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

Abstract

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 neruronal Ca²⁺ channels and nicotinic ACh receptors. In NG108-15 cells, nefiracetam (1 μM) 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 μM) and a long-term enhancement of the currents at micromolar concentrations (1 - 10 μM). 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 Ca²⁺-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.