Concentration-effect studies with topiramate on selected enzymes and intermediates of the GABA shunt

Sills, G. J., Leach, J. P., Kilpatrick, W. S., Fraser, C. M., Thompson, G. G. and Brodie, M. J. (2000) Concentration-effect studies with topiramate on selected enzymes and intermediates of the GABA shunt. Epilepsia, 41(s1), pp. 30-34. (doi: 10.1111/j.1528-1157.2000.tb02168.x) (PMID:10768297)

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Abstract

Purpose: Topiramate (TPM) is a new antiepileptic agent with a multifactorial mechanism of action. The drug potentiates responses to γ‐aminobutyric acid (GABA) at the GABAA receptor and has inhibitory effects on neuronal sodium channels, the AMPA/kainate subtype of glutamate receptor, and carbonic anhydrase. Recent evidence has, however, suggested that the drug also increases brain GABA concentrations in humans. These studies were designed to investigate the neurochemical basis of this observation. Methods: Adult male mice were randomised into two groups and administered TPM (0–1,000 mg/kg) intraperitoneally either as a single dose or daily for 8 days. At 4 h after the final dose, brain tissues were analysed for concentrations of GABA, glutamate, and glutamine and for the activities of GABA‐transaminase and glutamic acid decarboxylase. TPM levels in brain also were determined. Results: Single‐dose and repeated TPM treatments were without effect on all of the parameters investigated, although the drug was detectable in the brain at doses of 10 mg/kg. Conclusions: These results contradict the reported increase in brain GABA concentrations with TPM. More detailed studies are required to determine the basis of this clinical observation and the extent to which it contributes to the antiepileptic activity of the drug.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Sills, Dr Graeme
Authors: Sills, G. J., Leach, J. P., Kilpatrick, W. S., Fraser, C. M., Thompson, G. G., and Brodie, M. J.
College/School:College of Medical Veterinary and Life Sciences
Journal Name:Epilepsia
Publisher:Wiley
ISSN:0013-9580
ISSN (Online):1528-1167

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