Subacute Combined Degeneration

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.

Exploring Phytotherapy's Preventive and Therapeutic Impact on Global COVID-19 Management: A Narrative Review

Introduction: The WHO Emergency Committee advocates preventive strategies for COVID-19 management, emphasising vaccines as highly effective but acknowledging their limitations. Chloroquine and hydroxychloroquine, initially effective against COVID-19, were discontinued due to severe side effects. Further clinical trials are imperative to establish the safety and efficacy of new antiviral agents, some of which may have harmful effects on human development.

Objectives: The shortcomings of various conventional treatments have prompted urgent efforts to discover safe, natural compounds that may be useful in combating COVID-19. This study aims to review research that has investigated the potential of traditional phytotherapies used by different populations for the prevention and symptomatic treatment of COVID-19 infection.

Methods: This paper reviewed scientific studies published through searching on search engines such as PubMed, Scopus, Google Scholar, ScienceDirect and Elsevier from May until October 2023.

Results: The preventive and anti-COVID-19 attributes of Traditional Chinese Medicine, Ayurvedic formulations and African medicinal plants have been substantiated in research. In Nepal, recommendations endorse the utilisation of medicinal plants for herbal teas and homemade sanitizers. Zingiber officinale, Curcuma longa L. and Curcuma xanthorriza Roxb., along with Camellia sinensis are crucial Indonesian medicinal plants with potential for treating COVID-19. Z. officinale was predominantly chosen for relieving coughs and sore throats associated with COVID-19 in Saudi Arabia.

Discussion: The immunomodulatory properties of medicinal plants, which may prove useful in combating COVID-19, have been verified via elevation of the level of peripheral WBCs, IgM, IgG; inhibition of leukotrienes and prostaglandins, maintenance of the integrity of intestinal mucosal barrier and regulation of HMGB1. The antiviral effects of herbs, including the inhibition of viral DNA and RNA replication, down-regulation of oxidative stress, and the impediment of SARS-CoV-2 access to vascular endothelial cells, suggest their potential to facilitate earlier recovery from COVID-19 infection.

Conclusion: Advancing scientific research in phytotherapy promises the possibility of novel approaches for effectively managing future infectious diseases and pandemics.

Understanding Alzheimer’s Disease and its Metal Chelation Therapeutics: A Narrative Review

The neurodegenerative disorders are age-related illnesses that cause the morphology or activity of neurons to deteriorate over time. Alzheimer’s disease is the most frequent neurodegenerative illness in the long run. The rate of advancement might vary, even though it is a progressive neurological illness. Various explanations have been proposed, however the true etiology of Alzheimer’s disease remains unclear. Most pharmacological interventions are based on the cholinergic theory, that is earliest idea. In accordance with the amyloid hypothesis, the buildup of beta-amyloid in brain regions is the primitive cause of illness. There is no proof that any one strategy is useful in avoiding Alzheimer’s disease, though some epidemiological studies have suggested links within various modifiable variables, such as cardiovascular risk, diet and so on. Different metals like zinc, iron, and copper are naturally present in our bodies. In metal chelation therapy drugs are used to jam the metal ions from combining with other molecules in the body. Clioquinol is one of the metal chelation drugs used by researchers. Research on metal chelation is still ongoing. In the present review, we go over the latest developments in prevalence, incidence, etiology, or pathophysiology of our understanding of Alzheimer’s disease. Additionally, a brief discussion on the development of therapeutic chelating agents and their viability as Alzheimer’s disease medication candidates is presented. We also assess the effect of clioquinol as a potential metal chelator.

Curcumin Combats against Organophosphate Pesticides Toxicity: A Review of the Current Evidence and Molecular Pathways

Organophosphate compounds are regarded as a class of pesticides that are used in farming. Their extensive use, especially in developing countries, is a serious public health problem. Numerous studies have shown the effects of these toxins on various parts of the human and other vertebrates’ bodies, including the cardiovascular, hepatobiliary, renal, and reproductive systems. Curcumin is a polyphenol compound obtained from the rhizome of the Curcuma longa. Curcumin has been known as a dietary spice, food additive, and traditional medicine since many years ago. In recent decades, the medicinal characteristics, clinical aspects, and biological activity of curcumin have been extensively examined. The most examined positive characteristics of curcumin are its anti- inflammatory and anti-oxidant qualities. This review will deal with the pharmacological properties of curcumin as well as an update of currently available studies in terms of curcumin’s uses and function against organophosphate pesticides-induced toxicity on different human organs.

Gene Therapy for Chronic Traumatic Brain Injury: Challenges in Resolving Long-term Consequences of Brain Damage

The gene therapy is alluring not only for CNS disorders but also for other pathological conditions. Gene therapy employs the insertion of a healthy gene into the identified genome to replace or replenish genes responsible for pathological disorder or damage due to trauma. The last decade has seen a drastic change in the understanding of vital aspects of gene therapy. Despite the complexity of traumatic brain injury (TBI), the advent of gene therapy in various neurodegenerative disorders has reinforced the ongoing efforts of alleviating TBI-related outcomes with gene therapy. The review highlights the genes modulated in response to TBI and evaluates their impact on the severity and duration of the injury. We have reviewed strategies that pinpointed the most relevant gene targets to restrict debilitating events of brain trauma and utilize vector of choice to deliver the gene of interest at the appropriate site. We have made an attempt to summarize the long-term neurobehavioral consequences of TBI due to numerous pathometabolic perturbations associated with a plethora of genes. Herein, we shed light on the basic pathological mechanisms of brain injury, genetic polymorphism in individuals susceptible to severe outcomes, modulation of gene expression due to TBI, and identification of genes for their possible use in gene therapy. The review also provides insights on the use of vectors and challenges in translations of this gene therapy to clinical practices.

A Focused Review on Molecular Signalling Mechanisms of Ginsenosides Anti-Lung Cancer and Anti-inflammatory Activities

Background: Ginseng (Panax ginseng Meyer) is a cultivated medicinal herb that has been widely available in the Asian region since the last century. Ginseng root is used worldwide in Oriental medicine. Currently, the global mortality and infection rates for lung cancer and inflammation are significantly increasing. Therefore, various preventative methods related to the activity of ginsenosides have been used for lung cancer as well as inflammation.

Methods: Web-based searches were performed on Web of Science, Springer, PubMed, and Scopus. A cancer statistical analysis was also conducted to show the current ratio of affected cases and death from lung cancer around the world.

Results: Ginsenosides regulate the enzymes that participate in tumor growth and migration, such as nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), extracellular signalregulated kinases 1/2 (ERK1/2), the gelatinase network metalloproteinase-2 (MMP-2/9) and activator protein 1 (AP-1). In addition, ginsenosides also possess anti-inflammatory effects by inhibiting the formation of proinflammatory cytokines (tumor necrosis factor-α) (TNF-α) and interleukin-1β (IL-1β) and controlling the activities of inflammatory signalling pathways, such as NF-κB, Janus kinase2/signal transducer, and activator of transcription 3 (Jak2/Stat3).

Conclusion: In several in vitro and in vivo models, P. ginseng showed potential beneficial effects in lung cancer and inflammation treatment. In this review, we provide a detailed and up-to-date summary of research evidence for antilung cancer and anti-inflammatory protective effects of ginsenosides and their potential molecular mechanisms.

Central Nervous System Disorders Associated to Immune Checkpoint Inhibitors

New therapies and alternatives for the containment of tumor progression are being proposed for the treatment of cancer. In this context, monoclonal therapies using Immune Checkpoint Inhibitors (ICI) come as a therapeutic proposal. They are responsible for immunological control by blocking PD-1, PD-L1 and CTLA-4 molecules. However, among the effects caused by therapy, the use of medications is associated with neurological diseases reported as an adverse effect, affecting the Central Nervous System (CNS) and causing a wide range of symptoms. In this regard, the present bibliographic review presents the main CNS disorders associated with this therapy, in addition to the incidence, symptoms and treatment of these diseases.

COVID-19, the Brain, and the Future: Is Infection by the Novel Coronavirus a Harbinger of Neurodegeneration?

The possible impact of viral infections on the development or pathogenesis of neurodegenerative disorders remains largely unknown. However, there have been reports associating the influenza virus pandemic and long-term infection with the Japanese encephalitis virus with the development of post-encephalitic Parkinsonism or von Economo’s encephalitis. In the last couple of years, there has been a worldwide pandemic caused by the novel coronavirus or severe acute respiratory syndrome coronavirus (SARS-CoV)-2, which causes a severe acute respiratory syndrome and is found to be associated with symptoms or complications of the central nervous system. Its possible involvement with the central nervous system is in line with emerging scientific evidence stating that the human respiratory coronaviruses can enter the brain, infect neural cells, persist in the brain, and cause activation of myelin-reactive T cells. Currently, there is a dearth of scientific information on the acute or possible long-term impact of infection with SARS-CoV-2 on the development of dementia and/or neurodegenerative diseases. This is related to the fact that the virus is ‘new,’ and its effects on humans are still being studied. This narrative review examines the extant literature for understanding the impact of coronavirus infections on the brain as there is a possibility that coronavirus disease 2019 (COVID-19) could increase the risk for the development of neurodegenerative diseases or hasten their progression.

Update on Myositis Therapy: From Today’s Standards to Tomorrow’s Possibilities

Inflammatory myopathies, in short, myositis, are heterogeneous disorders that are characterized by inflammation of skeletal muscle and weakness of arms and legs. Research over the past few years has led to a new understanding regarding the pathogenesis of myositis. The new insights include different pathways of the innate and adaptive immune response during the pathogenesis of myositis. The importance of non-inflammatory mechanisms such as cell stress and impaired autophagy has been recently described. New target-specific drugs for myositis have been developed and are currently being tested in clinical trials. In this review, we discuss the mechanisms of action of pharmacological standards in myositis and provide an outlook of future treatment approaches.

Neuroprotective Activities of Orientin: A Review

Orientin is a flavonoid C-glycoside found in many plants, and studies investigating its neuropharmacological benefits have received significant attention in recent years. Orientin has modulating effects on various neuropathological pathways such as Nrf2-ARE, PI3K/Akt, JNKERK1/ 2, and TLR4/NF-kB. Orientin, therefore, is evaluated for its benefits in various neurodegenerative diseases such as Alzheimer's and Huntington's disease. This paper reviews Orientin's neuroprotective mechanisms and benefits.

Role of Mechanoinsensitive Nociceptors in Painful Diabetic Peripheral Neuropathy

The cutaneous mechanisms that trigger spontaneous neuropathic pain in diabetic peripheral neuropathy (PDPN) are far from clear. Two types of nociceptors are found within the epidermal and dermal skin layers. Small-diameter lightly myelinated Aδ and unmyelinated C cutaneous mechano and heat-sensitive (AMH and CMH) and C mechanoinsensitive (CMi) nociceptors transmit pain from the periphery to central nervous system. AMH and CMH fibers are mainly located in the epidermis, and CMi fibers are distributed in the dermis. In DPN, dying back intra-epidermal AMH and CMH fibers leads to reduced pain sensitivity, and the patients exhibit significantly increased pain thresholds to acute pain when tested using traditional methods. The role of CMi fibers in painful neuropathies has not been fully explored. Microneurography has been the only tool to access CMi fibers and differentiate AMH, CMH, and CMi fiber types. Due to the complexity, its use is impractical in clinical settings. In contrast, a newly developed diode laser fiber selective stimulation (DLss) technique allows to safely and selectively stimulate Aδ and C fibers in the superficial and deep skin layers. DLss data demonstrate that patients with painful DPN have increased Aδ fiber pain thresholds, while C-fiber thresholds are intact because, in these patients, CMi fibers are abnormally spontaneously active. It is also possible to determine the involvement of CMi fibers by measuring the area of DLss-induced neurogenic axon reflex flare. The differences in AMH, CMH, and CMi fibers identify patients with painful and painless neuropathy. In this review, we will discuss the role of CMi fibers in PDPN.

