Abstract
The anticonvulsant effects of the inhibitor of the uptake of GABA, SKF 89976-A ( N-[4,4-diphenyl-3-butenyl]-nipecotic acid), were investigated using the amygdala kindling seizure model in rats. The time course of activity of the racemic mixture, given orally and the relative potencies of its d- and l-isomers, when given intraperitoneally, were tested. The drug SKF 89976-A was active, when given orally with anticonvulsant effects lasting 2–4 hr when given at 15 mg/kg and 4–6 hr when given at 30 mg/kg. Peak inhibition of severity of seizures occurred at 1 hr after administration with an ED 50 of 17.8 mg/kg. The d-isomer of SKF 89976-A was significantly more potent than the l-isomer and inhibited various parameters of kindled seizure activity in a dose-dependent manner. The l-isomer had significant effects on kindled seizures only at the largest dose (20 mg/kg). The ED 50 of the d-isomer for inhibition of severity of seizures measured 0.5 hr after intraperitoneal injection was, 11.2 mg/kg and the antiseizure effects of the d-isomer lasted for 2–3 hr. Side effects of SKF 89976-A such as sedation abdominal muscle relaxation rear limb splaying and ataxia were seen at 30 mg/kg; there was a marked suppression of seizure activity with no side effects at smaller doses. The characterization of a biphasic kindled seizure allows for speculation regarding the role of GABAergie mechanisms in its pathogenesis and of the mechanism of action of SKF 89976-A.
Published Version
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