Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 15, Number 34, 2009

Contents


New Therapeutic Strategies for Treatment of Neurodegenerative Diseases
Executive Editor: Aleksey G. Kazantsev


Editorial: Pp. 3917-3918 [PMID: 20044916 PubMed - indexed for MEDLINE]


Kinase Inhibitors as Potential Therapeutics for Acute and Chronic Neurodegenerative Conditions Pp. 3919-3939
G.D. Cuny
[Abstract] [Purchase Article] [PMID: 19751204 PubMed - indexed for MEDLINE]


Histone Deacetylase Inhibitors and Neurodegenerative Disorders: Holding the Promise Pp. 3940-3957
Antonello Mai, Dante Rotili, Sergio Valente and Aleksey G. Kazantsev
[Abstract] [Purchase Article] [PMID: 19751207 PubMed - indexed for MEDLINE]


Turning REST/NRSF Dysfunction in Huntington’s Disease into a Pharmaceutical Target Pp. 3958-3967
Dorotea Rigamonti, Cesare Mutti, Chiara Zuccato, Elena Cattaneo, and Alessandro Contini
[Abstract] [Purchase Article] [PMID: 19751206 PubMed - indexed for MEDLINE]


Current and Future Therapeutic Strategies for Parkinson’s Disease Pp. 3968-3976
Tiago Fleming Outeiro and Joaquim Ferreira
[Abstract] [Purchase Article] [PMID: 19751203 PubMed - indexed for MEDLINE]


RNAi Applications in Therapy Development for Neurodegenerative Disease Pp. 3977-3991
M. M. Maxwell
[Abstract] [Purchase Article] [PMID: 19751205 PubMed - indexed for MEDLINE]




Abstracts


[Back to top] [PMID: 20044916 PubMed - indexed for MEDLINE]
Editorial:New Therapeutic Strategies for Treatment of Neurodegenerative Diseases

COMPLEXITY OF NEURODEGENERATIVE DISEASE CHALENGES DRUG DISCOVERY

Currently there is no cure for neurodegenerative disorders such as Alzheimer’s, Parkinson’s, Huntington’s diseases, Amyotrophic Lateral Sclerosis, and many others, which cause long-term suffering and ultimately death of patients. These devastating neurodegenerative diseases affect the lives of many thousands of patients and their families. Basic research on neurodegenerative disorders has revealed a highly complex picture of disease pathology in man. Over the past decades, numerous studies have demonstrated that the pathogenesis of neurodegenerative disorders appears to involve the recruitment of multiple biochemical pathways, but no single molecular mechanism has emerged as the major contributor to neurodegeneration. Furthermore, it has become evident that multiple genetic, environmental, and other factors – including aging – contribute to and modulate disease onset, progression, and severity. Given such complexity of neurodegneration, it is clear that diverse therapeutic strategies must employed and tested in experimental disease models, to identify those that show promise in preclinical trials.

Over the years, therapeutic development has belonged almost exclusively to pharmaceutical and biotechnological companies. Recently, however, academic science has become more and more focused on various stages of drug discovery, complementing the R&D efforts of the pharmaceutical industry. Academic medicine is also highly capable of investigating and pursuing somewhat less traditional avenues of therapeutic development, an exercise that might be more constrained in an industrial setting.

The goal of this review series is to introduce some of the diverse therapeutic strategies, concepts and advances toward clinical development that focus on neurodegenerative disease, and are currently taking place in academic laboratories.

THERAPUTIC STRATEGIES FOR TREATMENT OF NEURODEGENERATION

Kinases belong a class of enzymes that regulate important cellular functions under both normal and pathophysiological conditions. A comprehensive review by G. Cuny [1] “Kinase inhibitors as potential therapeutics for acute and chronic neurodegenerative conditions” describes the advantages and challenges in development of selective and safe inhibitors for treatment of a broad range of human illnesses, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, amyotrophic lateral and multiple sclerosis, and ischemia and traumatic brain injury.

The family of histone deacetylases and sirtuins have emerged in recent years as important drug targets for treatment of a broad range of human neurological disorders. In their review, entitled “Histone deacetylase inhibitors and neurodegenerative disorders: holding the promise” A. Mai and colleagues [2] report recent progress in the development of selective ligands and discuss the efficacy of these small molecules in different models of neurodegeneration. Of particular interest, this review describes the discovery and development of ligands for the sirtuins, which are believed to regulate cellular metabolism and aging.