Drug-Induced Peripheral Neuropathy: Diagnosis and Management

Peripheral neuropathy comes in all shapes and forms and is a disorder which is found in the peripheral nervous system. It can have an acute or chronic onset depending on the multitude of pathophysiologic mechanisms involving different parts of nerve fibers. A systematic approach is highly beneficial when it comes to cost-effective diagnosis. More than 30 causes of peripheral neuropathy exist ranging from systemic and auto-immune diseases, vitamin deficiencies, viral infections, diabetes, etc. One of the major causes of peripheral neuropathy is drug-induced disease, which can be split into peripheral neuropathy caused by chemotherapy or by other medications. This review deals with the latest causes of drug-induced peripheral neuropathy, the population involved, the findings on physical examination and various workups needed and how to manage each case.

Differentiation Between Osteoporotic and Neoplastic Vertebral Fractures: State of The Art and Future Perspectives

Vertebral fractures are a common condition occurring in the context of osteoporosis and malignancy. These entities affect a group of patients in the same age range; clinical features may be indistinct and symptoms non-existing, and thus present challenges to diagnosis. In this article, we review the use and accuracy of different imaging modalities available to characterize vertebral fracture etiology, from well-established classical techniques to the role of new and advanced imaging techniques and the prospective use of artificial intelligence. We also address the role of imaging in treatment. In the context of osteoporosis, the importance of opportunistic diagnosis is highlighted. In the near future, the use of automated computer-aided diagnostic algorithms applied to different imaging techniques may be really useful to aid in diagnosis.

Endovascular Therapies for Type B Aortic Dissection

Aortic dissection is a life-threatening condition resulting from a tear in the intimal layer of the aorta, requiring emergent diagnosis and prompt multi-disciplinary management strategy for best patient outcomes. While type A dissection involving ascending aorta is best managed surgically due to high early mortality, Type B Aortic Dissection (TBAD) involving descending aorta generally has better outcomes with conservative management and medical therapy as a primary strategy is favored. However, there has been a recent paradigm shift in the management of TBAD due to late aneurysmal degeneration of TBAD, increasing morbidity and mortality in the long term. Late surgical intervention can be prevented by early endovascular intervention when combined with optimal medical therapy. In this narrative review, we explore available literature on different endovascular therapies for TBAD in different populations of patients.

The Link Between Conventional and Novel Anti-Cancer Therapeutics with Thrombotic Microangiopathy

Background: Kidney disease associated with cancer and anti-cancer therapies has been increasingly recognized in the field of onco-nephrology. In particular, drug-induced nephrotoxicity has important implications since most chemotherapeutic agents have a nephrotoxic potential. Also, standard creatinine clearance methods used for the measurement of kidney function have been questioned in cancer patients due to factors like low muscle mass and poor nutritional status. Overestimations of the glomerular filtration rate, not only can increase the nephrotoxic potential of different agents, but also further limit the use of first-line therapies.

Objective: This review covers specifically the drug-induced thrombotic microangiopathy and its two pathophysiologic mechanisms which include immune or idiosyncratic reactions, and non-immune or dose-dependent ones.

Conclusion: As novel cancer therapies are developed, it is paramount to pursue a better understanding of conventional and novel chemotherapeutic agents and their role in kidney disease.

Targeting Microglial Polarization to Improve TBI Outcomes

Traumatic Brain Injury (TBI) is still the worldwide leading cause of mortality and morbidity in young adults. Improved safety measures and advances in critical care have increased chances of surviving a TBI, however, numerous secondary mechanisms contribute to the injury in the weeks and months that follow TBI. The past 4 decades of research have addressed many of the metabolic impairments sufficient to mitigate mortality, however, an enduring secondary mechanism, i.e. neuroinflammation, has been intractable to current therapy. Neuroinflammation is particularly difficult to target with pharmacological agents due to lack of specificity, the blood brain barrier, and an incomplete understanding of the protective and pathologic influences of inflammation in TBI. Recent insights into TBI pathophysiology have established microglial activation as a hallmark of all types of TBI. The inflammatory response to injury is necessary and beneficial while the death of activated microglial is not. This review presents new insights on the therapeutic and maladaptive features of the immune response after TBI with an emphasis on microglial polarization, followed by a discussion of potential targets for pharmacologic and non-pharmacologic treatments. In aggregate, this review presents a rationale for guiding TBI inflammation towards neural repair and regeneration rather than secondary injury and degeneration, which we posit could improve outcomes and reduce lifelong disease burden in TBI survivors.

Endothelial Dysfunction Induced by Cadmium and Mercury and its Relationship to Hypertension

Hypertension is an important public health concern that affects millions globally, leading to a large number of morbidities and fatalities. The etiology of hypertension is complex and multifactorial, and it involves environmental factors, including heavy metals. Cadmium and mercury are toxic elements commonly found in the environment, contributing to hypertension. We aimed to assess the role of cadmium and mercury-induced endothelial dysfunction in the development of hypertension. A narrative review was carried out through database searches. In this review, we discussed the critical roles of cadmium and mercury in the etiology of hypertension and provided new insights into potential mechanisms of their effect, focusing primarily on endothelial dysfunction. Although the mechanisms by which cadmium and mercury induce hypertension have yet to be completely elucidated, evidence for both implicates impaired nitric oxide signaling in their hypertensive etiology.

Drug Repurposing: Promises of Edaravone Target Drug in Traumatic Brain Injury

Edaravone is a potent free-radical scavenger that has been in the market for more than 30 years. It was originally developed in Japan to treat strokes and has been used there since 2001. Aside from its anti-oxidative effects, edaravone demonstrated beneficial effects on proinflammatory responses, nitric oxide production, and apoptotic cell death. Interestingly, edaravone has shown neuroprotective effects in several animal models of diseases other than stroke. In particular, edaravone administration was found to be effective in halting amyotrophic lateral sclerosis (ALS) progression during the early stages. Accordingly, after its success in Phase III clinical studies, edaravone has been approved by the FDA as a treatment for ALS patients. Considering its promises in neurological disorders and its safety in patients, edaravone is a drug of interest that can be repurposed for traumatic brain injury (TBI) treatment. Drug repurposing is a novel approach in drug development that identifies drugs for purposes other than their original indication. This review presents the biochemical properties of edaravone along with its effects on several neurological disorders in the hope that it can be adopted for treating TBI patients.

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.

The Stroke-Induced Blood-Brain Barrier Disruption: Current Progress of Inspection Technique, Mechanism, and Therapeutic Target

Stroke is one of the leading causes of mortality and morbidity worldwide. The bloodbrain barrier (BBB) is a characteristic structure of microvessel within the brain. Under normal physiological conditions, the BBB plays a role in the prevention of harmful substances entering into the brain parenchyma within the central nervous system. However, stroke stimuli induce the breakdown of BBB leading to the influx of cytotoxic substances, vasogenic brain edema, and hemorrhagic transformation. Therefore, BBB disruption is a major complication, which needs to be addressed in order to improve clinical outcomes in stroke. In this review, we first discuss the structure and function of the BBB. Next, we discuss the progress of the techniques utilized to study BBB breakdown in in-vitro and in-vivo studies, along with biomarkers and imaging techniques in clinical settings. Lastly, we highlight the mechanisms of stroke-induced neuroinflammation and apoptotic process of endothelial cells causing BBB breakdown, and the potential therapeutic targets to protect BBB integrity after stroke. Secondary products arising from stroke-induced tissue damage provide transformation of myeloid cells such as microglia and macrophages to pro-inflammatory phenotype followed by further BBB disruption via neuroinflammation and apoptosis of endothelial cells. In contrast, these myeloid cells are also polarized to anti-inflammatory phenotype, repairing compromised BBB. Therefore, therapeutic strategies to induce anti-inflammatory phenotypes of the myeloid cells may protect BBB in order to improve clinical outcomes of stroke patients.

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.

Biological Signatures of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most prevalent and severe neurodegenerative disease affecting more than 0.024 billion people globally, more common in women as compared to men. Senile plaques and amyloid deposition are among the main causes of AD. Amyloid deposition is considered as a central event which induces the link between the production of β amyloid and vascular changes. Presence of numerous biomarkers such as cerebral amyloid angiopathy, microvascular changes, senile plaques, changes in white matter, granulovascular degeneration specifies the manifestation of AD while an aggregation of tau protein is considered as a primary marker of AD. Likewise, microvascular changes, activation of microglia (immune defense system of CNS), amyloid-beta aggregation, senile plaque and many more biomarkers are nearly found in all Alzheimer’s patients. It was seen that 70% of Alzheimer’s cases occur due to genetic factors. It has been reported in various studies that apolipoprotein E(APOE) mainly APOE4 is one of the major risk factors for the later onset of AD. Several pathological changes also occur in the white matter which include dilation of the perivascular space, loss of axons, reactive astrocytosis, oligodendrocytes and failure to drain interstitial fluid. In this review, we aim to highlight the various biological signatures associated with the AD which may further help in discovering multitargeting drug therapy.

Characterization, Bioactive Compounds and Antioxidant Potential of Açaí (Euterpe oleracea) Genotypes

Background: Açaí (Euterpe oleracea), a “superfruit” consumed worldwide, is a Brazilian Amazon native fruit, with high nutritive value due to its high content of lipids, proteins, and fibers, besides bioactive compounds, such as anthocyanins, carotenoids and phenolic compounds in its composition associated with biological action beneficial to health. The increased consumption of this fruit has stimulated breeding programs in the search of plants and fruits with higher productivity and bioactive compounds, generating information for the development of new cultivars with improved attributes. This work aimed to study six different genotypes of açaí, developed by the breeding program, evaluating their physicochemical characteristics and proximate composition, bioactive compounds and antioxidant activity.

Methods: The genotypes were analyzed for titratable acidity, pH, total soluble solids and proximate composition, such as moisture, protein, lipids, total fiber, carbohydrates and ashes contents. A spectrophotometric method using Folin-Ciocalteau reagent performed the phenolic compounds analysis and HPLC evaluated carotenoids and anthocyanins extracted exhaustively. The ABTS assay evaluated the antioxidant activity.

Results: The L06P13 and L09P09 genotype presented higher content of total fiber, carbohydrates, and ashes when compared to the commercial sample used as a standard. Furthermore, L22P13 genotype showed the highest content of total anthocyanins (6745.81 mg/100g), total carotenoids (118 μg/g) and antioxidant activity (674.83 μM Trolox/g) when compared to commercial sample.

Conclusion: The results revealed promising açaí genotypes and support the importance of advances in the area of functional foods and breeding programs.

Different Generations of Type-B Monoamine Oxidase Inhibitors in Parkinson’s Disease: From Bench to Bedside

Three inhibitors of type-B monoamine oxidase (MAOB), selegiline, rasagiline, and safinamide, are used for the treatment of Parkinson’s disease (PD). All three drugs improve motor signs of PD, and are effective in reducing motor fluctuations in patients undergoing long-term L-DOPA treatment. The effect of MAOB inhibitors on non-motor symptoms is not uniform and may not be class-related. Selegiline and rasagiline are irreversible inhibitors forming a covalent bond within the active site of MAOB. In contrast, safinamide is a reversible MAOB inhibitor, and also inhibits voltage- sensitive sodium channels and glutamate release. Safinamide is the prototype of a new generation of multi-active MAOB inhibitors, which includes the antiepileptic drug, zonisamide. Inhibition of MAOB-mediated dopamine metabolism largely accounts for the antiparkinsonian effect of the three drugs. Dopamine metabolism by MAOB generates reactive oxygen species, which contribute to nigro-striatal degeneration. Among all antiparkinsonian agents, MAOB inhibitors are those with the greatest neuroprotective potential because of inhibition of dopamine metabolism, induction of neurotrophic factors, and, in the case of safinamide, inhibition of glutamate release. The recent development of new experimental animal models that more closely mimic the progressive neurodegeneration associated with PD will allow to test the hypothesis that MAOB inhibitors may slow the progression of PD.

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.

