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Transport and metabolism of gamma-aminobutyric acid in neurons and glia: implications for epilepsy.

Abstract
One of the defects in human epilepsy appears to be the suboptimal functioning of at least certain central gamma-aminobutyric acid (GABA)-mediated synapses. Of the several approaches for the manipulation of the functional state of such synapses that have been investigated, the possibility of interference with GABA metabolism and GABA transport processes is reviewed. It is concluded that the efficiency of inhibitors of the GABA-metabolizing enzyme, GABA transaminase, as antiepileptic drugs is related to the ability of the inhibitors to increase selectively the synaptic or transmitter-related GABA levels. Whether or not this reflects different modes of action of these inhibitors on neuronal and glial GABA transaminase remains to be established. Inhibition of the GABA transport mechanisms seems to represent an alternative approach to increase synaptic GABA levels. Evidence is presented that inhibitors of glial GABA uptake possess anticonvulsant activity. A comparison of drugs that inhibit both neuronal and glial GABA uptake with selective glial GABA uptake inhibitors indicates that the latter type of inhibitor most effectively blocks seizure activity. Such a drug is 4,5,6,7-tetrahydroisoxazolo[4,5c]pyridin-3-ol (THPO), which unfortunately lacks the important property of easy penetration of the blood-brain barrier. Prodrugs of this glial-selective GABA uptake inhibitor may have pharmacological and therapeutic interest.
AuthorsA Schousboe, O M Larsson, J D Wood, P Krogsgaard-Larsen
JournalEpilepsia (Epilepsia) Vol. 24 Issue 5 Pg. 531-8 (Oct 1983) ISSN: 0013-9580 [Print] United States
PMID6311524 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • gamma-Aminobutyric Acid
Topics
  • Biological Transport
  • Epilepsy (metabolism)
  • Humans
  • Neuroglia (metabolism)
  • Neurons (metabolism)
  • Synaptic Transmission
  • gamma-Aminobutyric Acid (metabolism)

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