title: Post-stroke dementia. Nootropic drug modulation of neuronal nicotinic acetylcholine receptors.
abstract: 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, alpha-bungarotoxin (alpha-BuTX)-sensitive, rapidly desensitizing, alpha 7-type currents and alpha-BuTX-insensitive, slowly desensitizing, alpha 4 beta 2-type currents. Although alpha 7-type currents were only weakly inhibited by nefiracetam, alpha 4 beta 2-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 microM) 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 Gi/Go proteins are not involved. Pretreatment with cholera toxin did abolish nefiracetam potentiation. Thus, nefiracetam potentiation is mediated via Gs proteins. In conclusion, nefiracetam stimulates alpha 4 beta 2-type nnAChRs via Gs proteins at nanomolar concentrations. The potentiation of alpha 4 beta 2-type nnAChRs is thought to be at least partially responsible for cognitive enhancing action.
authors.affiliation: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.forename: J Z
authors.initials: JZ
authors.lastname: Yeh
authors.forename: T
authors.initials: T
authors.lastname: Narahashi
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002038:Bungarotoxins / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D002544:Cerebral Infarction / Q000188:drug therapy; D015140:Dementia, Vascular / Q000188:drug therapy; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018697:Nootropic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D011760:Pyrrolidinones / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D002038:Bungarotoxins; D018697:Nootropic Agents; D011760:Pyrrolidinones; D011978:Receptors, Nicotinic; D014665:Vasodilator Agents; C403531:nicotinic receptor alpha4beta2; C058876:nefiracetam; D000109:Acetylcholine