Post-stroke dementia: Nootropic drug modulation of neuronal nicotinic acetylcholine receptors

Nefiracetam is a new pyrrolidone nootropic drug that is being developed for clinical use in the treatment of post-stroke vascular-type and Alzheimer's-type dementia. Among a few neuroreceptors that have been identified as potential targets of nootropics, neuronal nicotinic acetylcholine receptors (nnAChRs) are deemed the most important since they are related to learning, memory, and Alzheimer's disease dementia. We have recently found potent stimulating action of nefiracetam on nnAChRs. Rat cortical neurons in long-term primary culture expressed nnAChRs. Whole-cell patch clamp experiments revealed two types of currents induced by ACh, α-bungarotoxin (α-BuTX)-sensitive, rapidly desensitizing, α7-type currents and α-BuTX-insensitive, slowly desensitizing, α4β2-type currents. Although α7-type currents were only weakly inhibited by nefiracetam, α4β2-type currents were potently and efficaciously potentiated by nefiracetam. Nefiracetam at 0.1 nM reversibly potentiated ACh-induced currents to 200-300% of control. Very high concentrations (about 10 μM) also potentiated these currents, but to a lesser extent, indicative of the bell-shaped dose-response relationship known to occur for nefiracetam, even in animal behavior experiments. Three specific inhibitors of each of PKA and PKC did not prevent nefiracetam from potentiating ACh-induced currents, indicating that these protein kinases are not involved in nefiracetam action. Pretreatment with pertussis toxin did not alter nefiracetam potentiation, indicating G_i/G_o proteins are not involved. Pretreatment with cholera toxin did abolish nefiracetam potentiation. Thus, nefiracetam potentiation is mediated via G_s proteins. In conclusion, nefiracetam stimulates α4β2-type nnAChRs via G_s proteins at nanomolar concentrations. The potentiation of α4β2-type nnAChRs is thought to be at least partially responsible for cognitive enhancing action.