Herbal Compounds with Special Reference to Gastrodin as Potential Therapeutic Agents for Microglia Mediated Neuroinflammation

Background: Activated microglia play a pivotal role neurodegenerative diseases by producing a variety of proinflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukin- 1beta (IL-1β) and nitric oxide (NO) that are toxic to neurons and oligodendrocytes.

Methods: In view of the above, suppression of microglia mediated neuroinflammation is deemed a therapeutic strategy for neurodegenerative diseases. Several potential Chinese herbal extracts have been reported to exert neuroprotective effects against neurodegenerative diseases targeting specifically at the activated microglia. In this connection, the phenolic glucoside gastrodin, a main constituent of the Chinese herbal medicine Gastrodia rhizoma, produced widely in the local community exhibits potential neuroprotective effects through suppression of neurotoxic proinflammatory mediators.

Results: Here, we first review the roles of activated microglia in different brain diseases. The effects of gastrodin on activated microglia are then considered. We have identified gastrodin as a putative therapeutic agent as it has been found to suppress microglial activation thus ameliorating neuroinflammation. More importantly, gastrodin downregulates the expression of renin angiotensin system (RAS) and production of proinflammatory mediators. Remarkably, gastrodin promotes Sirtuin 3 (Sirt3) up-regulation and nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX-2) down-regulation after ischemichypoxia in activated microglia mediated by AT1 or AT2 receptors which are angiotensin II receptors subtypes, indicating a possible molecular link between RAS and Sirt3 survival genes.

Conclusion: This review summarizes the beneficial effects of gastrodin acting on activated microglia along with other herbal compounds. Its efficacy in neuroprotection is consistent with some common herbal products in China.

Establishment of Retinal Degeneration Model in Rat and Monkey by Intravitreal Injection of Sodium Iodate

Background: Animal models play critical roles in studies of the etiology and therapy of retinal degeneration (RD).

Objective: To establish an RD model without severe systemic side effects in monkeys.

Methods: Cynomolgus monkeys and Sprague-Dawley rats were treated with intravenous and intravitreal sodium iodate (SI). Electroretinographic (ERG) recording, fluorescein fundus angiography (FFA), optical coherence tomography (OCT) and a retinal morphology examination were conducted to evaluate retinal function and structure. ARPE-19 cells were treated with SI to assess cell viability and morphology. Glutathione (GSH) was administered to SI-treated cultured cells and rats for mechanistic studies.

Results: Intravenous SI failed to induce RD in monkeys due to its lethal toxicity and the spontaneous recovery of visual function. However, intravitreal SI injection induced very rapid and severe retinal damage in both monkeys and rats. Different doses of SI were tested in both rats and monkeys, and the SI dose appropriate for the model was calculated. GSH partially rescued oxidative damage to SI-treated retinas. A combination of the appropriate dose of intravitreal SI and intravenous GSH generated moderate subacute RD.

Conclusions: An RD model was established in cynomolgus monkeys by intravitreal SI injection. The key advantages of this model are that lethal SI side effects can be avoided and that the structural and functional changes are similar to those in patients with RD, although the development of RD in the model is too rapid and more severe. An appropriate dose of SI plus systemic GSH generates delayed and moderate RD; this prolonged therapeutic window allows the development of new therapies, such as gene or stem cell-based therapy, for RD.

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.

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.

Furan-induced Oxidative Stress and DNA Damage in Diabetic and Nondiabetic Rats’ Blood and Protective Effect of Lycopene

Aim: This study aims to determine the adverse effect of furan in terms of oxidative stress parameters, DNA damage and the formation of micronucleus (MN) on experimental diabetic and nondiabetic rat’s blood and protective potency of the lycopene.

Methods: In the current study, fifty six adult wistar albino male rats were divided into eight groups of seven rats in each. 28 days after the application, biochemical (SOD, CAT, GPx, MDA) changes with trolox equivalent antioxidant capacity (TEAC) and ferric reducing antioxidant power (FRAP), DNA damage and formation of MN as well as membran structure of erythrocytes in the blood tissue samples were studied. Leucocytes were used for DNA damage with comet assay.

Results: Furan has been adverse effect on antioxidant enzyme systems and MDA level of erythrocytes and leucocytes, decreased TEAC and FRAP values, increased DNA damage, MN and deteriorated cells’ morphology in non-diabetic rat’s blood. These changes were seen in diabetes treatment groups, too. The results shown that the administration of lycopene could have a harmful efficiency against treatment with furan in the diabetic and non-diabetic rat’s blood.

Conclusion: It was seen that antioxidant enzymes activities, TEAC and FRAP values increased, the levels of MDA, tail DN%, mean tail length and MN decreased and improved membrane structure in the blood cells. Also, these data shown that the lycopene has more protective effects in erythrocytes and leucocytes of non-diabetic groups than diabetic groups.

Autoimmunity and Frontotemporal Dementia

Background: Frontotemporal Dementia (FTD) is a neurodegenerative disorder which asymmetrically affects the frontotemporal lobe, characterized by behavioural abnormalities, language impairment, and deficits of executive functions. Genetic studies identified mutations causing the disease, namely Microtubule Associated Protein Tau (MAPT), Granulin (GRN) and chromosome 9 open reading frame 72 (C9orf72) mutations, which contributed to elucidate the molecular pathways involved in brain depositions of either Tau or TAR DNA-binding protein 43 (TDP43) inclusions. However, in the majority of sporadic FTD patients, the mechanisms triggering Tau or TDP43 protein deposition are still to be uncovered.

Objective: We aimed to present an extensive evaluation of literature data on immune homeostasis in FTD, in order to provide potentially evidence-based approaches for a disease still orphan of any treatment.

Methods: A structured search of bibliographic databases from peer-reviewed literature was pursued focusing on autoimmunity in the brain and FTD.

Results: One-hundred-fourteen papers were included in this review. The majority of studies (32) were represented by extensive literature revision on immunity, central nervous system (CNS) and autoimmunity; neuroimaging papers (11) in autoimmune diseases were evaluated, and immunomodulatory approaches (25) were revised. Six papers were found specifically related to FTD and autoimmune hypothesis, the other papers referring to current state of art on FTD.

Conclusion: Overall this review contribute to expand the knowledge of a possible immune hypothesis in FTD, suggesting therapeutic perspectives in autoimmune related neurodegeneration, to reduce or revert the disease.

Neuroimaging Features of Acquired Metabolic and Toxic Encephalopathies

Background: Toxic and metabolic encephalopathies are easily misinterpreted or overlooked in daily neuroimaging practices.

Aims: This review aims to summarize the imaging features of a number of acquired metabolic and toxic encephalopathies.

Discussion: These conditions are not diagnosed easily. Imaging is very important in terms of diagnosis, assessment of treatment response and prediction of prognosis. Therefore, it is important for radiologists to know the imaging features of relatively frequent acquired metabolic and toxic encephalopathies.

Conclusion: Integration of clinical information with the MRI findings can help physicians in diagnosis and treatment of the underlying disease.

Genetics and Therapies for GM2 Gangliosidosis

Tay-Sachs disease, caused by impaired β-N-acetylhexosaminidase activity, was the first GM2 gangliosidosis to be studied and one of the most severe and earliest lysosomal diseases to be described. The condition, associated with the pathological build-up of GM2 ganglioside, has acquired almost iconic status and serves as a paradigm in the study of lysosomal storage diseases. Inherited as a classical autosomal recessive disorder, this global disease of the nervous system induces developmental arrest with regression of attained milestones; neurodegeneration progresses rapidly to cause premature death in young children. There is no effective treatment beyond palliative care, and while the genetic basis of GM2 gangliosidosis is well established, the molecular and cellular events, from diseasecausing mutations and glycosphingolipid storage to disease manifestations, remain to be fully delineated. Several therapeutic approaches have been attempted in patients, including enzymatic augmentation, bone marrow transplantation, enzyme enhancement, and substrate reduction therapy. Hitherto, none of these stratagems has materially altered the course of the disease. Authentic animal models of GM2 gangliodidosis have facilitated in-depth evaluation of innovative applications such as gene transfer, which in contrast to other interventions, shows great promise. This review outlines current knowledge pertaining the pathobiology as well as potential innovative treatments for the GM2 gangliosidoses.

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.

Leber's Hereditary Optic Neuropathy: Novel Views and Persisting Challenges

Background & Objective: Leber's hereditary optic neuropathy is an inherited form of optic neuropathy, genetically and pathophysiologically based on mitochondrial insufficiency causing bilateral loss of central vision mostly amongst young adults. Despite being one of the most common mitochondrial diseases, the explanation for its pathophysiological background and effective clinical solutions remain elusive. Widening the scope in the search for pathological findings beyond the optic system has yielded several non-ophthalmologic findings, which might imply that Leber's hereditary optic neuropathy is in fact a multi-systemic disease.

Conclusion: The aim of this review is to provide an overview of literature regarding the epidemiology, etiology, pathogenesis, clinical features, diagnostics and possible treatment options and drug targets, as well as presenting challenges related to the disease and proposing a diagnostic algorithm based on current clinical experience.

Pernicious Anemia: Fundamental and Practical Aspects in Diagnosis

Background: Pernicious Anemia (PA), the most common cause of cobalamin deficiency anemia worldwide, is an autoimmune disease of multifactorial etiologies involving complex environmental and immunological factors. Although it was first reported by Addison in 1849 with subsequent advances in understanding of pathogenesis and molecular biology, diagnosis of PA is still challenging for clinicians because of its complexity and diverse clinical presentations.

Conclusion: Herein, we provide an overview of PA, mainly focusing on its scientific and practical aspects in diagnosis. We also discuss the limitations of currently available diagnostic tools for the evaluation of cobalamin deficiency and PA.

Genetic Modifications of Icosahedral Plant Virus-based Nanoparticles for Vaccine and Immunotherapy Applications

Vaccine development is one of the greatest achievements of modern medicine. Vaccines made of live-attenuated pathogens can revert to virulent live strains, which causes safety concerns. On the other hand, the use of purified antigenic components as subunit vaccines is safer, but less effective, as these components induce lower levels of protective immunity. Multiple copy presentation of an antigenic determinant in a well-ordered and well-defined orientation on a nanosized particle can mimic the natural host-pathogen surface interaction to provide antigen stability and immunogenicity similar to that of conventional vaccines with improved safety. The icosahedral symmetry of plant viral capsid based nanoparticles is highly ordered and their multivalent structured protein nanostructures facilitate genetic modifications that result in the display of heterologous epitopes or antigens attached to coat proteins. These recombinant plant virus-based nanoparticles (PVNs) provide platforms for the induction of humoral and cellular immune responses to genetically fused antigens from pathogenic viruses, bacteria, tumors, and toxins in man and animals. Here, we comprehensively review the developments of several recombinant PVNs as prophylactic and/or therapeutic vaccines for the prevention or treatment of several microbial diseases, pathologies, and toxin poisoning.

Impact of Cytokines and Chemokines on Alzheimer’s Disease Neuropathological Hallmarks

Background: Alzheimer’s disease (AD) is the most common neurodegenerative disorder, neuropathologically characterized by aggregates of β-amyloid peptides, which deposit as senile plaques, and of TAU protein, which forms neurofibrillary tangles. It is now widely accepted that neuroinflammation is implicated in AD pathogenesis.

Method: Indeed, inflammatory mediators, such as cytokines and chemokines (chemotactic cytokines) can impact on the Alzheimer´s amyloid precursor protein by affecting its expression levels and amyloidogenic processing and/or β -amyloid aggregation. Additionally, cytokines and chemokines can influence kinases’ activities, leading to abnormal TAU phosphorylation. To date there is no cure for AD, but several therapeutic strategies have been directed to prevent neuroinflammation. Anti-inflammatory, but also anti-amyloidogenic compounds, such as flavonoids were shown to favourably modulate some pathological events associated with neurodegeneration.

Conclusion: This review focuses on the role of cytokines and chemokines in AD-associated pathologies, and summarizes the potential anti-inflammatory therapeutic approaches aimed at preventing or slowing down disease progression.

