Qume, Michelle; (1994) Pharmacological studies on gaba-transaminase inhibitors. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the mammalian central nervous system (CNS). A GABA dysfunction has been implicated in epilepsy, hence pharmacological approaches to the treatment of this disease include the enhancement of GABA-mediated transmission. γ-Vinyl GABA (GVG) and ethanolamine-O-sulphate (EOS) are both mechanism-based irreversible inhibitors of GABA-transaminase (GABA-T), the enzyme responsible for the catabolism of GABA and are therefore candidates for antiepileptic therapy; GVG is widely available as an anticonvulsant for the treatment of drug-resistant epilepsy. The effect of oral treatment with GVG and EOS for 2, 8 and 21 days was examined on various pharmacological systems. Following treatment with GVG and EOS, GABA-T activity was significantly depressed in liver, brain and kidney, with subsequent elevations observed in brain, liver and plasma GABA content, with a surprising decrease in kidney GABA content. The in vitro and in vivo (microdialysis) hippocampal release (basal and K+ stimulated) of endogenous GABA was investigated following GVG and EOS administration. Increases in both basal and stimulated GABA release were observed following GABA-T inhibition. In control tissues in vitro, lowering the Ca++ content of the incubation medium led to a decrease in K+ stimulated GABA release, however this Ca++ dependence was not observed following GVG or EOS treatment. Following the elevation in brain GABA content due to GABA-T inhibition, the binding of radioactive ligands to GABAA, GABAB and flunitrazepam (FNZ) binding sites were investigated to determine if changes in binding had occurred. No change was observed in GABAA and FNZ binding, however GABAB binding was significantly depressed to 55% of control values following 21 days treatment with GVG. Two, 8 and 21 day dosing schedules were employed to investigate any tolerance occurring in these pharmacological systems following prolonged treatment. The decrease in specific binding of 3H-GABA to GABAB sites was the only observed indication of tolerance having taken place.

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