Pharmacological study on Alzheimer's drugs targeting calcium/calmodulin-dependent protein kinase 2
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- Moriguchi Shigeki
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan
書誌事項
- タイトル別名
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- Pharmacological Study on Alzheimer's Drugs Targeting Calcium/Calmodulin-Dependent Protein Kinase II
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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.
収録刊行物
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- Journal of Pharmacological Sciences
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Journal of Pharmacological Sciences 117 (1), 6-11, 2011
公益社団法人 日本薬理学会
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詳細情報 詳細情報について
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- CRID
- 1390001205178738816
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- NII論文ID
- 10029895756
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- NII書誌ID
- AA11806667
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- ISSN
- 13478648
- 13478613
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- NDL書誌ID
- 11243190
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
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