CNS & Neurological Disorders -Drug Targets

ISSN: 1871-5273

CNS & Neurological Disorders - Drug Targets
Volume 7, Number 2, April 2008

Contents

Role of Ion Channels in Neurological Disorders
Guest Editor: Johannes J. Krupp


Editorial Pp.120-121


Ion Channel Screening Technology Pp. 122-128
Michael A. Dabrowski, Kim Dekermendjian, Per-Eric Lund, Johannes J. Krupp, Jon Sinclair and Olof Larsson
[Abstract]


Ionotropic Glutamate Receptors & CNS Disorders Pp. 129-143
Derek Bowie
[Abstract]


Voltage-Gated Sodium Channels in Neurological Disorders Pp. 144-158
Mohamed Chahine, Aurélien Chatelier, Olga Babich and Johannes J. Krupp
[Abstract]


Transient Receptor Potential Vanilloid 1 and Xenobiotics Pp. 159-171
E. Cuypers, M. Dabrowski, L. Horoszok, G.E. Terp and J. Tytgat
[Abstract]


Protein-Protein Interactions and Subunit Composition of Ion Channels Pp. 172-186
Uwe Schulte
[Abstract]


The Role of Neurogenesis in Neurodegenerative Diseases and its Implications for Therapeutic Development Pp. 187-210
Andrea Abdipranoto, Sara Wu, Sandy Stayte and Bryce Vissel
[Abstract]


GABAA Receptors, Anesthetics and Anticonvulsants in Brain Development Pp. 211-224
Oliver Henschel, Keith E. Gipson and Angelique Bordey
[Abstract]




Abstracts


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Editorial

Ion channels are a key target class for the pharmaceutical industry and available drugs that target ion channels combine clinical benefit with commercial success. Primary research is continuously uncovering potential new ion channel targets in virtually all possible disease indications, including numerous neurological disorders. This trend is expected to continue for a long time to come: ion channels are at the center of the primary physiological function of the nervous system, the processing and flow of neuronal signals. Their dysfunction is likely to be causative or at least involved in many neurological disorders and neurodegenerative diseases. While continuous progress is being made, ion channels thus remain underexploited as drug targets within the CNS, and substantial research efforts are continued to be invested into ion channels both from academia and pharmaceutical industry.

The reviews in this issue are built around the role of ion channels in neurological disorders. Due to the breath of this scope, only a selection of ion channel families are discussed in more detail, while additional reviews address the role of ion channels in neurodegenerative diseases and neurogenesis in more general terms, or focus on recent technological advances in the field of ion channel research. An overview of the latest technologies used to assess ion channel activity is provided in the review by Dabrowski et al., in which the authors review available ion channel screening technologies and describe recent advancements that have made it possible to integrate electrophysiological ion channel screening into early lead generation stages of drug discovery. A preview of a previously undisclosed collaborative effort in the field aimed at development of a medium throughput electrophysiology screening platform for ligand-gated ion channels is included. Ligand-gated ion channels are also the topic of the paper by Bowie, in which the author argues that our understanding of the physiological and pathological regulation of ionotropic glutamate receptors has advanced to the point that their causative contribution to various neurological disorders can be dissected. As an example, it is highlighted how defects in AMPA receptor trafficking are important to Fragile X mental retardation, and how ectopic expression of kainate receptor synapses contributes to the pathology of temporal lobe epilepsy, promising that future drug development in the area may lead towards a cure rather than a symptomatic treatment of these diseases. The review by Chahine et al. focusses on voltage-gated sodium channels. A wide variety of human channelopathies have been described for several members of this ion channel family, causing distinct, and often severe, neurological and other pathological disorders. This has rekindled interest and focus within the pharmaceutical industry onto this ion channel family, with considerable efforts being invested into developing isoform-specific inhibitors of voltage-gated sodium channels. Another ion channel family that has received considerable attention in the last decade is the transient receptor potential channel family, specifically the capsaicin receptor TRPV1. The review by Cuypers et al. discusses known plant and animal toxins active at this important ion channel. The review also includes a review of synthetic compounds active at this channel, including the description of several new and previously undescribed TRPV1-inhibitors from AstraZeneca. The review by Schulte refocusses the readers attention to the technical challenges and opportunities in ion channel research, specifically those associated with the fact that ion channels are protein complexes. The composition of an ion channel complex can determine key physiological and pharmacological properties of the ion channel under investigation. It is thus important to determine the relevant subunit composition of an ion channel complex targeted by pharmaceutical agents. In this context, the author critically reviews the available technologies for studying protein-protein interactions and their application to ion channels. The last two papers of this issue highlight, each with its own specific angle, the role of ion channels in neurogenesis. The scene is set with the review by Abdipranoto et al. that addresses the role of neurogenesis in various neurodegenerative diseases. With most present research in the area focussing on the mechanisms that lead to neurodegeneration and with therapeutic approaches almost exclusively targeting the prevention of neuronal loss, the authors suggest that an understanding of the role of neurogenesis in the adult CNS is equally critical and may indeed be the key for real therapeutic breakthrough in the future. As a case in point the authors highlight several ion channels implicated in neurodegeneration, such as NMDA, AMPA, GABA and nicotinic acetylcholine receptors. Indeed, all of these ion channels also play an important role in neurogenesis and neuroregeneration. Finally, Henschel et al. bridge from basic science to the clinic in their review of the main inhibitory neurotransmitter in the adult brain, GABA. After an extensive review of the basic science in the area, the authors focus on the role of GABA in neurogenesis and brain development, especially during late embryonic and early neonatal periods. The authors highlight concerns associated with extended clinical usage of GABAergic drugs such as anesthetics, sedatives, and anticonvulsants during early development, that may lead to long-term cognitive deficits.

