The anti-dementia drug nefiracetam facilitates hippocampal synaptic transmission by functionally targeting presynaptic nicotinic ACh receptors

Nefiracetam, a pyrrolidone derivative developed as an anti-dementia drug, p ersistently potentiated currents through neuronal nicotinic acetylcholine ( ACh) receptors (alpha 7, alpha 4 beta 2) expressed in Xenopus oocytes, and the potentiation was blocked by either the selective protein kinase C (PKC) inhibitors, GF109203X and staurosporine, or co-expressed active PKC inhibi tor peptide. In primary cultures of rat hippocampal neurons, nefiracetam in creased the rate of nicotine-sensitive miniature excitatory postsynaptic cu rrents, without affecting the amplitude, and the increase was inhibited by GF109203X. In addition, the drug caused a marked increase in the glutamate release from electrically stimulated guinea pig hippocampal slices, and the effect was abolished by the nicotinic ACh receptor antagonists, alpha-bung arotoxin and mecamylamine. Nefiracetam induced a long-lasting facilitation of synaptic transmission in both the CAI area and the dentate gyrus of rat hippocampal slices, and the facilitation was inhibited by alpha-bungarotoxi n and mecamylamine. Such facilitatory action was still found in the hippoca mpus with selective cholinergic denervation. The results of the present stu dy, thus, suggest that nefiracetam enhances activity of nicotinic ACh recep tors by interacting with a PKC pathway, thereby increasing glutamate releas e from presynaptic terminals, and then leading to a sustained facilitation of hippocampal neurotransmission. This may represent a cellular mechanism u nderlying the cognition-enhancing action of nefiracetam. The results also p rovide the possibility that nefiracetam could be developed as a promising t herapeutic drug for senile dementia or Alzheimer's disease. (C) 2000 Elsevi er Science B.V. All rights reserved.