Sodium channels and therapy of central nervous system diseases.
Voltage-dependent Na+ channels have long been recognized targets for anti-arrhythmic and local anesthetic drugs. Since the mid-1980s, Na+ channels have become widely accepted as the primary target of anticonvulsants with pharmacological profiles similar to phenytoin, carbamazepine, and lamotrigine. Results from animal models and a few preliminary clinical trials suggest that this class of drugs may also offer significant potential for reducing the neuronal damage caused by ischemic stroke, head trauma, and perhaps certain neurodegenerative diseases. Studies using site-directed mutations of Na+ channels with electrophysiology have provided extensive insight into both the physiology and the interaction of drug molecules with ion channels. This review includes an introduction to Na+ channel structure, molecular biology, and physiology as they relate to pharmacology. A review of several in vitro actions of Na+ channel blockers is provided. Neuroprotective actions with a variety of Na+ channel blockers in models of central nervous system disease in animals and in vitro models are reviewed. Although many voltage-dependent Na+ channel blockers have additional pharmacological targets, the hypothesis that anticonvulsant and neuroprotective actions results from the blockade of Na+ channels is explored.
Taylor
C P
CP
Department of Neurological and Neurodegenerative Diseases, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co. Ann Arbor, Michigan 48105, USA.
Narasimhan
L S
LS
D000595:Amino Acid Sequence; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism; D002493:Central Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D018696:Neuroprotective Agents / Q000737:chemistry / Q000627:therapeutic use*; D017386:Sequence Homology, Amino Acid; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
D000927:Anticonvulsants; D018696:Neuroprotective Agents; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin