Nihon Yakurigaku Zasshi 1998 Oct 01;112 Suppl 1:41P-43P. doi: 10.1254/fpj.112.supplement_41.

[Facilitatory actions of the cognitive enhancer nefiracetam on neuronal Ca2+ channels and nicotinic ACh receptors: their intracellular signal transduction pathways].

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Nootropics are proposed to serve as cognition enhancers. The underlying mechanism, however, is largely unknown. We have attempted to assess the intracellular signal transduction pathways mediating the action of nefiracetam, a nootropic agent, on neuronal Ca2+ channels and nicotinic ACh receptors. In NG108-15 cells, nefiracetam (1 microM) enhanced the activities of N/L-type Ca2+ channels without affecting T-type The nefiracetam action was mimicked by dibutyryl cAMP (1 mM), or blocked by pertussis toxin (PTX), indicating that PTX-sensitive inhibitory G-proteins and cAMP-dependent pathways mediate the drug action. Nefiracetam also exerted a dose-dependent biphasic effect on Torpedo nicotinic acetylcholine (nACh) receptors expressed in Xenopus oocytes, in which the drug induced a short-term depression of ACh-evoked currents at submicromolar concentrations (0.01-0.1 microM) and a long-term enhancement of the currents at micromolar concentrations (1-10 microM). The depression was caused by activation of PTX-sensitive G-protein-regulated cAMP-dependent protein kinase (PKA) with subsequent phosphorylation of the ACh receptors; in contrast, the enhancement was caused by activation of Ca(2+)-dependent protein kinase C (PKC) and the ensuing PKC phosphorylation of the receptors. It is concluded that nefiracetam interacts with PKA and PKC pathways, which may explain a cellular mechanism for the action of cognitive enhancers.

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Genes referenced: camp