both in physiology and pathology, by the highly dynamic structural and functional rearrangements that constantly occur into the nervous system, globally known as plasticity. Moreover, the idea that the pathophysiology of several neuropsychiatric disorders might involve epigenetic mechanisms is increasingly taking place due to accumulating experimental data and by the evidence of a synergistic interaction between genes and environment beneath most sporadic forms of these diseases. In this paper we will review the available evidence on the use of epigenome-modifying drugs in the field of neuropsychiatry, shortly describing for each disease the underlying assumptions of an epigenetic dysregulation.

Genetic Variants in Diseases of the Extrapyramidal System

Knowledge on the genetics of movement disorders has advanced significantly in recent years. It is now recognized that disorders of the basal ganglia have genetic basis and it is suggested that molecular genetic data will provide clues to the pathophysiology of normal and abnormal motor control. Progress in molecular genetic studies, leading to the detection of genetic mutations and loci, has contributed to the understanding of mechanisms of neurodegeneration and has helped clarify the pathogenesis of some neurodegenerative diseases. Molecular studies have also found application in the diagnosis of neurodegenerative diseases, increasing the range of genetic counseling and enabling a more accurate diagnosis. It seems that understanding pathogenic processes and the significant role of genetics has led to many experiments that may in the future will result in more effective treatment of such diseases as Parkinson’s or Huntington’s. Currently used molecular diagnostics based on DNA analysis can identify 9 neurodegenerative diseases, including spinal cerebellar ataxia inherited in an autosomal dominant manner, dentate-rubro-pallido-luysian atrophy, Friedreich’s disease, ataxia with oculomotorapraxia, Huntington's disease, dystonia type 1, Wilson’s disease, and some cases of Parkinson's disease.

Pathogenic Mechanisms and Therapeutic Strategies in Spinobulbar Muscular Atrophy

We review the genetic and clinical features of spinobulbar muscular atrophy (SBMA), a progressive neuromuscular disorder caused by a CAG/glutamine tract expansion in the androgen receptor. SBMA was the first polyglutamine disease to be discovered, and we compare and contrast it with related degenerative disorders of the nervous system caused by expanded glutamine tracts. We review the cellular and animals models that have been most widely used to study this disorder, and highlight insights into disease pathogenesis derived from this work. These model systems have revealed critical aspects of the disease, including its hormone dependence, a feature that underlies disease occurrence only in men with the mutant allele. We discuss how this and other findings have been translated to clinical trials for SBMA patients, and examine emerging therapeutic targets that have been identified by recent work.

Induced Pluripotent Stem Cell-Based Studies of Parkinson's Disease: Challenges and Promises

A critical step in the development of effective therapeutics to treat Parkinson’s disease (PD) is the identification of molecular pathogenic mechanisms underlying this chronically progressive neurodegenerative disease. However, while animal models have provided valuable information about the molecular basis of PD, the lack of faithful cellular and animal models that recapitulate human pathophysiology is delaying the development of new therapeutics. The reprogramming of somatic cells to induced pluripotent stem cells (iPSC) using delivery of defined combinations of transcription factors is a groundbreaking discovery that opens great opportunities for modeling human diseases, including PD, since iPSC can be generated from patients and differentiated into disease-relevant cell types, which would capture the patients’ genetic complexity. Furthermore, human iPSC-derived neuronal models offer unprecedented access to early stages of the disease, allowing the investigation of the events that initiate the pathologic process in PD. Recently, human iPSC-derived neurons from patients with familial and sporadic PD have been generated and importantly they recapitulate some PD-related cell phenotypes, including abnormal α-synuclein accumulation in vitro, and alterations in the autophagy machinery. This review highlights the current PD iPSC-based models and discusses the potential future research directions of this field.

