NDLI: Molecular targets for antiepileptic drug development

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Molecular targets for antiepileptic drug development

Content Provider	Springer Nature Link
Author	Meldrum, Brian S. Rogawski, Michael A.
Copyright Year	2007
Abstract	This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the α subunits of voltage-gated Na$^{+}$ channels and also T-type voltage-gated Ca$^{2+}$ channels) or influence GABA-mediated inhibition. Recently, α2-δ voltage-gated Ca$^{2+}$ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na$^{+}$ channels and GABA$_{A}$ receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca$^{2+}$ channel subunits and auxiliary proteins, A- or M-type voltage-gated K$^{+}$ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA$_{B}$ and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated currentI $_{h}$; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na$^{+}$ channels underlying persistent Na$^{+}$ currents or GABA$_{A}$ receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.
Starting Page	18
Ending Page	61
Page Count	44
File Format	PDF
ISSN	19337213
Journal	NeuroRX
Volume Number	4
Issue Number	1
e-ISSN	18787479
Language	English
Publisher	Springer-Verlag
Publisher Date	2007-01-01
Publisher Institution	American Society for Experimental NeuroTherapeutics
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Epilepsy channelopathy antiepileptic drug sodium channel calcium channel potassium channel GABA receptor glutamate receptor GABA transporter glutamate transporter gap junction Neurosciences Neurology Neurosurgery Neurobiology
Content Type	Text
Resource Type	Article
Subject	Neurology (clinical) Pharmacology Pharmacology (medical)

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