title: Pharmacological study on Alzheimer's drugs targeting calcium/calmodulin-dependent protein kinase II.
abstract: In the brain of Alzheimer's disease patients, down-regulation of both cholinergic and glutamatergic systems have been found and is thought to play an important role in impairment of cognition, learning, and memory. Nefiracetam is a pyrrolidine-related nootropic drug exhibiting various pharmacological actions such as a cognitive-enhancing effect. The present study was undertaken to elucidate mechanisms underlying the action of nefiracetam on glutamatergic receptors and intracellular protein kinases. N-Methyl-D-aspartate (NMDA)-evoked currents were recorded from rat cortical neurons in long-term cultured primary neurons using the whole-cell patch-clamp technique. NMDA-evoked currents were greatly and reversibly potentiated by bath application of nefiracetam, resulting in a bell-shaped dose-response curve. The maximum potentiation of 170% relative to the control was produced at 10 nM. Treatment with an inhibitor of the glycine binding site of the NMDA receptor, 7-chlorokynurenic acid, at 1 µM prevented augmentation of NMDA-evoked currents by nefiracetam. In rat hippocampal CA1 slices, field excitatory postsynaptic potentials were recorded by stimulation of Schaffer collateral/commissural pathways. Nefiracetam treatment significantly enhanced long-term potentiation (LTP) with the same bell-shaped dose-response curve. Furthermore, nefiracetam-induced LTP enhancement was closely associated with calcium/calmodulin-dependent protein kinase II (CaMKII) activation with concomitant increase in phosphorylation of AMPA-type glutamate receptor subunit 1 (GluA1) (Ser-831) as a postsynaptic CaMKII substrate. In conclusion, nefiracetam enhances NMDA-receptor function through stimulation of its glycine binding site and nefiracetam-induced CaMKII activation likely contributes to improvement of cognition, learning, and memory.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan. shigeki@mail.pharm.tohoku.ac.jp
authors.forename: Shigeki
authors.initials: S
authors.lastname: Moriguchi
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats
chemical_list: D011760:Pyrrolidinones; C058876:nefiracetam; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2