Johannes J. Krupp
AstraZeneca R&D Södertälje
Molecular Pharmacology Department, B209
Forskargatan
15185 Södertälje
Sweden
E-mail: johannnes.krupp@astrazeneca.com


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Ion Channel Screening Technology
Michael A. Dabrowski, Kim Dekermendjian, Per-Eric Lund, Johannes J. Krupp, Jon Sinclair and Olof Larsson

Ion channels are at present the third biggest target class in drug discovery. Primary research is continually uncovering potential new ion channel targets in indications such as cancer, diabetes and respiratory diseases, as well as the more established fields of pain, cardiovascular disease, and neurological disorders. Despite the physiological significance and therapeutic relevance in a wide variety of biological systems, ion channels still remain under exploited as drug targets. This is to a large extent resulting from the historical lack of screening technologies to provide the throughput and quality of data required to support medicinal chemistry. Although technical challenges still lie ahead, this historic bottleneck in ion channel drug discovery is now being overcome by novel technologies that can be integrated into lead generation stages of ion channel drug discovery to allow the development of novel therapeutic agents. This review describes the variety of technologies available for ion channel screening and discusses the opportunities these technologies provide. The challenges that remain to be addressed are highlighted.


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Ionotropic Glutamate Receptors & CNS Disorders
Derek Bowie

Disorders of the central nervous system (CNS) are complex disease states that represent a major challenge for modern medicine. Although aetilogy is often unknown, it is established that multiple factors such as defects in genetics and/or epigenetics, the environment as well as imbalance in neurotransmitter receptor systems are all at play in determining an individual’s susceptibility to disease. Gene therapy is currently not available and therefore, most conditions are treated with pharmacological agents that modify neurotransmitter receptor signaling. Here, I provide a review of ionotropic glutamate receptors (iGluRs) and the roles they fulfill in numerous CNS disorders. Specifically, I argue that our understanding of iGluRs has reached a critical turning point to permit, for the first time, a comprehensive re-evaluation of their role in the cause of disease. I illustrate this by highlighting how defects in AMPA receptor (AMPAR) trafficking are important to fragile X mental retardation and ectopic expression of kainate receptor (KAR) synapses contributes to the pathology of temporal lobe epilepsy. Finally, I discuss how parallel advances in studies of other neurotransmitter systems may allow pharmacologists to work towards a cure for many CNS disorders rather than developing drugs to treat their symptoms.


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Voltage-Gated Sodium Channels in Neurological Disorders
Mohamed Chahine, Aurélien Chatelier, Olga Babich and Johannes J. Krupp

Voltage-gated sodium channels play an essential biophysical role in many excitable cells such as neurons. They transmit electrical signals through action potential (AP) generation and propagation in the peripheral (PNS) and central nervous systems (CNS). Each sodium channel is formed by one α-subunit and one or more β-subunits. There is growing evidence indicating that mutations, changes in expression, or inappropriate modulation of these channels can lead to electrical instability of the cell membrane and inappropriate spontaneous activity observed during pathological states. This review describes the biochemical, biophysical and pharmacological properties of neuronal voltage-gated sodium channels (VGSC) and their implication in several neurological disorders.


