Abstract
Effects of acute administration of vigabatrin (VGB) that has significant GABA-mimetic properties were studied for its antiinflammatory, antigranuloma effects in rats and thermoregulatory actions in mice. Treatment of rats with VGB (125, 250 and 500 mg/kg, i.p doses) caused a significant and persistent inhibition in the carrageenan induced paw edema. Inhibitory effect at high dose (500 mg/kg, which was about 10-fold of the maximal effective dose 50 mg/kg in humans) was 40-, 41- and 39% of the control at 2-, 3- and 4 hours afier the treatment. In cotton-pellet-granuloma study, only the high dose was significantly (P<0.05) effective and inhibition in granuloma was 17 and 28% of the control at 250 and 500 mg/kg doses, respectively. In another model, leukocyte migration to the inflamed peritoneal cavity was used as a parameter in rats. In this model, VGB (500 mg/kg, i.p) induced a significant (P<0.05) reduction in leukocyte migration to the inflamed peritoneal cavity when administered 30 min before carrageenan. This was comparable to indomethacin (10 mg/kg) that also caused a significant (P<0.05) reduction in leukocyte migration. The inhibition in the leukocyte migration was 66 and 61% with VGB and indomethacin, respectively. In thermoregulation studies, the rectal temperature of normothermic mice declined dose dependently. In another part of this study all the doses of VGB induced a significant reduction in body temperature at 45 min following drug administration in yeast-induced hyperpyrexic mice. The hypothermic response diminished after 90 min, 3 hours and 6 hours of treatment at 125, 250 and 500 mg/kg doses respectively and none of the dose showed any change in rectal temperature at 24-hour study point. The results of the present study indicate that vigabatrin has the potential to induce anti-edema, antigranuloma and leukocyte anti-migratory effects in inflamed peritoneal cavity and reduce the rectal temperature in normothermic as well as hyperthermia-induced mice with acute regimen. These effects are thought to be the result of GABA accumulation, its interaction with PG biosynthesis and other neuromediators.
Highlights
Drugs such as y-vinyl GABA, y-acetylenic GABA or aminooxyacetic acid increase brain and cerebrospinal fluid concentrations of y-aminobutyric acid (GABA), an inhibitory neurotransmitter, by binding irreversibly to GABA-transaminase (GABA-T).'" Extensive clinical use of VGB has shown that it is potentially effective against different seizure types, especially against complex partial seizures in epileptic cases697and in experimental models for the treatment of secondary generalized epilepsies and partialIt has a proven eficacy in adjuvant therapy in patients with refractoryDuring the last few years, many investigators have explored the correlation of VGB therapy and central GABA systems in epilepsy, analgesia, mania and certain other disease conditions
Protocols and administration ~rocedures Carraaeenan-inducednaw edema in rat A total of 30 rats divided in 5 groups were injected with 0.1 ml of 1% freshly prepared aqueous suspension of carrageenan into the hind paw of each rat to produce acute inflammation as described by Winter et al.37Treatment groups were as follows: Group 1 served as control; Group 2 was injected intraperitoneally (i.p) with indomethacin (25 mg/kg); Groups 3, 4 and 5 were injected with VGB 125, 250 or 500 mg/kg (i.p) respectively, 30 min before carrageenan injection
The treatment with the low dose (125 mg/kg) of VGB did not show any effect on paw edema, while the inhibition caused by intermediate and high dose was quite significant at ail the observation points till 240 min
Summary
Drugs such as y-vinyl GABA (vigabatrin, VGB), y-acetylenic GABA or aminooxyacetic acid increase brain and cerebrospinal fluid concentrations of y-aminobutyric acid (GABA), an inhibitory neurotransmitter, by binding irreversibly to GABA-transaminase (GABA-T).'" Extensive clinical use of VGB has shown that it is potentially effective against different seizure types, especially against complex partial seizures in epileptic cases697and in experimental models for the treatment of secondary generalized epilepsies and partialIt has a proven eficacy in adjuvant therapy in patients with refractoryDuring the last few years, many investigators have explored the correlation of VGB therapy and central GABA systems in epilepsy, analgesia, mania and certain other disease conditions. Drugs such as y-vinyl GABA (vigabatrin, VGB), y-acetylenic GABA or aminooxyacetic acid increase brain and cerebrospinal fluid concentrations of y-aminobutyric acid (GABA), an inhibitory neurotransmitter, by binding irreversibly to GABA-transaminase (GABA-T).'" Extensive clinical use of VGB has shown that it is potentially effective against different seizure types, especially against complex partial seizures in epileptic cases697and in experimental models for the treatment of secondary generalized epilepsies and partial. It has a proven eficacy in adjuvant therapy in patients with refractory. Literature has revealed that GABA is involved in temperature regulation,'l epilepsy,'"4 mania," analgesia,26-28Huntington's chorea and Parkinson's disease,[29] anxiety, sedation and anesthesia3' and muscle asti tic it^.^^ It is evident that GABA-ergic agents have some side effects and, as a consequence, measurable quantities of GABA were found in the peripheral organs and fluids suggesting that this inhibitory neurotransmitter may regulate some functions outside the central nervous system ( c N s ) . ~ ~O-th~e~r studies have suggested that GABAergic mechanism might be connected with some states in experimental animals and hurnan ~ . ~ ~ . ' ~ Evidence is suggestive of the extensive interconnecting neurons which link the GABA-ergic with the monominergic and serotonergic systems, raising the possibility that analgesic, thermoregulatory and some other effects of GABA could be mediated, at least partially, by the interaction of these systems
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