Unique mechanism of action of Alzheimer's drugs on brain nicotinic acetylcholine receptors and NMDA receptors.
While a variety of hypotheses have been proposed for the cause of Alzheimer's disease, our knowledge is far from complete to explain the disease making it difficult to develop the methods for treatment. In the brain of Alzheimer's patients, both neuronal nicotinic acetylcholine (nACh) receptors and NMDA receptors are known to be down-regulated. Thus four anticholinesterases have been developed and approved for the treatment in the U.S.A. However, these are not ideal drugs considering their side effects and limited effectiveness. Nefiracetam is being developed for the treatment of Alzheimer's and other patients with dementia, and has unique actions in potentiating the activity of both nACh and NMDA receptors as demonstrated by in vitro patch clamp experiments using rat cortical neurons in primary culture. Nefiracetam potentiated alpha4beta2-like ACh- and NMDA-induced currents at nanomolar concentrations forming bell-shaped dose-response curves with the maximum potentiation occurring at 1 and 10 nM, respectively. Nefiracetam potentiated nACh receptor currents via G(s) proteins, but not G(i)/G(o) proteins, PKA or PKC. Nefiracetam potentiation of NMDA currents occurred via interactions with the glycine binding site of the NMDA receptor. The nefiracetam potentiation of both nACh and NMDA receptors in a potent and efficacious manner is deemed responsible for its cognitive enhancing action.
Narahashi
Toshio
T
Department of Molecular Pharmacology Biological Chemistry, Northwestern University Medical School, 303 E. Chicago Avenue, Chicago, IL 60611, USA. tna597@northwestern.edu
Marszalec
William
W
Moriguchi
Shigeki
S
Yeh
Jay Z
JZ
Zhao
Xilong
X
D000109:Acetylcholine / Q000494:pharmacology; D000157:Aconitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002038:Bungarotoxins / Q000494:pharmacology; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D018738:Hexamethonium / Q000494:pharmacology; D008464:Mecamylamine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D011494:Protein Kinases / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D011978:Receptors, Nicotinic / Q000187:drug effects*
D002038:Bungarotoxins; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D018697:Nootropic Agents; D011760:Pyrrolidinones; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; C058876:nefiracetam; C054634:methyllycaconitine; D004079:Dihydro-beta-Erythroidine; D018738:Hexamethonium; D008464:Mecamylamine; D011494:Protein Kinases; D019204:GTP-Binding Proteins; D000109:Acetylcholine; D000157:Aconitine