A. Contini and co-authors [3] describe a non-traditional and novel therapeutic strategy in their review, “Turning REST/NRSF dysfunction in Huntington’s Disease into a pharmaceutical target”. To achieve neuroprotective effects, the authors propose pharmacological targeting of the neuronal transcriptional repressor REST/NRSF complex to upregulate expression of brain-derived neurotrophic factor (BDNF). The authors report the discovery of potent small molecules that are capable of upregulating levels of BDNF, which functions as a neuronal survival factor. The proposed approach could be beneficial for various neurodegenerative diseases, as BDNF is critical for neuronal survival.

L-DOPA, a dopamine receptor agonist, is the only known drug for the symptomatic treatment of Parkinson’s disease and is currently widely used. Unfortunately L-DOPA lacks a long-term neuroprotective effect, and its efficacy declines with disease progression. In their review, “Current and Future Therapeutic Strategies for Parkinson’s Disease”, T. Outeiro and J. Frerreira [4] discuss new therapeutic strategies, and of particular interest is the proposed approach of targeting neurotoxic oligomers of the alpha-synuclein protein. Targeting toxic oligomers, formed by misfolding of mutant proteins, is a universally attractive approach that could prove beneficial for treatment of other neurodegenerative disorders including Alzheimer’s and Huntington’s diseases, etc.

The molecular basis and therapeutic opportunity of highly selective and potent gene silencing by RNA interference is described by M. Maxwell [5] in the review “RNAi Applications in Therapy Development for Neurodegenerative Disease”. Furthermore, this review discusses the application of RNAi methodology to expedite drug target identification and to validate potential targets in both in vitro and in vivo models of neurodegeneration.

The burden of neurodegenerative diseases is too high for society to accept. The synergistic efforts of academic medicine and the pharmaceutical industry provide a great opportunity to eradicate these diseases in near future. More and more, collaborations are being forged between university and company scientists to address these goals, and this trend can be only welcomed.

REFERENCES

[1] Cuny G. Kinase inhibitors as potential therapeutics for acute and chronic neurodegenerative conditions. Curr Pharm Des 2009; 15(34): 3919-3939.
[2] Mai A, Rotili D, Valente S, Kazantsev AG. Histone deacetylase inhibitors and neurodegenerative disorders: holding the promise. Curr Pharm Des 2009; 15(34): 3940-3957.
[3] Rigamonti D, Mutti C, Zuccato C, Elena Cattaneo E, Contini A. Turning REST/NRSF dysfunction in Huntington’s Disease into a pharmaceutical target. Curr Pharm Des 2009; 15(34): 3958-3967.
[4] Outeiro TF, Frerreira J. Current and future therapeutic strategies for Parkinson’s disease. Curr Pharm Des 2009; 15(34): 3968-3976.
[5] Maxwell MM. RNAi applications in therapy development for neurodegenerative disease. Curr Pharm Des 2009; 15(34): 3977-3991.


Aleksey G. Kazantsev
Harvard Medical School
Massachusetts General Hospital
CNY114 16th Street,
Charlestown, MA 02129
USA


[Back to top] [Purchase Article] [PMID: 19751204 PubMed - indexed for MEDLINE]
Kinase Inhibitors as Potential Therapeutics for Acute and Chronic Neurodegenerative Conditions
G.D. Cuny

Kinases, which number > 500 in humans, are a class of enzymes that participate in an array of important functions within normal cellular physiology and during various pathological conditions. Due to the key role of kinases in the regulation of all aspects of cellular signaling and the well established contribution of kinase dysregulation to the etiology of many human pathologies, the development of kinase inhibitors has emerged as a therapeutic strategy for the treatment of human disease, including most notably oncology. Difficulties generating selective inhibitors have hampered their use in other therapeutic areas with less tolerance for off-target effects. However, with an increasing understanding of kinase structures and with the advent of newer inhibitor design strategies more highly selective inhibitors are beginning to emerge. This has prompted interest in utilizing kinase inhibitors in therapeutic areas beyond oncology, including acute and chronic neurodegenerative conditions for which disease modify therapies are lacking. This review provides a background in acute (i.e. brain ischemia and traumatic brain injury) and chronic (i.e. Alzheimer’s, Parkinson’s, Huntington’s disease, amyotrophic lateral sclerosis and multiple sclerosis) neurodegenerative conditions. Then, the role of several kinase (i.e. JNK3, p38 MAPK, ERK, PKCδ, ROCKII, GSK3, Cdk5, MLK, EphB3 kinase, RIP1 kinase, LRRK2, TTBK1, ASK1, CK, DAPK, and PKN1) that could serve as potential therapeutic targets for these maladies are reviewed.