Molecular Targets of Tannic Acid in Alzheimer's Disease

Tannic acid (TA) is a naturally occurring plant-derived polyphenol found in several herbaceous and woody plants, including legumes, sorghum, beans, bananas, persimmons, rasberries, wines and a broad selection of teas. Clinically, TA has strong antioxidant/free radical scavenging, antiinflammatory, anti-viral/bacterial, and anti-carcinogenic properties. While the aetiology of Alzheimer’s disease (AD) remains unclear, this complex multifactorial neurodegenerative disorder remains the most common form of dementia, and is a growing public health concern worldwide. The neuroprotective effects of TA against AD have been shown in several in vitro and in vivo models of AD. Apart from its potent antioxidant and anti-inflammatory roles, evidence suggests that TA is also a natural inhibitor of β-secretase (BACE1) activity and protein expression. BACE1 is the primary enzyme responsible for the production and deposition of Aβ peptide. TA also destabilises neurotoxic amyloid beta (Aβ) fibrils in vitro. Apart from its effects on the Aβ cascade, TA can also inhibit the in vitro aggregation of tau peptide, a core component of intracellular neurofibrillary tangles (NFTs). This review summarizes the relevance of TA and TA-related vegetable extracts (tannins) in the pathogenesis of AD and its enzymatic targets. It also highlights the significance of TA as an important lead compound against AD.

Patents on Therapeutic and Cosmetic Applications of Bioactives of Crocus Sativus L. and their Production through Synthetic Biology Methods: A Review

Background: Saffron (Crocus sativus L.) has a long history of use as a food additive and a traditional medicine for treating a number of disorders. Prominent bioactives of saffron are crocin, crocetin and safranal.

Objective: The aim of this study was to carry out an extensive patent search to collect information on saffron bioactives and their derivatives as therapeutic and cosmeceutical agents. All patents related to the area of interest published globally till date have been reviewed. Moreover, a recent synthetic biology approach to cost effective and consistent production of saffron bioactives has been highlighted.

Methods: A patent search strategy was designed based on keywords and concepts related to Crocus sativus L. and its bioactives- safranal, crocin and crocetin in combination with different patent classification codes relevant to the technology areas. This search strategy was employed to retrieve patents from various patent databases. The patents which focused on therapeutic or cosmetic applications and claimed compositions comprising crocin, crocetin or safranal as the main active component were selected and analysed.

Results: Maximum patenting activity was noticed towards the use of these bioactives in the treatment of neurological disorders followed by multiple uses of the same compound, use in treatment of metabolic disorders and use as cosmeceuticals. Interestingly, there were no patent records related to use of these bioactives in treating infectious disorders.

Conclusion: Our patent analysis points out the populous and less explored uses of saffron bioactives and areas where there is further scope for research and growth. Recently developed synthetic biology approach is contributory in improving availability, consistency and cost effectiveness of saffron bioactives.

Mevalonate Cascade and Small Rho GTPase in Spinal Cord Injury

The mevalonate pathway has been extensively studied for its involvement in cholesterol synthesis. Inhibition of this pathway using statins (3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors; HMGR inhibitors) is the primarily selected method due to its cholesterol-lowering effect, making statins the most commonly used (86-94%) cholesterol-lowering drugs in adults. This pathway has several other by-products that are affected by statins including GTPase molecules (guanine triphosphate-binding kinases), such as Rho/Rho-associated coiled kinase (ROCK) kinases, that are implicated in other diseases, including those of the central nervous system (CNS). These molecules control several aspects of neural cell life including axonal growth, cellular migration, and cell death, and therefore, are of increasing interest in the field of spinal cord injury (SCI).

Limited regeneration capacity of nerve fibers in adult CNS has been considered the main obstacle for finding a SCI cure. Over the past two decades, the identity of inhibitory factors for regeneration has been widely investigated. It is well-established that the Rho/ROCK kinase system is specifically activated by the components of damaged spinal cord tissue, including oligodendrocytes and myelin, as well as extracellular matrix. This has led many groups to hypothesize that statin therapy may in fact enhance the current neurorestorative approaches. In this mini-review, a summary of SCI pathophysiology is discussed and the current literature targeting the regeneration obstacles in SCI are reviewed, with special attention to recent publications of the past decade. In addition, we focus on the current literature involving the use of pharmacological and molecular inhibitors of small GTPase molecules for treatment of neurotrauma. Inhibiting these molecules has been shown to increase neuroprotection, enhance axonal regeneration, and facilitate the implementation of cell replacement therapies. Based upon available literature, the need for clinical trials involving targeted inhibition of GTPase molecules remains strong. Some of these drugs are widely used for other diseases, and therefore re-purposing their application for neurotrauma can be fasttracked. These approaches can potentially modify the inhibitory environment of nervous tissue to allow the spontaneous repair capacity of injured tissue.

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.

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.

The Neuroprotective Role of Repetitive Transcranial Magnetic Stimulation (rTMS) for Neurodegenerative Diseases: A Short Review on Experimental Studies

There are rapidly replicating human data suggesting the therapeutic and neurorestorative role of transcranial magnetic stimulation in various neurological and psychiatric disorders. However there are only limited experimental studies in the literature enlighting the neurobiological mechanisms of this technique. In the light of these findings, we aimed to review the neuroprotective effect of rTMS in various animal studies. We have shown that rTMS may exert significant neuroprotective effect through acting on the neuroinflammation, excitotoxicity, oxidative stress and Aß aggregation.

May Patients with Alcohol Liver Disease Benefit from Herbal Medicines?

Alcoholism is currently listed as the third leading cause of death. Chronic alcohol consumption brings serious medical complications like gastrointestinal, cardiovascular, musculoskeletal, respiratory system disorders. Liver can be seriously damage by alcohol misuse. Alcoholic Liver Disease (ALD) is the first important warning sign of alcohol abuse. Since effective therapies for ALD are still limited, natural products in the treatment of ALD become very important. In this regard, there have been done very few clinical trials with poor results. Silymarin, glycyrrhizin, garlic show some promising results in ALD patients while the in vivo and in vitro studies with green tee, quercetin and curcumin indicate positive effect on patients with ALD.

New Insights on the Mode of Action of Microcystins in Animal Cells - A Review

Microcystins (MCs) are the most commonly occurring hepatotoxins produced by cyanobacteria. The inhibition of PP2A is widely assumed as the principal mechanism of toxicity of MCs, however recently it has been found that MC modulates PP2A activity not only by direct inhibition of its activity, but also by regulating its expression. Nevertheless the mechanisms of toxicity of MCs seem to be more complex to interpret than expected. The induction of some cellularmolecular mechanisms appears to be biphasic in time and concentration of MC and in most cases related with the intracellular ROS generation. These intracellular ROS levels cause oxidative stress which leads to changes in several markers of MC-LR-induced oxidative stress ultimately resulting in apoptosis or cell damage and also genotoxicity. MCs can also induce severe changes in the cytoskeleton elements: microfilaments, intermediate filaments and microtubules, which results in changes in the cytoskeleton architecture and cell viability. There are also indications that there are second messengers involved in MC-LR mediated cytotoxicity and apoptosis. Different congeners of these toxins induce different degrees of responses in the cell, assumed to be related with the capacity of toxin internalization, affinity towards PP1 and PP2A, and the ability to cause oxidative stress. MCs have also been implicated in neurotoxicity and in damages in reproductive organs. The regulation of transcription factors and proto-oncogenes by MC is the mode of action of MCs tumor promotion. This review summarizes mainly the findings from the last five years about the molecular mechanisms behind MC toxicity in animal cells.

Chronic Exposure to Low-Level Cadmium in Diabetes: Role of Oxidative Stress and Comparison with Polychlorinated Biphenyls

Among the most important physiological functions, maintenance of the oxidation reduction equilibrium in cells stands out as a major homeostatic event. Many environmental contaminants efficiently trap cellular reducing compounds, but the actual importance of this mode of toxicity is far from being precisely known. This statement applies to cases of slowly developing chronic diseases, such as neurodegenerations, diabetes, and many others. The involvement of oxidative challenge in diabetes is considered in connection with chronic dietary exposure to low-level concentrations of cadmium. Comparison is made with polychlorobiphenyl molecules (PCB): they are structurally unrelated to cadmium, they preferentially distribute into different organs than cadmium, and they follow different metabolic pathways. Yet, they have also pro-oxidative properties, and they are associated with diabetes. Since neither cadmium nor PCB is a direct oxidant, they both follow indirect pathways to shift the redox equilibrium. Thus, a difference must be made between the adaptable response of the organism, i.e. the anti-oxidant response, and the irreversible damage generated by oxidizing species, i.e. oxidative damage, when exposure occurs at low concentrations. The approximate border between high and low levels of exposure is estimated in this review from the available relevant data, and the strengths and weaknesses of experimental models are delineated. Eventually, chronic low level exposure to these contaminants sparks cellular responses setting ground for dysfunction and disease, such as diabetes: oxidative damage is an accompanying phenomenon and not necessarily an early mechanism of toxicity.

Therapeutic Approaches Targeting Pathological Tau Aggregates

Neurodegenerative diseases characterized by the accumulation of tau aggregates are increasing in prevalence to epidemic-like levels and there is currently no effective treatment. For many years, the focus of tau-based research was on the fibrillar, neurofibrillary tangles. However, the compilation of evidence obtained from numerous laboratories in the past few years suggests that soluble intermediate aggregates—tau oligomers—are actually the most toxic protein species in disease. Thus, therapeutic agents that target oligomeric tau specifically may be the most effective routes for treatment. A great deal of progress has been made in the pre-clinical evaluation of a number of different anti-tau therapeutics. Upstream modulators of tau modifications have been evaluated and may provide some benefits, but likely will not be capable of eliminating toxic tau entirely. Protein chaperones capable of modulating the structure of tau and targeting it for degradation are another field of study, however, the broad effects of chaperones make side effects a concern. Thus, more specific agents capable of eliminating the most toxic species in disease are promising. Small molecules designed to inhibit aggregation, as well as immunotherapy with antibodies specific for toxic tau aggregates present the most advancement as potential treatments. The concerted effort across a number of groups to investigate potential mechanisms to inhibit tau toxicity represents great progress in the field and provides hope that effective treatments will be discovered.

Biomaterial and Stem Cell Interactions: Histological Biocompatibility

Advancements in biomaterials and stem cell technology have lead current medical technology to tissue engineering and regenerative medicine. Human engineered cartilage, bone, fascia, tendon, nerve and skin tissues have been used for the treatment of tissue injuries and degenerative diseases in combination with embryonic, fetal or adult stem and progenitor cells. Mesenchymal stem cells are one of the most extensively studied adult stem cell population and are widely utilized in cell therapies. Regeneration and 3-dimensional reconstruction of specialized connective tissues by combining differently originated micro and nanoscaled, natural or synthetic scaffolds with stem or progenitor cells are highly expected to guarantee patients to maintain acceptable life quality. In this review we discuss the important issues in biomaterial and stem cell interactions based on histological biocompatibility, updating recent basic research in this field and addressing possible future perspectives.

Identifying S100B as a Biomarker and a Therapeutic Target For Brain Injury and Multiple Diseases

The calcium binding protein S100B has attracted great attention as a biomarker for a variety of diseases. S100B is mainly expressed in glial cells and functions through intracellular and extracellular signaling pathways. The biological roles of S100B have been closely associated with its concentrations and its physiological states. The released S100B can bind to the receptor of advanced glycation end products and induce the initiation of multiple cell signaling transductions. The regulation of S100B bioactivities has been suggested through phosphoinositide 3 kinase/Akt, p53, mitogen-activated protein kinases, transcriptional factors including nuclear factor-kappaB, and cyclic adenosine monophosphate. The levels of S100B in the blood may function to predict the progress or the prognosis of many kinds of diseases, such as cerebrovascular diseases, neurodegenerative diseases, motor neuron diseases, traumatic brain injury, schizophrenia, depression, diabetes mellitus, myocardial infarction, cancer, and infectious diseases. Given that the activity of S100B has been implicated in the pathological process of these diseases, S100B should not be simply regarded as a biomarker, it may also function as therapeutic target for these diseases. Further elucidation of the roles of S100B may formulate innovative therapeutic strategies for multiple diseases.

