重症うつ病の「救命」薬、低用量ケタミンはなぜ数時間で症状を緩和できるのか?(How can low-dose ketamine, a ‘lifesaving’ drug for major depression, alleviate symptoms within hours? UB research reveals how)

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2024-11-13 バッファロー大学(UB)

ニューヨーク州立大学バッファロー校(UB)の研究者は、低用量のケタミンが主要なうつ病の症状を数時間以内に緩和し、その効果が数日間持続するメカニズムを解明しました。ケタミンは、脳内のN-メチル-D-アスパラギン酸(NMDA)受容体に結合し、その活動を選択的に抑制することで、迅速な抗うつ効果を発揮します。この発見は、ケタミンの効果的な使用法の理解や、類似の薬剤開発に貢献する可能性があります。

<関連情報>

低用量ケタミンによるNMDA受容体のアロステリック阻害 Allosteric inhibition of NMDA receptors by low dose ketamine

Jamie A. Abbott,Han Wen,Beiying Liu,Sheila S. