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

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Abstract:

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.



Document Type: Research Article

Publication date: April 1, 2008

More about this publication?
  • CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.

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