Commentary: Neurorestoratology: A Concept and Emerging Discipline in the Treatment of Neurological Disorders

Role of Nanotechnology for Enzyme Replacement Therapy in Lysosomal Diseases. A Focus on Gaucher’s Disease

Lysosomal storage diseases (LSDs) comprise a group of rare inherited chronic syndromes that cause deficiency of specific native enzymes within the lysosomes. The macromolecular compounds that are usually catabolized by lysosomal enzymes are accumulated within these organelles, causing progressive damage to tissues, skeleton and organs and, in several cases, the central nervous system (CNS). The damage caused by substrate accumulation finally results in physical deterioration, functional impairment and potential death. Up to date, the most promising therapy for most LSDs is enzyme-replacement therapy (ERT), which provides patients with the corresponding active enzyme. However, these enzymes do not have enough stability in blood, the treatment must be therefore periodically administrated by i.v. infusion under medical supervision, and immunogenicity issues are frequent. In addition, affected areas within the CNS, where the blood-brain barrier (BBB) is a major obstacle, cannot be reached by the enzymes. Nanotechnology can provide useful carriers to successfully protect and preserve enzymes, and transport them through the BBB towards brain locations. Several strategies based on targeting specific receptors on the BBB have led to nanoparticles that successfully carry sensitive molecules to the brain. Then, the main LSDs are described and a thorough review of nanotechnology strategies for brain delivery studied up to date is presented.

Rabbit Models of Ocular Diseases: New Relevance for Classical Approaches

Over 100 million individuals are affected by irreversible visual impairments and blindness worldwide, while ocular diseases remain a challenging problem despite significant advances in modern ophthalmology. Development of novel drugs and drug delivery mechanisms, as well as advanced ophthalmological techniques requires experimental models including animals, capable of developing ocular diseases with similar etiology and pathology, suitable for future trials of new therapeutic approaches. Although experimental ophthalmology and visual research are traditionally performed on rodent models, these animals are often unsuitable for pre-clinical drug efficacy and safety studies, as well as for testing novel drug delivery approaches, e.g. controlled release of pharmaceuticals using intra-ocular implants. Therefore, rabbit models of ocular diseases are particularly useful in this context, since rabbits can be easily handled, while sharing more common anatomical and biochemical features with humans compared to rodents, including longer life span and larger eye size. This review provides a brief description of clinical, morphological and mechanistic aspects of the most common ocular diseases (dry eye syndrome, glaucoma, age-related macular degeneration, light-induced retinopathies, cataract and uveitis) and summarizes the diversity of current strategies for their experimental modeling in rabbits. Several applications of some of these models in ocular pharmacology and eye care strategies are also discussed.

Non Pharmacological Strategies to Promote Spinal Cord Regeneration: A View on Some Individual or Combined Approaches

Spinal cord injury (SCI) is a complex condition that can result in functional impairment and paralysis, and occurs more frequently in young men. Several studies tested diverse treatments; however none achieved effective neuronal regeneration or improvement in neural function. Current research is being performed in areas such as cellular therapy (Schwann cells, embryonic stem cells, pluripotent stem cells, mesenchymal stem cells and olfactory cells), growth factors (BDNF), inhibitory molecules, fibroglial scar, gene therapies, etc. Some strategies have provided encouraging results by themselves, others have been tested as a combination, showing an improved outcome after SCI. Combined strategies could be more effective than individual therapies; for instance, cotransplantation of cells at the injury site to maximize their effect has been used, and it has demonstrated a greater efficacy in comparison to grafts of stem cells or of a particular cell type. The combination of neurotrophic factors such as BDNF and NT- 3 enhances axonal regeneration and myelination; other therapies include the use of biological matrices in combination with inhibitors of glial scar formation. Chondroitinase ABC (ChABC) has shown synergistic effects with other strategies, specifically to improve regeneration and functional recovery after SCI. Experimental evidence suggests that it is possible to obtain better results with a combination of strategies, which justifies further research for therapeutic approaches. This review intends to compile the most relevant information about available up-to-date therapeutic strategies that are administered alone or in combination with others, and have offered the best results in neural regeneration after spinal cord injury.

Experimental and Clinical Advances in Immunotherapy Strategies for Spinal Cord Injury Target on MAIs and Their Receptors

In the injured adult mammalian central nervous system (CNS), the failure of axonal regeneration is thought to be attributed, at least in part, to various myelin-associated inhibitors (MAIs), such as Nogo, myelinassociated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp) around the damaged site. Interestingly, these three structurally different inhibitors share two common receptors, Nogo-66 receptor (NgR) and paired immunoglobulin-like receptor B (PirB), and transduce the inhibitory signal into neurons via their complex combinant and co-receptors, such as p75 neurotrophin receptor (p75NTR), Nogo receptor-interacting protein 1 (LINGO-1), and TROY. Accordingly, targeting of the whole myelin or just portions by immunization has been proved to be neuroprotective and is able to promote regeneration in the injured spinal cords. In the past few years, vaccine approaches were initially achieved and could induce the production of antibodies against inhibitors in myelin to block the inhibitory effects and promote functional recovery in spinal cord injury (SCI) models by immunizing with MAIs, such as purified myelin, spinal cord homogenates, or their receptors with the concept of protective autoimmunity formulated. However, for safety consideration, further work is necessary before the immunotherapy strategies can be adopted to treat human injured spinal cords.

Histone Deacetylase (HDAC) Inhibitors - emerging roles in neuronal memory, learning, synaptic plasticity and neural regeneration

Epigenetic regulation of neuronal signalling through histone acetylation dictates transcription programs that govern neuronal memory, plasticity and learning paradigms. Histone Acetyl Transferases (HATs) and Histone Deacetylases (HDACs) are antagonistic enzymes that regulate gene expression through acetylation and deacetylation of histone proteins around which DNA is wrapped inside a eukaryotic cell nucleus. The epigenetic control of HDACs and the cellular imbalance between HATs and HDACs dictate disease states and have been implicated in muscular dystrophy, loss of memory, neurodegeneration and autistic disorders. Altering gene expression profiles through inhibition of HDACs is now emerging as a powerful technique in therapy. This review presents evolving applications of HDAC inhibitors as potential drugs in neurological research and therapy. Mechanisms that govern their expression profiles in neuronal signalling, plasticity and learning will be covered. Promising and exciting possibilities of HDAC inhibitors in memory formation, fear conditioning, ischemic stroke and neural regeneration have been detailed.

Chemotherapy-Induced Peripheral Neuropathic Pain and Rodent Models

Painful peripheral neuropathies resulting from cancer chemotherapy treatment is frequently dose-dependent and may diminish following dose reduction or termination of chemotherapy. However, dose reduction or treatment termination could lead to reemergence of the cancer. In addition, chemotherapy-induced peripheral neuropathy (CIPN) may persist long after termination of chemotherapy. Thus, there is a need for treatments to ameliorate pain during the course of an effective cancer treatment regimen. Because the mechanism underlying CIPN has yet to be fully characterized, there is a current lack of effective treatments for CIPN. Preclinical studies in CIPN rodent models have suggested a number of potential neuropathological mechanisms, which could serve as platforms for the development of novel therapeutics. Although a number of potential analgesic therapies have demonstrated robust efficacy in preclinical studies, rigorous clinical testing has yet to fully validate the preclinical findings. The lack of congruence between preclinical and clinical findings could be in part due to the phylogenetic distance between the main model species and humans. Thus, a CIPN model in nonhuman primates could serve to bridge the translational gap between laboratory findings in small animals and clinical utility. The current review points out the short comings of current CIPN rodent models and suggests the use of large animals, such as the nonhuman primate, to narrow the translational gap between preclinical and clinical findings and the discovery of novel therapeutics.

Neurogenic plasticity of mesenchymal stem cell, an alluring cellular replacement for traumatic brain injury

Traumatic brain injury (TBI) imposes horrendous neurophysiological alterations leading to most devastating forms of neuro-disability. Which includes impaired cognition, distorted locomotors activity and psychosomatic disability in both youths and adults. Emerging evidence from recent studies has identified mesenchymal stem cells (MSCs) as one of the promising category of stem cells having excellent neuroregenerative capability in TBI victims. Some of the clinical and animal studies reported that MSCs transplantation could cure neuronal damage as well as improve cognitive and locomotors behaviors in TBI. However, mechanism behind their broad spectrum neuroregenerative potential in TBI has not been reviewed yet. Therefore, in the present article, we present a comprehensive data on the important attributes of MSCs, such as neurotransdifferentiation, neuroprotection, axonal repair and plasticity, maintenance of blood-brain integrity, reduction of reactive oxygen species (ROS) and immunomodulation. We have reviewed in detail the crucial neurogenic capabilities of MSCs in vivo and provided consolidated knowledge regarding their cellular remodeling in TBI for future therapeutic implications.

Oxidative stress and Parkinson’s disease: New hopes in treatment with herbal antioxidants

Parkinson's disease (PD) is a neurodegenerative disorder due to dopamine deficit in substatia nigra. PD is mainly a sporadic disease with unestablished etiology. However, exposure to environmental toxins, head trauma, inflammation, and free radicals are potential reasons. Recently, the role of oxidative stress in neurological abnormalities, including PD, has been particularly addressed. Antioxidant remedies, particularly herbal antioxidants, have revealed new perspectives of research and therapy as possible preventive and therapeutic approaches for PD. In this paper, we reviewed the recently published papers on the effects of herbal medicines on PD alongside the pathogenesis of PD with regard to oxidative stress.

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.

Adipose Tissue and Bone Marrow as Sources for Cell-based Therapeutic Angiogenesis in Ischemic Tissues: Biological Foundation and Clinical Prospects for Age-related Vascular Disease

It is well established that aging is a significant risk factor for homeostatic imbalance, decline in vascular regenerative capacity and development of vascular disease with progressive organ dysfunction. Over the past decade therapeutic developments have improved the prognosis for those with vascular disease, mortality rates have nevertheless remained actually unchanged. Clearly, there is a need for alternative strategies for the treatment of vascular disease. Adipose tissue and bone marrow have been shown to contain adult mesenchymal stem cells that have therapeutic applications in regenerative medicine. In vivo experiments suggest that these cells are capable of replacing ischemic damaged tissues. The potential use of cell-based therapeutic angiogenesis has been proposed as an alternative treatment solutions for age-related vascular disease. This review outlines the current knowledge about adipose tissue and bone marrow as a sources of stem and progenitor cells, these cells contribution to ischemic damaged tissues regenerative processes and factors that may affect their decreased function in aging individuals. Moreover, it was described the cell-based therapeutic strategies that are currently being tested in clinical trials as well as clinical outcomes demonstrated after cell transplantation and emphasize possible mechanisms counteracting pathophysiological events of ischemia.

The Management and Outcomes of Pharmacological Treatments for Tinnitus

Tinnitus, a phantom sensation experienced by people around the world, currently is endured without a known cure. Some find the condition tolerable, while others are tortured on a daily basis from the incessant phantom noises. For those who seek treatment, oftentimes, they have a comorbid condition (e.g., depression, anxiety, insomnia), which is treated pharmaceutically. These products aim to reduce the comorbities associated with tinnitus thereby minimizing the overall burden present. Because of the phantom nature of tinnitus, it is often compared to neurologic pain. Since pain can be managed with pharmaceutical options, it is reasonable to assume that similar agents might work to alleviate tinnitus. The effects of antidepressants, benzodiazepines, anticonvulsants, and glutamate antagonists are reviewed in this paper. Table 1 summarizes the pharmaceutical products discussed. Due to the variety of comorbid factors and potential causes of tinnitus, there may not be one pharmaceutical treatment that will combat every type of tinnitus. Nevertheless, a product that finally addresses the true cause of tinnitus, and not just its comorbidities, will benefit millions of people worldwide.