[Back to top] [Purchase Article] [PMID: 19751207 PubMed - indexed for MEDLINE]
Histone Deacetylase Inhibitors and Neurodegenerative Disorders: Holding the Promise
Antonello Mai, Dante Rotili, Sergio Valente and Aleksey G. Kazantsev

Neurodegenerative disorders (NDs) such as Huntington’s disease, Alzheimer’s disease, Parkinson disease, amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich’s ataxia, and others are multi-factorial illnesses, in which many pathways (still poorly understood) act serially and in parallel to give a determined pathologic phenotype. Thus, presently there are no effective cures for these diseases. Some phenotypic as well as mechanistic features, common to the most of NDs, can be linked to epigenetic defects, that can lead to alteration of acetylation homeostasis and impairment of the histone acetyltransferase (HAT): histone deacetylase (HDAC) balance. Here we survey most of the recent applications of HDAC inhibitors in the cited NDs, and we make the point of our (up to now) knowledge about the involvement of singular HDAC/SIRT isoform in NDs and other CNS pathologies.


[Back to top] [Purchase Article] [PMID: 19751206 PubMed - indexed for MEDLINE]

Turning REST/NRSF Dysfunction in Huntington’s Disease into a Pharmaceutical Target
Dorotea Rigamonti, Cesare Mutti, Chiara Zuccato, Elena Cattaneo, and Alessandro Contini

REST/NRSF is a transcription factor that represses transcription of several neuronal genes by binding to a DNA regulatory motif known as Repressor Element 1/Neuron-restrictive silencer element (RE1/NRSE). In Huntington’s Disease, an inherited degenerative disease affecting the brain, REST/NRSF enters pathologically into the nucleus of affected cells, leading to the activation of the RE1/NRSE sites and causing decreased transcription of several important neuronal genes. Following this discovery, an effort has begun by some of the authors aimed at identifying compounds capable of antagonizing REST/NRSF silencing activity. Here we will review the underlying basis for focusing pharmaceutical efforts on REST/NRSF-RE1/NRSE system as well as some of the strategies for a rational drug design approach. We will highlight approaches aimed at identifying or designing small molecules able to impact REST/NRSF nuclear translocation, its DNA binding or, more generally, the formation of the REST/NRSF transcriptional complex, in the attempt to restore neuronal gene transcription in pathological conditions of the brain.


[Back to top] [Purchase Article] [PMID: 19751203 PubMed - indexed for MEDLINE]
Current and Future Therapeutic Strategies for Parkinson’s Disease
Tiago Fleming Outeiro and Joaquim Ferreira

The heterogeneity of symptoms and disease progression observed in synucleinopathies, of which Parkinson’s disease (PD) is the most common representative, poses large problems for its treatment and for the discovery of novel therapeutics. The molecular basis for pathology is currently unclear, both in familial and in sporadic cases. While the therapeutic effects of L-DOPA and dopamine receptor agonists are still the gold standards for symptomatic treatment in PD, the development of neuroprotective and/or neurorestorative treatments for these disorders faces significant challenges due to the poor knowledge of the putative targets involved. Recent experimental evidence strongly suggests a central role for neurotoxic α-synuclein oligomeric species in neurodegeneration. The events leading to protein oligomerization, as well as the oligomeric species themselves, are likely amenable to modulation by small molecules, which are beginning to emerge in high throughput compound screens in a variety of model organisms. The therapeutic potential of small molecule modulators of oligomer formation demands further exploration and validation in cellular and animal disease models in order to accelerate human drug development.


[Back to top] [Purchase Article] [PMID: 19751205 PubMed - indexed for MEDLINE]
RNAi Applications in Therapy Development for Neurodegenerative Disease
M. M. Maxwell

RNA-mediated interference (RNAi) is a powerful tool for experimental manipulation of gene expression and is widely used to investigate gene function both in vitro and in vivo. RNAi refers to an evolutionarily conserved cellular mechanism for sequence-specific post-transcriptional gene silencing, in which double-stranded RNAs promote selective degradation of homologous cellular mRNAs. Because RNAi-based techniques can be employed to reduce expression of specific genes, this approach holds great promise as a therapy for diverse diseases, including devastating neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases and amyotrophic lateral sclerosis (ALS). Importantly, in recent years RNAi has also emerged as a key tool in target identification and validation studies designed to complement traditional (i.e., small molecule-based) drug development strategies. These studies harness the power of RNAi-mediated reverse genetics to probe disease-associated pathways in both cell-based and animal models, and thus may provide critical data needed to focus drug development efforts around disease-relevant targets. This review highlights recent progress in the preclinical development of RNAi-based therapeutics for neurodegenerative disease and discusses the particular challenges that disorders of the central nervous system (CNS) pose for this approach. It further describes current applications of RNAi techniques for target identification and validation studies and underscores the importance of this methodology to developing treatments for neurological diseases.