The present study was aimed at determining whether nefiracetam might have a persistent cognition-enhancing effect in animals with sustained cerebral ischemia. Sustained cerebral ischemia was induced by injecting 700 microspheres into the right internal carotid artery of rats [microsphere-embolized (ME) rats]. The ME and sham-operated rats were treated with 10 mg/kg/day nefiracetam p.o. from the first to the 9th day after the operation. The escape latency of the ME rat in the water maze test, when performed on days 7 to 9 after the operation, was lengthened. This effect was attenuated by the delayed treatment with nefiracetam. The nefiracetam-treated ME rat showed a shortened escape latency in the retention test on day 17 as well as in the contraposition test on day 18. These results indicate that a persistent improvement of the spatial memory function impaired by sustained cerebral ischemia was achieved even after cessation of treatment with nefiracetam. The functional damage to learning and memory was associated with decreases in the membranous adenylyl cyclase I and cytosolic protein kinase A (PKA) catalytic subunit and regulatory subunit proteins in the right hippocampus and cerebral cortex. The delayed treatment with nefiracetam appreciably prevented the decreases in these proteins. The present study suggests that nefiracetam may have an ability to cause persistent improvement of learning and memory function, possibly through protection against the ischemia-induced impairment to the adenylyl cyclase/cAMP/PKA signal transduction pathway.
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