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Transient Receptor Potential Vanilloid 1 and Xenobiotics
E. Cuypers, M. Dabrowski, L. Horoszok, G.E. Terp and J. Tytgat

Over the last couple of years, transient receptor potential vanilloid 1(TRPV1) channels have been a hot topic in ion channel research. Since this research field is still rather new, there is not much known about the working mechanism of TRPV1 and its ligands. Nevertheless, the important physiological role and therapeutic potential are promising. Therefore, extensive research is going on and a lot of natural as well as synthetic compounds are already described. In this review, we briefly give an overview of capsaicin’s history and the current knowledge of its working mechanism and physiological role. We discuss the best known plant molecules acting on TRPV1 and highlight the latest discovery in TRPV1 research: animal venoms and toxins acting on TRPV1 channels. In an effort to give the complete image of TRPV1 ligands known today, the most promising synthetic compounds are presented. Finally, we present a novel pharmacophore model describing putative ligand binding domains.


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Protein-Protein Interactions and Subunit Composition of Ion Channels
Uwe Schulte

Ion channels are integral membrane proteins that enable the passive flow of inorganic ions by forming hydrated pores across biological membranes. Their pore-forming alpha subunits determine ion permeation and provide the machinery for gating. In addition, channel class specific accessory proteins termed beta, gamma and delta subunits have been found that modulate or even determine key properties like channel gating (e.g. activation, inactivation properties), surface expression, targeting and stability. Moreover, some of these subunits constitute binding sites for toxins as well as for therapeutic drugs. With the development of more powerful proteomic and molecular biology-based methods, a vastly increasing number of proteins interacting with ion channels has recently been described. These results are providing novel insight into ion channel function and at the same time challenging classical concepts of beta subunits and ion channel drug targets. They are also raising questions about functional validation and reliability of these methods. This review focuses on the potentials and limitations of modern “-omic” protein-protein interaction analyses and their application to ion channels. After recapitulating fundamental thermodynamic and biochemical principles underlying protein-protein interactions, current methods for their systematic identification are critically reviewed. Selected examples of newly characterized ion channel complexes will then be discussed to illustrate the implications for molecular understanding as well as for the effective selection and screening of ion channel drug targets.


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The Role of Neurogenesis in Neurodegenerative Diseases and its Implications for Therapeutic Development
Andrea Abdipranoto, Sara Wu, Sandy Stayte and Bryce Vissel

Neurodegenerative diseases are characterised by a net loss of neurons from specific regions of the central nervous system (CNS). Until recently, research has focused on identifying mechanisms that lead to neurodegeneration, while therapeutic approaches have been primarily targeted to prevent neuronal loss. This has had limited success and marketed pharmaceuticals do not have dramatic benefits. Here we suggest that the future success of therapeutic strategies will depend on consideration and understanding of the role of neurogenesis in the adult CNS. We summarize evidence suggesting that neurogenesis is impaired in neurodegenerative diseases such as Parkinson's, Alzheimer's and Amyotrophic Lateral Sclerosis, while it is enhanced in stroke. We review studies where stimulation of neurogenesis is associated with restored function in animal models of these diseases, suggesting that neurogenesis is functionally important. We show that many current therapeutics, developed to block degeneration or to provide symptomatic relief, serendipitously stimulate neurogenesis or, at least, do not interfere with it. Importantly, many receptors, ion channels and ligand-gated channels implicated in neurodegeneration, such as NMDA, AMPA, GABA and nicotinic acetylcholine receptors, also play an important role in neurogenesis and regeneration. Therefore, new therapeutics targeted to block degeneration by antagonizing these channels may have limited benefit as they may also block regeneration. Our conclusion is that future drug development must consider neurogenesis. It appears unlikely that drugs being developed to treat neurodegenerative diseases will be beneficial if they impair neurogenesis. And, most tantalizing, therapeutic approaches that stimulate neurogenesis might stimulate repair and even recovery from these devastating diseases.


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GABAA Receptors, Anesthetics and Anticonvulsants in Brain Development
Oliver Henschel, Keith E. Gipson and Angelique Bordey

GABA, acting via GABAA receptors, is well-accepted as the main inhibitory neurotransmitter of the mature brain, where it dampens neuronal excitability. The receptor’s properties have been studied extensively, yielding important information about its structure, pharmacology, and regulation that are summarized in this review. Several GABAergic drugs have been commonly used as anesthetics, sedatives, and anticonvulsants for decades. However, findings that GABA has critical functions in brain development, in particular during the late embryonic and neonatal period, raise worthwhile questions regarding the side effects of GABAergic drugs that may lead to long-term cognitive deficits. Here, we will review some of these drugs in parallel with the control of CNS development that GABA exerts via activation of GABAA receptors. This review aims to provide a basic science and clinical perspective on the function of GABA and related pharmaceuticals acting at GABAA receptors.