Drugs and Rhabdomyolysis: From Liver to Kidney

Rhabdomyolysis is a syndrome due to a damage of skeletal muscle and the leakage of intracellular contents into the extracellular fluid and the circulation. Several causes may induce rhabdomyolysis and the major one is the crush syndrome. Most cases of non-traumatic rhabdomyolysis are related to drugs. Many molecules are subject to hepatic metabolism and the concomitant use of drugs, as statins, with other medications acting as substrates of the same isoenzymes can interact and increase the risk of myopathy.

Subclinical rise of creatine kinase may be the expression of rhabdomyolysis that can present as a medical emergency such as acute kidney injury (AKI), compartment syndrome, cardiac dysrhythmias and disseminated intravascular coagulopathy.

The main pathophysiological mechanisms of myoglobinuric-related AKI are renal vasoconstriction, formation of intraluminal casts and direct cytotoxicity promoted by heme-protein.

The aim of this review is to analyze the pathophysiology of myolysis, the causes of rhabdomyolysis and especially the link between the liver and the kidney, which can represent the connecting element for the development of the syndrome.

Lipases in Medicine: An Overview

Lipases are part of the family of hydrolases that act on carboxylic ester bonds. They are involved in catalyzing the hydrolysis of triglycerides (TG) into chylomicrons and very low density lipoprotein (VLDL) particles. Uses of lipases are evolving rapidly and currently they are reported to show high potential in medicine. Intensive study and investigations have led researchers to explore lipases for their use in substitution therapy, where in enzyme deficiency during diseased conditions is compensated by their external administration. In our body, they are used to break down fats present in food so that they can be absorbed in the intestine and deficiency of lipases leads to malabsorption of fats and fat-soluble vitamins. Lipases help a person who has cystic fibrosis, Alzheimer’s disease, atherosclerosis and act as a candidate target for cancer prevention and therapy. They act as diagnostic tool and their presence or increasing levels can indicate certain infection or disease. Obesity causes metabolic disease and is a serious health problem around the world. Thus inhibiting digestive lipase to reduce fat absorption has become the main pharmacological approach to the treatment of obesity in recent years.

Therapeutic Angiogenesis in Ischemic Tissues by Growth Factors and Bone Marrow Mononuclear Cells Administration: Biological Foundation and Clinical Prospects

The processes of new vessels formation in tissues are supported by two definite mechanisms: de novo development of blood vessels (vasculogenesis) through the accumulation of progenitor cells during early prenatal stage, and extension of a pre-existing microcirculatory network by endothelial cell germination (angiogenesis), the essential mechanism of blood vessel formation in postnatal period. Angiogenesis is associated with a series of inductive, permissive and restrictive communications that result in the appearance, differentiation, and formation of new vessels. The goal of therapeutic angiogenesis is to improve blood circulation, relay survival factors and regenerative stem cell populations to sites of tissue repair, and ultimately recover function and form of the tissue. Growth factors and bone marrow mononuclear cells represent a very interesting research field for the realization of therapeutic angiogenesis in ischemic tissues. They provide a potential key component in the healing processes of ischemic injured tissues.

Disruption of Circadian Rhythms and Sleep in Critical Illness and its Impact on the Development of Delirium

Purpose: This article reviews our current understanding of the relationships between critical illness, circadian disruption, and delirium.

Summary: Delirium is a common and morbid complication of hospitalization, particularly in the setting of critical illness and intensive care unit (ICU) admission. Critical illness involves a host of acute metabolic, hormonal and inflammatory responses that appear to disrupt normal sleep architecture and precipitate cerebral dysfunction. The intervention-heavy environment of the ICU further disrupts normal circadian rhythms and increases delirium risk. Despite strong evidence for correlation of sleep disruption, critical illness and delirium, causal relationships remain difficult to prove. Delirium is almost certainly a multifactorial condition. This article reviews proposed pathophysiologic mechanisms and potential therapeutic targets. In the absence of definitive pharmacologic therapy, interventions prioritizing maintenance of normal circadian, sleep, and behavioral patterns have shown promise in delirium risk reduction.

Is the Modulation of Autophagy the Future in the Treatment of Neurodegenerative Diseases?

The pathogenesis of neurodegenerative diseases involves altered activity of proteolytic systems and accumulation of protein aggregates. Autophagy is an intracellular process in which damaged organelles and long-lived proteins are degraded and recycled for maintaining normal cellular homeostasis. Disruption of autophagic activity in neurons leads to modify the cellular homeostasis, causing deficient elimination of abnormal and toxic protein aggregates that promotes cellular stress and death. Therefore, induction of autophagy has been proposed as a reasonable strategy to help neurons to clear abnormal protein aggregates and survive. This review aims to give an overview of some of the main modulators of autophagy that are currently being studied as possible alternatives in the search of therapies that slow the progression of neurodegenerative diseases, which are incurable to date.

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.

Imaging Neuroinflammation in Ischemic Stroke and in the Atherosclerotic Vascular Disease

Neuroinflammation is a complex biological response to any injury occurring to the central nervous system. It is mainly characterized by the recruitment of immune system cells, namely the microglial cells, in the site of injury. Once activated, microglia expresses a cholesterol transporter protein (TSPO), previously also known as peripheral type benzodiazepine receptor. PK11195 is a ligand for TSPO and, labelled with a positron emitter, it is also the most used tracer for PET molecular imaging to in vivo map the microglia activation in various neurological disorders, including ischemic stroke. Recent [¹¹C]PK11195 PET studies proved activated microglia both locally in the area of the infarct and at distance along the affected fibre tracts, suggesting the presence of two different microglia subtypes with peculiar functions in disease progression. The aim of this review is to discuss the most recent knowledge about imaging neuroinflammation in ischemic stroke and in the atherosclerotic and vascular inflammatory disorders, trying to elucidate the interplay between the clinical course and the activation of a microglial response.

The Intracellular Domain of Amyloid Precursor Protein is a Potential Therapeutic Target in Alzheimer’s Disease

Amyloid-β (Aβ) is widely believed to cause Alzheimer’s disease (AD), as it is the major constituent of the amyloid plaques observed in the brains of people with AD (the so-called amyloid hypothesis). Based on this hypothesis, therapies utilizing immune responses against Aβ have been performed and have succeeded in effectively removing amyloid plaques, but have shown no evidence of improvements in survival and/or cognitive function. Thus, it may be necessary to think about this problem from a different viewpoint. γ-Secretase was initially identified as an enzyme that cleaves amyloid precursor protein (APP) and produces Aβ. Although the primary function of -secretase has not been fully clarified, this enzyme is well known to play a central regulatory role in Notch signaling. After the shedding of the Notch ectodomain by metalloproteases, γ-secretase releases the intracellular domain (ICD) of Notch, which immediately translocates to the nucleus to modify the expression of certain genes. Recently, many type 1 transmembrane proteins have also been reported as substrates for γ-secretase. Interestingly, several of these substrates may share a γ-secretase-regulated signaling mechanism similar to that of Notch. Indeed, we have demonstrated that the ICD of APP (AICD) induces dynamic changes in gene expression and neuron-specific apoptosis, suggesting that APP also has a signaling mechanism that is closely linked with AD. In this review, we first summarize the evidence that γ-secretase–regulated mechanisms similar to Notch signaling may play wide-ranging roles in signaling events involving type 1 transmembrane proteins, including APP. We also focus on the possibility that APP signaling is involved in the onset and progression of AD. Based on these ideas, we hypothesize that APP signaling, especially AICD, may be an attractive therapeutic target in AD.

Insights into the Role of Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases in Health and Disease

Matrix metalloproteinases (MMPs) are family zinc containing calcium dependent enzymes. They can degrade the different components of extracellular matrixin normal as well as in abnormal condition. MMPs have been found in vertebrates, invertebrates and plants. The synthesis, translocation and function of MMPs are mostly associated with different signaling cascades. The functions of MMPs are intricately regulated by its specific endogenous regulators or the inhibitors known as tissue inhibitor of metalloproteinases (TIMPs) in the time of activation and in inhibition. MMPs and TIMPs are involved in the regulation of cell characteristics in normal as well as the state of human morbidity and mortality. There are numerous roles of MMPsin normal physiological processes and that are good. Again, the ugly is the abnormal activity or overexpression of MMPs that has the distinct role in many disease processes. Presently, broad-spectrum synthetic as well as natural MMP inhibitors have been developed or isolated for the treatment of manyfatal diseases and also sometime for managing the critical complications there in. Therefore, the diverse role of all the MMPs and TIMPs cannot be explained precisely in a particular review because of their multidirectional and multifunctional behavior in mammals. This review is a very small effort to delineate some of the progresses not all in a precise manner with an elaborative description of MMPs towards their multifaceted functions in the light of human physiology and pathology concerned.

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.

Cocaine Dependence and Stroke: Pathogenesis and Management

Cocaine abuse remains a devastating medical problem for our society. Current concepts suggest that both hemorrhagic and ischemic stroke, particularly in young people, can result as a consequence of cocaine exposure. We provide an analysis of mechanisms of injury and a discussion of the pharmacological management of stroke following cocaine use. Preclinical research suggests that the cause of cocaine-mediated stroke is multifactorial and involves vasospasm, changes in cerebral vasculature, and platelet aggregation. We suggest that drugs able to induce vasospastic, thrombogenic, or neurotoxic effects of cocaine could be suitable as therapeutic agents. In contrast caution should be exerted when using anti-platelet and thrombolytic agents in cocaine users with stroke.

Neonatal Brain Hemorrhage (NBH) of Prematurity: Translational Mechanisms of the Vascular-Neural Network

Neonatal brain hemorrhage (NBH) of prematurity is an unfortunate consequence of preterm birth. Complications result in shunt dependence and long-term structural changes such as posthemorrhagic hydrocephalus, periventricular leukomalacia, gliosis, and neurological dysfunction. Several animal models are available to study this condition, and many basic mechanisms, etiological factors, and outcome consequences, are becoming understood. NBH is an important clinical condition, of which treatment may potentially circumvent shunt complication, and improve functional recovery (cerebral palsy, and cognitive impairments). This review highlights key pathophysiological findings of the neonatal vascular-neural network in the context of molecular mechanisms targeting the posthemorrhagic hydrocephalus affecting this vulnerable infant population.

Metformin: Repurposing Opportunities for Cognitive and Mood Dysfunction

Background: Cognitive deficits differentially affect individuals with type 2 diabetes mellitus (T2DM) and mood disorders. Accumulating evidence implicates disturbances in metabolism as salient to cognitive function. Thus, the mitigation of metabolic disturbances may preserve or ameliorate cognitive function. This review aims to evaluate available evidence investigating the effects of metformin on cognitive function as well as summarize putative mechanistic properties related to these clinical effects.

Methods: A PubMed search was conducted using the search words including, but not limited to: metformin, Major Depressive Disorder, type 2 diabetes mellitus, and cognitive dysfunction. All English language articles published from 1990 to July 2014 were reviewed.

Results: Extant preclinical and clinical data have been mixed, wherein both cognitive disruption and pro-cognitive effects have been reported with the administration of metformin. Sound mechanistic evidence supports metformin as a treatment; however, the heterogeneity of study designs has contributed to an inability to arrive at an unequivocal conclusion regarding metformin effects upon cognition.

Conclusion: Available evidence does not provide a robust signal for improvement in cognition in either mood disorder or T2DM samples. Notwithstanding, it is premature to label metformin as a “no-go” agent for further testing and development for cognitive dysfunction. A well designed, proof-of-concept trial of metformin investigating its possible cognitive effects in mood disorders is therefore warranted.

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.

