Abstract
We have evaluated vigabatrin (γ-vinyi-γ-aminobutyric acid), an irreversible inhibitor of γ-aminobutyric acid (GABA)-transarninase responsible for GABA degradation, for its effects on nociceptive response, changes in spontaneous locomotor activity and body temperature in mice after a prolonged treatment regimen. The mice received vigabatrin 0.26% w/v chronically in drinking water for 7, 14 and 21 days. Changes in locomotion, body temperature and nociception were recorded after 7, 14 and 21 days respectively in different groups. Also, possible withdrawal symptoms were determined up to three days after 7, 14 or 21 days of treatment. In another experiment the animals were given acutely, 250 mg/kg of vigabatrin by oral gavage and the changes in response to the said parameters were assessed 90 min after treatment. Acute treatment increased the latency in the hot-plate reaction time and a highly significant decline in locomotion and body temperature. In contrast to the acute treatment studies, there were essentially no effects of vigabatrin on nociception, locomotor activity or body temperature either on the last day of each treatment or upon withdrawal for the next consecutive three days. We conclude that the changes in nociception, locomotion and body temperature after acute treatment with vigabatrin are due to neuromediator interactions and a possible direct effect of GABA accumulation. After prolonged treatment tolerance to the pharmacological effects of vigabatrin develop that was evident by no change in nociception, locomotion and body temperature. This may be attributed to the possible failure in the maintenance of GABA pools resulting in a reduction in enhanced GABA release mediated by vigabatrin in acute treatment. Further studies of mechanisms by which vigabatrin tolerance develops to these pharmacological responses are warranted.
Highlights
Vigabatrin is an enzyme-activated irreversible inhibitor of y-arninobutyric acid -transaminase (GABA-T; EC, 2.6.1.19)~'the enzyme responsible for degrading of the neurotransmitterGABA
Vigabatrin interfereswith the GABA and produces antinociception in the hotplate test maximum at [4,5,6] hours of its admini~trationI.n~d~uction of antinociception between these periods was correlated to an increase in GABA levels after acute treatment and had already been reported.'9722In one study25dealing with chronic treatment, tolerance to antiseizure action of vigabatrin in epileptic gerbils had been described
This problem was further explored by Neal and who demonstrated that chronic treatment with vigabatrin results in a significant decrease in glutamic acid decarboxylase (GAD) activity in cerebral cortex and cord
Summary
Vigabatrin is an enzyme-activated irreversible inhibitor of y-arninobutyric acid -transaminase (GABA-T; EC, 2.6.1.19)~'the enzyme responsible for degrading of the neurotransmitterGABA. Vigabatrin interfereswith the GABA and produces antinociception in the hotplate test maximum at [4,5,6] hours of its admini~trationI.n~d~uction of antinociception between these periods was correlated to an increase in GABA levels after acute treatment and had already been reported.'9722In one study25dealing with chronic treatment, tolerance to antiseizure action of vigabatrin in epileptic gerbils had been described This problem was further explored by Neal and who demonstrated that chronic treatment with vigabatrin results in a significant decrease in glutamic acid decarboxylase (GAD) activity in cerebral cortex and cord. In the treatment groups the drinking fluid (vigabatrin 0.26%) was substituted with water at the end of each treatment period and the impact of withdrawal on the said parameters was measured after [24,48] and 72 hours (consecutivethree days) of the last treatment In another experiment one group of mice was treated with vigabatrin acutely (0.31111 of 21mgW25g animal 2 250 mglkg; P.O.)I.n comparison a control group was given orally the same volume of tap water. Investigations and results Acute vigabatrin treatment of mice resulted in significant increase in hot-plate latency (P
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