Presynaptic nicotinic acetylcholine receptors as a functional target of nefiracetam in inducing a long-lasting facilitation of hippocampal neurotransmission.
Nefiracetam (1-10 microM), a nootropic (or cognition-enhancing) agent, persistently potentiated currents through Torpedo acetylcholine (ACh) receptors expressed in Xenopus oocytes as a result of interacting with a protein kinase C pathway and the ensuing protein kinase C phosphorylation of the receptors. A similar effect was found in neuronal nicotinic ACh receptors (alpha4beta2 and alpha7). In contrast, the other nootropic agents such as piracetam and aniracetam had no potentiating action on the receptors. A sustained enhancement in the activity of nicotinic ACh receptors induced by nefiracetam caused a marked increase in the glutamate release, leading to a long-term potentiation-like facilitation of hippocampal synaptic transmissions. One of the consistent neuropathologic features of the Alzheimer brain is a loss of nicotinic ACh receptors. This fact, together with the results of our study, raises the possibility that the loss of nicotinic ACh receptors may be a key factor in the decline of cognitive function observed in Alzheimer disease and that agents targeting neuronal nicotinic ACh receptors like nefiracetam could, therefore, be of great therapeutic importance.
Nishizaki
T
T
Department of Physiology, Kobe University School of Medicine, Japan.
Matsuoka
T
T
Nomura
T
T
Kondoh
T
T
Watabe
S
S
Shiotani
T
T
Yoshii
M
M
D000109:Acetylcholine / Q000378:metabolism*; D000544:Alzheimer Disease / Q000503:physiopathology*; D000818:Animals; D003072:Cognition Disorders; D004594:Electrophysiology; D005973:Glutamine / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D018697:Nootropic Agents / Q000494:pharmacology*; D009865:Oocytes; D011493:Protein Kinase C / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D014981:Xenopus
D018697:Nootropic Agents; D011760:Pyrrolidinones; D011978:Receptors, Nicotinic; D005973:Glutamine; C058876:nefiracetam; D011493:Protein Kinase C; D000109:Acetylcholine