Pharmacological study on Alzheimer's drugs targeting calcium/calmodulin- dependent protein kinase II

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. © the japanese pharmacological society.