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.