Effects of nefiracetam on spatial memory function and acetylcholine and GABA metabolism in microsphere-embolized rats

The present study aimed to determine whether nefiracetam, N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, a cognition enhancer, has an effect on learning and memory function in sustained cerebral ischemia, and whether the effect, if any, may accompany modification of the cholinergic or gamma-aminobutyric acid (GABA)ergic system, which are conceived to be involved in the learning and memory function, in the ischemic brain. Sustained cerebral ischemia was induced by the injection of 700 microspheres into the right hemisphere of the rat. The animals were treated once daily with 10 mg/kg nefiracetam p.o. from 15 h after the operation to either 10 days for the water maze study, or 3 or 5 days after the operation for neurochemical examination. Microsphere-embolized rats showed stroke-like symptoms 15 h after the operation and lengthened the escape latency in the water maze task on days 7-10, suggesting a spatial learning dysfunction. The delayed treatment did not reduce the stroke-like symptoms, but effectively shortened the escape latency. The animals at days 3 and 5 after the operation showed decreases in acetylcholine content and choline acetyltransferase activity, which were not prevented by nefiracetam. The microsphere-embolized rats showed decreases in GABA content and glutamic acid decarboxylase activity. The delayed treatment appreciably restored GABA content in the hippocampus on day 5 and reversed glutamic acid decarboxylase activity in both brain regions on day 5. These results suggest that the GABAergic activity rather than the cholinergic activity may be, at least in part, involved in the pharmacological effects of nefiracetam in the ischemic brain.