Tryptamine Induces Axonopathy and Mitochondriopathy Mimicking Neurodegenerative Diseases via Tryptophanyl-tRNA Deficiency

Neurodegeneration is induced by tryptamine, a human diet constituent, which easily crosses the blood/brain barrier. Tryptamine neurotoxicity, caused by tryptophanyl-tRNA synthetase (TrpRS) inhibition and downregulation leads to tryptophanyl-tRNA deficiency and synthesis of aberrant proteins. We identified axonal defects in hippocampus of tryptamine- treated mice similar to those observed in human brain of patients with Alzheimer's disease, multiple sclerosis and epilepsy using anti-TrpRS site-directed antibodies. The axonal defects are characterized by swellings that accumulate abnormal amounts of helical filaments and amyloid. Tryptamine produced a decreased density of somatic mitochondria concomitant with neuronal loss in mouse hippocampus. In addition, tryptamine evoked accumulation and clustering of small mitochondria in mouse hippocampus causing axonal swellings. Similarly, mitochondrial fission, fusion and clustering were revealed in human neuronal cells after tryptamine administration. Moreover the tryptamine-induced mitochondrial neuropathology includes electron-dense deposits comprising helical fibrils, cristae disruption, cristolysis, mitochondrial swelling and mitochondria-derived vesicles. TrpRS+ helical filamentous tangles formed in both neuronal and kidney cells following tryptamine treatment suggest a tryptamine broad cytotoxic repertoire in damaging vital organs. Tryptamine elicited vesicularization of inner and outer mitochondrial membranes, axonal and cell membranes. Ultrastructurally, fragmentation of swollen degenerated mitochondria, small mitochondria clustering and neurofibrillary tangles are associated with axonal membrane protrusions attributed as neuritic swellings at a lower magnification. TrpRS+ axonal swellings associated with neuropathology of patients and tryptamine-treated human cells suggest that under toxic concentrations, tryptamine is implicated as a causative agent in neurodegeneration resembling that defining a number of human diseases.

Histone Post-translational Modifications in Huntington’s and Parkinson’s Diseases

Gene expression is controlled by several epigenetic mechanisms involving post-translational modification of histones (acetylation, phosphorylation and others). These mechanisms in the brain are not only important for normal function but also for the development of pathologies when their derangement does occur. The present review deals with post-translational modifications of histones in two neurodegenerative diseases characterized by different etiology and pathological progression, Huntington’s disease and Parkinson’s disease. A relatively large body of evidence supports an important role of these mechanisms in Huntington’s disease while knowledge of similar mechanisms in Parkinson’s disease is at a lower degree of understanding. Starting from available information on pathologies, the present state of possible therapeutic targets is considered and future developments are discussed.

Lysine Acetyltransferases CBP and p300 as Therapeutic Targets in Cognitive and Neurodegenerative Disorders

Neuropsychiatric pathologies, including neurodegenerative diseases and neurodevelopmental syndromes, are frequently associated with dysregulation of various essential cellular mechanisms, such as transcription, mitochondrial respiration and protein degradation. In these complex scenarios, it is difficult to pinpoint the specific molecular dysfunction that initiated the pathology or that led to the fatal cascade of events that ends with the death of the neuron. Among the possible original factors, epigenetic dysregulation has attracted special attention. This review focuses on two highly related epigenetic factors that are directly involved in a number of neurological disorders, the lysine acetyltransferases CREB-binding protein (CBP) and E1A-associated protein p300 (p300). We first comment on the role of chromatin acetylation and the enzymes that control it, particularly CBP and p300, in neuronal plasticity and cognition. Next, we describe the involvement of these proteins in intellectual disability and in different neurodegenerative diseases. Finally, we discuss the potential of ameliorative strategies targeting CBP/p300 for the treatment of these disorders.

The Multifunctional Mesencephalic Locomotor Region

In 1966, Shik, Severin and Orlovskii discovered that electrical stimulation of a region at the junction between the midbrain and hindbrain elicited controlled walking and running in the cat. The region was named Mesencephalic Locomotor Region (MLR). Since then, this locomotor center was shown to control locomotion in various vertebrate species, including the lamprey, salamander, stingray, rat, guinea-pig, rabbit or monkey. In human subjects asked to imagine they are walking, there is an increased activity in brainstem nuclei corresponding to the MLR (i.e. pedunculopontine, cuneiform and subcuneiform nuclei). Clinicians are now stimulating (deep brain stimulation) structures considered to be part of the MLR to alleviate locomotor symptoms of patients with Parkinson’s disease. However, the anatomical constituents of the MLR still remain a matter of debate, especially relative to the pedunculopontine, cuneiform and subcuneiform nuclei. Furthermore, recent studies in lampreys have revealed that the MLR is more complex than a simple relay in a serial descending pathway activating the spinal locomotor circuits. It has multiple functions. Our goal is to review the current knowledge relative to the anatomical constituents of the MLR, and its physiological role, from lamprey to man. We will discuss these results in the context of the recent clinical studies involving stimulation of the MLR in patients with Parkinson’s disease.