Isomers of 4-[¹⁸F]fluoro-proline: Radiosynthesis, Biological Evaluation and Results in Humans Using PET

Proline and hydroxyproline represent major constituents of mammalian structural proteins, especially of collagen. An efficient radiosynthesis of the ¹⁸F-labeled proline derivatives cis-/trans-4-[¹⁸F]fluoro-L-proline was developed two decades ago with the aim to investigate various diseases with altered collagen synthesis using Positron-Emission- Tomography (PET). A number of studies have explored cis-4-[¹⁸F]fluoro-L-proline uptake in various pathologies associated with increased collagen formation and in neoplastic lesions, but so far the results have not been very promising. Trans-4-[¹⁸F]fluoro-L-proline has not yet been investigated in detail, however the compound exhibits considerable differences in metabolic behavior and biodistribution compared with its cis-enantiomer. In recent years, the D-isomers of cis- /trans-4-[¹⁸F]fluoro-proline have been considered as PET tracers as well, and it was observed that both exhibit a preferred uptake into the brain compared with their L-isomers. Surprisingly, a high uptake of cis-4-[¹⁸F]fluoro-D-proline was found in brain areas exhibiting secondary neurodegeneration as well as in areas of radionecrosis after treatment of brain tumors. In this article, the present knowledge on the biological and physiological properties of cis-/trans-4-[¹⁸F]fluoro-D/L-proline and the results in various pathologies are reviewed, including some previously unpublished results from our laboratory.

Phosphodiesterases as Therapeutic Targets for Huntington’s Disease

Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and emotional and psychiatric disturbances. The genetic mutation is characterized by a CAG expansion, resulting in the formation of a mutant huntingtin protein with an expanded polyglutamine repeat region. Mutated huntingtin has been shown to impair a number of physiological activities by interacting with several factors. In particular, cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) are severely affected by mutant huntingtin. In this view, drugs targeted at counteracting CREB loss of function and BDNF decrease have been considered as powerful tools to treat HD. Recently, cyclic nucleotide phosphodiesterase (PDE) inhibitors have been used successfully to increase levels of CREB and BDNF in HD models. Indeed, PDE4, 5 or 10 inhibitors have been shown to afford neuroprotection and modulation of CREB and BDNF.

In this review, we will summarize the data supporting the use of PDE inhibitors as the therapeutical approach to fight HD and we will discuss the possible mechanisms of action underlying these effects.

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.

Chondroitin Sulfate Glycosaminoglycans for CNS Homeostasis-Implications for Material Design

Chondroitin sulfate proteoglycans (CSPGs) are complex biomolecules that are known to facilitate patterning of axonal direction and cell migration during the early growth and development phase of the mammalian central nervous system (CNS). In adults, they continue to control neuronal plasticity as major constituents of the “peri-neuronal nets” (PNNs) that surround adult CNS neurons. CSPGs are also barrier-forming molecules that are selectively upregulated by invading reactive astroglia after injury to the CNS, and are responsible for the active repulsion of regenerating neurons post-injury. Recent evidence however suggests that the diverse sulfated glycosaminoglycan (GAG) side chains attached to CSPGs are key components that play paradoxical roles in influencing nerve regeneration post-injury to the CNS. Sulfated GAG repeats attached to the CSPG core protein help mediate cell migration, neuritogenesis, axonal pathfinding, and axonal repulsion by directly trapping and presenting a whole host of growth factors to cells locally, or by binding to specific membrane bound proteins on the cell surface to influence cellular function. In this review, we will present the current gamut of interventional strategies used to bridge CNS deficits, and discuss the potential advantages of using sulfated GAG based biomaterials to facilitate the repair and regeneration of the injured CNS.

Mitochondrial Disorders in Adults

Mitochondrial Disorders (MD) include a heterogeneous group of inherited disorders due to molecular defects mainly affecting the mitochondrial oxidative phosphorylation system. Because the respiratory chain is under control of two different genomes (nuclear DNA-nDNA and mitochondrial DNA-mtDNA), mitochondrial genetics is quite complex and may justify the extreme clinical heterogeneity of these diseases. Clinically, MD usually involve multiple tissues, mainly affecting organs with high energy request as central nervous system and skeletal muscle. They may present at any age, with different onsets, clinical presentation and progression from an isolated involvement of vision or hearing to a multisystemic degenerative disorders with stroke-like episodes, peripheral neuropathy, ophthalmoparesis, seizures, cardiopathy, hepatopathy, endocrinopathies, etc. Over the last 50 years, it became evident that MD represent an important part of the general medicine. The complexity of clinical and genetic spectrum of those disorders is still increasing. The aim of this review is to walk through mitochondrial genetics, highlighting novel clinical entities.

Genetic Basis of Mitochondrial Optic Neuropathies

Over two decades have elapsed since the first mtDNA point mutation was associated with Leber’s hereditary optic neuropathy (LHON) in 1988. We have subsequently witnessed a substantial understanding of the molecular basis of hereditary optic neuropathies, as well as of their clinical features and pathogenic mechanisms. It became clear that the large majority of genetic optic neuropathies have a primary or an indirect involvement of mitochondrial functions, justifying the definition of “mitochondrial optic neuropathies”. Despite this progress many unsolved features remain to be understood, such as incomplete penetrance and variable clinical expressivity in LHON and dominant optic atrophy (DOA), gender prevalence in LHON, and complex gene/environment interactions in both LHON and DOA. The most recent advancement in our understanding of the molecular basis of mitochondrial optic neuropathies is the topic of this review. In particular, we analyze the role that mitochondrial biogenesis may play in the compensatory mechanisms that underlie incomplete penetrance and clinical expressivity, a scenario relevant for the possible design of future therapeutic approaches.

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.

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.

Amantadine, Apomorphine and Zolpidem in the Treatment of Disorders of Consciousness

Survivors of severe brain injuries may end up in a state of ‘wakeful unresponsiveness’ or in a minimally conscious state. Pharmacological treatments of patients with disorders of consciousness aim to improve arousal levels and recovery of consciousness. We here provide a systematic overview of the therapeutic effects of amantadine, apomorphine and zolpidem in patients recovering from coma. Evidence from clinical trials using these commonly prescribed pharmacological agents suggests positive changes of the patients’ neurological status, leading sometimes to dramatic improvements. These findings are discussed in the context of current hypotheses of these agents’ therapeutic mechanisms on cerebral function. In order to improve our understanding of the underlying pathophysiological mechanisms of these drugs, we suggest combining sensitive and specific behavioral tools with neuroimaging and electrophysiological measures in large randomized, double-blind, placebo-controlled experimental designs. We conclude that the pharmacokinetics and pharmacodynamics of amantadine, apomorphine and zolpidem need further exploration to determine which treatment would provide a better neurological outcome regarding the patient’s etiology, diagnosis, time since injury and overall condition.

Disorders of Consciousness and Pharmaceuticals that Act on Oxygen Based Amino Acid and Monoamine Neurotransmitter Pathways of the Brain

Oxygen based neurotransmitters in the synapses of the brain are proposed to play an important role in the generation of consciousness. They include the amino acids glutamate and GABA which use Krebs cycle precursors for their synthesis, and the monoamines dopamine, noradrenalin, adrenalin and serotonin, which are derived from tyrosine and tryptophan.

During ischemia after an acute brain injury, a GABA surge often initiates brain suppression. It has been proposed that with chronic ischemia, a secondary, possibly epigenetic response occurs when neurotransmitters deplete, a glucose and oxygen saving mechanism termed neurodormancy that may invoke alternative long term low energy metabolic pathways in the brain, encountered in Disorders of Consciousness.

Some medications can reverse Disorders of Consciousness in some patients. Virtually all of them act on neurotransmitter systems that use oxygen as a building block or as an energy source within the brain. Pharmaceuticals that act in the oxygen based amino acid systems of the brain include the GABAergic medications zolpidem and baclofen, while those that act in the monoamine axes include the dopaminergic medications L Dopa, amantadine, bromocriptine, apomorphine and methylphenidate, and the noradrenergic and serotonergic medications desipramine, amitriptyline, protriptyline and fluoxetine. Another group are the cholinesterase inhibitors, responsible for increasing acetylcholine, which is synthesized from the Krebs cycle initiator, acetyl CoA.

It appears that pharmaceuticals that are active in the oxygen based neurotransmitter pathways of the brain are successful to arouse to consciousness patients that suffer from its disorders. Research needs to be supported as foundation to understand the biochemical mechanisms that are involved in consciousness disorders and to explore further the pharmacological treatment possibilities for these devastating neurological conditions.

Cardiac and Muscular Involvement in Idiopathic Inflammatory Myopathies: Noninvasive Diagnostic Assessment and the Role of Cardiovascular and Skeletal Magnetic Resonance Imaging

Idiopathic inflammatory myopathies (IIMs) are rare autoimmune diseases and include dermatomyositis, polymyositis, necrotizing myopathy and inclusion body myositis; they are characterized by inflammation of skeletal muscle and other internal organs and may potentially lead to irreversible damage and death. Only a small percentage of IIM has clinically overt cardiac disease; however, heart involvement is one of the leading causes of death and therefore, early detection remains a challenge.

Biochemical markers and non-invasive methods such as the electrocardiogram and echocardiography have a role in diagnosis, but lack sensitivity in identifying patients with early, sublinical cardiac abnormalities. Endomyocardial and skeletal muscle biopsies are very useful, but invasive techniques and cannot be used for routine follow-up. Cardiac and skeletal magnetic resonance imaging, due to their capability to perform tissue characterization, has emerged as novel techniques for the early detection and follow-up of myocardial and skeletal muscle tissue changes (oedema, inflammation, fibrosis) in IIM. However, the clinical implications of using these approaches and their cost /benefit ratio require further evaluation.

Phosphorothioate Oligonucleotides: Effectiveness and Toxicity

Background: Many experimental and clinical studies have focused on the antisense strategy. In this context phosphorothioate oligonucleotides are compounds addressed to hybridize to a targeted mRNA inducing a variety of effects including inhibition of the expression of proteins involved in different pathological processes and preventing translation. Methods: In this review, we provide an update on clinical efficacy and toxicological profile of phosphorothioate oligonucleotides used in experimental and clinical studies, also focusing on the use of the antisense strategy in the context of Duchenne muscular dystrophy which is a key pathology to study different aspects of this therapy. Pubmed/Medline was searched using the keyword “Phosphorotioate” combined with “Antisense”, “Oligonucleotide” and “Duchenne muscular dystrophy”. Conclusions: Phosphorothioate oligonucleotide transient activation of the complement cascade represents the most evident toxicological response, as showed by in vivo studies. It is also known that many of these compounds induce a prolongation of activated partial thromboplastin time, a reaction which is often highly transient and proportional to the oligonucleotide plasma concentrations, making that effect clinically insignificant for the current treatment regimens. In summary, current evidence shows limited untoward effects and reversibility of the damage induced, at least for some of those compounds, with promising effectiveness for treatment of various pathologies.

Approaching Neurological Diseases to Reduce Mobility Limitations in Older Persons

The rapidly increasing elderly population poses a major challenge for future health-care systems. Neurological diseases in older persons are particularly common and coexist with other clinical conditions.

This is not surprising given that, for example, even patients with Alzheimer Disease (AD) could have relevant extrapyramidal signs at the moment of the diagnosis with motor signs having more negative prognostic value. Longitudinal studies conducted on Parkinson Disease (PD) showed that, after 20 years, dementia is not only present in almost all survivors but is also the main factor influencing nursing home admission.

Recently, it has been reported the importance of Comprehensive Geriatric Assessment (CGA: comprehensive evaluation of cognition, depressive symptoms, mobility and functional assessment) as a tool reducing morbidity in frail older patients admitted to any acute hospital unit. The CGA should be considered as a technological device, for physicians who take care of older persons affected by overlapping neurological diseases. CGA is an extraordinary and cost effective instrument even in patients with advanced neurological diseases where allows to collect valuable information for an effective plan of management.

