Identification and preclinical testing of novel antiepileptic compounds.
Procedures for identifying novel antiepileptic drugs (AEDs) are changing and need to change more. Widespread reliance on two primary screens has led to the identification of novel compounds that resemble either phenytoin (suppressing high-frequency repetitive firing in cultured neurons and prolonging inactivation of voltage-dependent sodium channels identified by the maximal electroshock test) or benzodiazepines (potentiating the inhibitory effect of gamma-aminobutyric acid (GABA), identified by the threshold pentylenetetrazol test). Advances in molecular neurobiology have identified specific molecular targets (subunits of ion channels, neurotransmitter receptors, and transporters) and have made them available in a form permitting high-throughput screening. AEDs can be designed to interact with specific sites on the target molecules. Alternatively, the molecular screens can be used to identify active components in natural products, including folk remedies. Preclinical in vivo screens can be improved by using animals with genetic or acquired epilepsies that have similar modifications in the properties of the target molecules as do human epilepsy syndromes. Future work is likely to define molecular targets for AEDs that will block or reverse chronic epileptogenesis.
Meldrum
B S
BS
Department of Clinical Neurosciences, Institute of Psychiatry, University of London, England.
D000251:Adenosine Triphosphatases / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002478:Cells, Cultured; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D007473:Ion Channels / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D051379:Mice; D009431:Neural Conduction / Q000187:drug effects; D009433:Neural Inhibition / Q000187:drug effects; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000927:Anticonvulsants; D007473:Ion Channels; D017981:Receptors, Neurotransmitter; D005680:gamma-Aminobutyric Acid; D000251:Adenosine Triphosphatases