A Valuable Animal Model of Spinal Cord Injury to Study Motor Dysfunctions, Comorbid Conditions, and Aging Associated Diseases

Most animal models of contused, compressed or transected spinal cord injury (SCI) require a laminectomy to be performed. However, despite advantages and disadvantages associated with each of these models, the laminectomy itself is generally associated with significant problems including longer surgery and anaesthesia (related post-operative complications), neuropathic pain, spinal instabilities, deformities, lordosis, and biomechanical problems, etc. This review provides an overview of findings obtained mainly from our laboratory that are associated with the development and characterization of a novel murine model of spinal cord transection that does not require a laminectomy. A number of studies successfully conducted with this model provided strong evidence that it constitutes a simple, reliable and reproducible transection model of complete paraplegia which is particularly useful for studies on large cohorts of wild-type or mutant animals - e.g., drug screening studies in vivo or studies aimed at characterizing neuronal and non-neuronal adaptive changes post-trauma. It is highly suitable also for studies aimed at identifying and developing new pharmacological treatments against aging associated comorbid problems and specific SCI-related dysfunctions (e.g., stereotyped motor behaviours such as locomotion, sexual response, defecation and micturition) largely related with ‘command centers’ located in lumbosacral areas of the spinal cord.

Targeting TRPs in Neurodegenerative Disorders

Neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis present a significant medical challenge in the modern world. Recent evidence indicates that perturbation of neuronal Ca2+ homeostasis is involved in the pathogenesis of these neurodegenerative disorders. Transient receptor potential (TRP) channels are non-selective cation channels that are expressed in various cell types and tissues, and play an important role in regulating Ca2+ signaling in both non-neuronal and neuronal cells. TRP channels are related to the onset or progression of several diseases, and defects in the genes encoding TRP channels (so-called “TRP channelopathies”) underlie certain neurodegenerative disorders due to their abnormal Ca2+ signaling properties. In this article, we review recent findings regarding the relationship between TRPs and neurodegenerative disorders, and discuss the therapeutic potential of targeting TRP channels pharmacologically.

Protein Homeostasis as a Therapeutic Target for Diseases of Protein Conformation

Protein misfolding and aggregation are widely implicated in an increasing number of human diseases providing for new therapeutic opportunities targeting protein homeostasis (proteostasis). The cellular response to proteotoxicity is highly regulated by stress signaling pathways, molecular chaperones, transport and clearance machineries that function as a proteostasis network (PN) to protect the stability and functional properties of the proteome. Consequently, the PN is essential at the cellular and organismal level for development and lifespan. However, when challenged during aging, stress, and disease, the folding and clearance machineries can become compromised leading to both gain-of-function and loss-offunction proteinopathies. Here, we assess the role of small molecules that activate the heat shock response, the unfolded protein response, and clearance mechanisms to increase PN capacity and protect cellular proteostasis against proteotoxicity. We propose that this strategy to enhance cell stress pathways and chaperone activity establishes a cytoprotective state against misfolding and/or aggregation and represents a promising therapeutic avenue to prevent the cellular damage associated with the variety of protein conformational diseases.

Molecular Chaperone Disorders: Defective Hsp60 in Neurodegeneration

Chaperonins, a subgroup of molecular chaperones, form ring-shaped structures and assist folding of proteins by enclosing them in their inner cavity. The mitochondrial Hsp60/Hsp10 chaperonin system is essential for cell viability and only a very small number of mutations causing human disease have so far been found that appear to selectively affect neuronal tissues. We here review the knowledge on the mammalian Hsp60/Hsp10 system and discuss evidence and observations, which may explain why this is the case. The Hsp60 mutations shown to be associated with neurodegenerative diseases mildly affect the protein and leave residual function. We present arguments for the notion that the neuron/glia specificity may be due to an effect of Hsp60 deficiency on myelination, a neuron-specific property. The substrates of the Hsp60/Hsp10 system are only poorly defined, but the combination of deficiency of a number of mitochondrial enzymes and proteins that are highly dependent on this system for folding is the likely trigger for deficient myelination. However, a number of experimental observations indicate that Hsp60 may also have roles outside mitochondria and deficiency of Hsp60 due to mutation may also affect myelination via these signaling pathways. Taken together, it appears that mild Hsp60 deficiency primarily affects neuronal and/or glia cells whereas more severe deficiency of Hsp60 would affect all tissues and not be compatible with life. We discuss in the end what approaches may lead to a further understanding of the functions of the Hsp60/Hsp10 system in mammalian cells and thus its role in disease conditions.