Acute Antithrombotic Treatment of Ischemic Stroke

Antithrombotic medication is a cornerstone of acute ischemic stroke treatment and secondary prevention. The efficacy of thrombolysis with alteplase in acute stroke has been demonstrated in several clinical trials. This safe and costeffective therapy has transformed the practice of stroke care and has led to subsequent trials of other antithrombotic medications for treatment of ischemic stroke in the acute phase. These antithrombotics include thrombolytic, antiplatelet and anticoagulant agents. While, no other medication has yet demonstrated adequate efficacy, our current and evolving understanding of infarct expansion, ischemic penumbra, collateral circulation and the blood brain barrier is allowing testing of antithrombotic medications tailored to individual patient pathophysiology in clinical trials. This understanding accompanies developments in neuroimaging and organization of stroke care that allow for wide-spread recruitment in these trials. Alteplase remains the mainstay treatment of arterial acute ischemic stroke; however, anticoagulation is the standard therapy for cerebral venous sinus thrombosis. Antithrombotic use in acute stroke, arterial and venous, has demonstrated efficacy but leaves many questions unanswered. This patient population is a fertile ground for novel research, especially as it relates to; combination antithrombotic therapy, combination of pharmacological and mechanical thrombolysis, and the transition to secondary prevention. Here we review the current antithrombotics in the acute phase of ischemic stroke highlighting the evidence-base and areas of uncertainty.

Mesenchymal Stromal Cell Therapy for Cardio Renal Disorders

Chronic kidney disease carries a very high mortality risk, in particular from cardiac diseases. Often heart failure and renal failure coincide, a phenomenon referred to as the cardio renal syndrome. In recent years, it has become clear that not only fibrotic repair but also restoration of damaged kidney and heart can occur and the use of cell therapy has been advanced as a means to activate endogenous repair mechanisms or even to re-introduce repairing tissue. In this perspective, mesenchymal stromal cells are of particular interest, since these cells have both immune modulating and reparative functions and are on the brink of entering the clinical arena. Indeed, MSCs can trigger numerous therapeutic biologic processes that contribute to both renal and cardiac repair; however exact mechanisms of actions are largely unknown. In the present review we have made a critical appraisal of the data available with respect to origin and function of MSCs, and we discuss both preclinical as well as clinical evidence on their therapeutic potential in kidney and heart disease.

The Role of Renal Nerve Ablation for the Management of Resistant Hypertension and other Disease Conditions: Benefits and Concerns

The sympathetic nervous system is overactivated in resistant hypertension and several other disease conditions. A reciprocal association between the brain and the kidney has been described, in that sympathetic overactivity affects renal function while renal injury stimulates central sympathetic drive. Renal nerve ablation has been recently introduced as a potential alternative for the management of resistant hypertension, mainly due to current limitations in pharmacologic antihypertensive therapy. Data accumulated thus far point towards an efficacious and safe interventional method for the management of treatment resistance, with additional benefits on glucose metabolism and cardiac structure and function. Furthermore, beneficial effects have been observed in patients with chronic kidney disease, obstructive sleep apnea, polycystic ovary syndrome, and sympathetically driven tachyarrhythmias. However, as with every novel technique, several questions need to be answered and concerns need to be addressed before the wide application of this interventional approach.

The Future of Collateral Artery Research

In the event of obstructive coronary artery disease, collateral arteries have been deemed an alternative blood source to preserve myocardial tissue perfusion and function. Monocytes play an important role in modulating this process, by local secretion of growth factors and extracellular matrix degrading enzymes. Extensive efforts have focused on developing compounds for augmenting the growth of collateral vessels (arteriogenesis). Nonetheless, clinical trials investigating the therapeutic potential of these compounds resulted in disappointing outcomes. Previous studies focused on developing compounds that stimulated collateral vessel growth by enhancing monocyte survival and activity. The limited success of these compounds in clinical studies, led to a paradigm shift in arteriogenesis research. Recent studies have shown genetic heterogeneity between CAD patients with sufficient and insufficient collateral vessels. The genetic predispositions in patients with poorly developed collateral vessels include overexpression of arteriogenesis inhibiting signaling pathways. New directions of arteriogenesis research focus on attempting to block such inhibitory pathways to ultimately promote arteriogenesis. Methods to detect collateral vessel growth are also critical in realizing the therapeutic potential of newly developed compounds. Traditional invasive measurements of intracoronary derived collateral flow index remain the gold standard in quantifying functional capacity of collateral vessels. However, advancements made in hybrid diagnostic imaging modalities will also prove to be advantageous in detecting the effects of pro-arteriogenic compounds.

Future Directions in the Treatment of Neuropathic Pain: A Review on Various Therapeutic Targets

Neuropathic pain is caused by structural lesion leading to functional abnormalities in central and peripheral nervous system. Neuropathic pain in itself is not always a disease, as it arises due to consequences of other diseases like diabetes, spinal cord injury, degenerative neuronal diseases and cancer. Current strategies of neuropathic pain treatment have provided relief to the patients to some extent, but complete cure is still a distant dream. In the future, it is hoped that a combination of new and improved pharmaceutical developments combined with careful clinical trials and increased understanding of neuroplasticity will lead to improved and effective pain management strategies leading to improved quality of life. In this review we have discussed various therapeutic targets of neuropathic pain and their pathophysiological mechanisms. Current status of drugs used for treatment of neuropathic pain have also been discussed in the review.

Neurovascular Changes in Acute, sub-Acute and Chronic Mouse Models of Parkinson’s Disease

Although selective neurodegeneration of nigro-striatal dopaminergic neurons is widely accepted as a cause of Parkinson’s disease (PD), the role of vascular components in the brain in PD pathology is not well understood. However, the neurodegeneration seen in PD is known to be associated with neuroinflammatory-like changes that can affect or be associated with brain vascular function. Thus, dysfunction of the capillary endothelial cell component of neurovascular units present in the brain may contribute to the damage to dopaminergic neurons that occurs in PD. An animal model of PD employing acute, sub-acute and chronic exposures of mice to methyl-phenyl-tetrahydropyridine (MPTP) was used to determine the extent to which brain vasculature may be damaged in PD. Fluoro-Turquoise gelatin labeling of microvessels and endothelial cells was used to determine the extent of vascular damage produced by MPTP. In addition, tyrosine hydroxylase (TH) and NeuN were employed to detect and quantify dopaminergic neuron damage in the striatum (CPu) and substantia nigra (SNc). Gliosis was evaluated through GFAP immunohistochemistry. MPTP treatment drastically reduced TH immunoreactive neurons in the SNc (20.68±2.83 in acute; 22.98±2.14 in sub-acute; 10.20 ±2.24 in chronic vs 34.88 ±2.91in controls; p<0.001). Similarly, TH immunoreactive terminals were dramatically reduced in the CPu of MPTP treated mice. Additionally, all three MPTP exposures resulted in a decrease in the intensity, length, and number of vessels in both CPu and SNc. Degenerative vascular changes such as endothelial cell ‘clusters’ were also observed after MPTP suggesting that vasculature damage may be modifying the availability of nutrients and exposing blood cells and/or toxic substances to neurons and glia. In summary, vascular damage and degeneration could be an additional exacerbating factor in the progression of PD, and therapeutics that protect and insure vascular integrity may be novel treatments for PD.

Multi-Target-Directed Ligands and other Therapeutic Strategies in the Search of a Real Solution for Alzheimer’s Disease

The lack of an adequate therapy for Alzheimer’s Disease (AD) contributes greatly to the continuous growing amount of papers and reviews, reflecting the important efforts made by scientists in this field. It is well known that AD is the most common cause of dementia, and up-to-date there is no prevention therapy and no cure for the disease, which contrasts with the enormous efforts put on the task. On the other hand many aspects of AD are currently debated or even unknown. This review offers a view of the current state of knowledge about AD which includes more relevant findings and processes that take part in the disease; it also shows more relevant past, present and future research on therapeutic drugs taking into account the new paradigm “Multi-Target-Directed Ligands” (MTDLs). In our opinion, this paradigm will lead from now on the research toward the discovery of better therapeutic solutions, not only in the case of AD but also in other complex diseases. This review highlights the strategies followed by now, and focuses other emerging targets that should be taken into account for the future development of new MTDLs. Thus, the path followed in this review goes from the pathology and the processes involved in AD to the strategies to consider in on-going and future researches.

Dysregulation of Neurotrophic and Haematopoietic Growth Factors in Alzheimer’s Disease: From Pathophysiology to Novel Treatment Strategies

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. Growth factors have been demonstrated to act in a synergistic way in angiogenesis and neurogenesis contributing to self-healing powers of the adult human brain. A growing body of evidence demonstrates that levels of many growth factors (neurotrophins and hematopoietins) are altered in cerebrospinal fluid and peripheral blood from AD patients and in animal models of AD. The present review summarizes the role of several neurotrophic growth factors (e.g., BDNF, SCF, NGF, GDNF) and haematopoietic growth factors (e.g., G-CSF, VEGF, SDF-1) in AD. Moreover, we summarize recent studies evaluating the diagnostic and prognostic value of growth factor levels in blood and cerebrospinal fluid in patients with AD and discuss the potential role of these growth factors as a promising new therapeutic approach in AD.

Highly Organized Nanostructures for Brain Drug Delivery - New Hope or Just a Fad?

The blood-brain barrier significantly impedes treatment of central nervous system disorders by preventing drug entry into the brain. Several strategies have been developed to overcome this problem, but progress has been hampered due to a lack of efficacious drug delivery systems (DDS). Now, owing to DDS, therapeutic compounds can be transported to the site of action and accumulate there. This modern approach allows one to decrease the required dose of drug and, therefore, minimize toxicity and side effects. Also, treatment efficiency is increased. Highly organized nanostructures made of biological, polymeric or carbon-based materials are promising carriers in drug delivery to the brain, due to their unique and easily tailorable properties. The drug can be either attached to or entrapped in a carrier. To achieve greater site specificity and selectivity, DDS can be also modified with suitable ligands, providing identification of the molecular site of action. This review illustrates recent advances in using highly-organized structures: dendrimers, fullerenes, liposomes, micelles, nanogels, nanoparticles and nanotubes for this purpose. We also discuss advantages and limitations of each system.

The Role of Oxidative Stress in Methamphetamine and MDMA-induced Toxicity

Methamphetamine and 3, 4-methylenedioxymethamphetamine are psychoactive recreational hallucinogenic substances with considerable CNS stimulatory effects. Acute or sub-chronic exposure to METH or MDMA can damage several organs. Many different organs may be involve. There is evidence for neurotoxicity, cardiotoxicity, hepatotoxicity and nephrotoxicity. Many of these mechanisms are complex and difficult to explain.

There is emerging consensus that oxidative stress play a paramount role in the molecular toxicity of both METH and MDMA. Free radicals can arise secondary to oxidative deamination of monoamines, cathecolamines autoxidation, hypothermia, lipoperoxidation and even cellular death. There is very little doubt that the toxic effects of METH and MDMA are mediated either by the direct effect of METH and MDMA or by its redox active metabolites. Metabolites formed in liver cells can reach the others organs (heart, kidney, brain, etc) and produce their own toxic effects inducing cellular oxidative stress and lipoperoxidation. The present review is aimed to further clarify the mechanisms of METH and MDMA-induced toxicity, mainly focusing on the role of oxidative stress pathway.

Autophagy: A Major Target of Cadmium Nephrotoxicity

Cadmium toxicity remains a major public health concern, despite a huge amount of work to explain its effects. The kidney is the most sensitive organ; and we recently provide the first evidence of a direct upregulation of autophagy by cadmium particularly in response to environmental relevant concentrations. Investigation of autophagy is greatly progressed and various strategies have been reported for studying this molecular process in different biological systems both in physiological and stress conditions. Furthermore, mechanisms of cadmium-induced autophagy in renal cells continue to be of interest given the unknown physiologic function of this metal. Cadmium is persistent within cytosol; it might damage proteins continuously and induces oxidative stress. The aim of this review is a critical analysis of knowledge about autophagic mechanisms induced by cadmium. We also report data obtained in different experimental studies, using cadmium and other xenobiotics, highlighting similarities in the induction of autophagic processes. A more detailed discussion will concern the role of autophagy in cadmium exposed renal proximal convoluted tubule since it is a suitable model system extremely sensitive to environmental stress and cadmium is one of the most nephrotoxic metals to which humans are exposed. We finally conclude that deficiency of autophagic process may be the origin of cadmium nephrotoxicity.