DNAJ Proteins and Protein Aggregation Diseases

Many neurodegenerative diseases are late onset diseases, associated with aggregation of proteins, implying that aged cells are more susceptible to proteotoxic stress. It is known that with aging, there is a decline in the functionality of chaperone networks and on the other hand, accumulation of damaged proteins occurs. Together, this has a cumulative effects on cellular protein homeostasis. Several studies have revealed that availability of DNAJ proteins, the cochaperones to the Hsp70 machine, could be a rate-limiting factor in handling diseased proteins within the cell. In this review, we highlight how DNAJ proteins can affect aggregation of disease-causing proteins, if and how this depends on their function as Hsp70 co-chaperones, and how much this depends on the type of protein causing the disease. Finally, we will discuss the five known degenerative diseases that are linked to mutations in individual DNAJ members and what mechanism may underlie these DNAJ chaperonopathies.

The Journey From Metabolic Profiling to Biomarkers: The Potential of NMR Spectroscopy Based Metabolomics in Neurodegenerative Disease Research

Neurodegenerative diseases have become a “hot” topic in recent years. A major factor for this is that as life expectancy of the population in developed countries increases, so does the probability of developing neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), to name the two most well-known. In many cases, however, neurological and mental diseases are poorly understood. In particular, there is a lack of specific biomarkers which would allow early unambiguous identification of a neurodegenerative disease, distinguishing between e.g. AD; PD; PD with dementia; and Dementia with Lewy bodies, or indicating therapeutic effects. Ultimately, this complicates the search for effective treatments. Thus, there is a high demand for preclinical work to elucidate underlying disease mechanisms and pave the way for disease management.

In terms of biomarker research, hope has been set on small molecules that participate in metabolism, since they provide a closer link between cellular mechanisms (with genetic as well as environmental inputs) and the disease phenotype. More specifically, it is expected that not one but a combination of several metabolites may serve as an indicator for disease onset and progression, given that neurodegenerative diseases, whilst often described as “idiopathic”, are understood to arise from complex pathologies expressing themselves with a broad spectrum of phenotypes. Therefore, non-targeted metabolic profiling appears to offer great potential for biomarker discovery in this area.

One of the major technical platforms for non-targeted metabolic profiling is high resolution nuclear magnetic resonance (NMR) spectroscopy, a technique that is also available for the non-invasive application in vivo. Hence, in theory, biomarker discovery research using NMR spectroscopy based metabolomics provides a promising means for translation from in vitro/ex vivo research to eventual clinical use. This review will therefore discuss the potential for NMR spectroscopy based metabolomics to be applied to biomarker discovery in the field of neurodegenerative disease.

Cognitive Dysfunction in FMR1 Premutation Carriers

Premutation carriers of the fragile X mental retardation gene (especially men) older than 50 may develop a neurodegenerative disease, the fragile X-associated tremor/ataxia syndrome (FXTAS). Carriers may present with varied cognitive impairments. Attention, working memory, declarative and procedural learning, information processing speed, and recall are among the cognitive domains affected. Executive dysfunction is a prominent deficit, which has been demonstrated mostly in men with FXTAS. In more advanced stages of FXTAS, both men and women may develop a mixed cortical-subcortical dementia, manifested by psychomotor slowing and deficits in attention, retrieval, recall, visuospatial skills, occasional apraxia, as well as overt personality changes. Studies have shown dementia rates as high as 37-42% in older men with FXTAS, although more research is needed to understand the prevalence and risk factors of dementia in women with FXTAS. Neuropsychiatric symptoms are common and reflect the dysfunction of underlying frontal-subcortical neural circuits, along with components of the cerebellar cognitive affective syndrome. These include labile or depressed mood, anxiety, disinhibition, impulsivity, and (rarely) psychotic symptoms. In this paper we review the information available to date regarding the prevalence and clinical picture of FXTAS dementia. Differential diagnosis may be difficult, given overlapping motor and non-motor signs with several other neurodegenerative diseases. Anecdotal response to cholinesterase inhibitors and memantine has been reported, while symptomatic treatments can address the neuropsychiatric manifestations of FXTAS dementia.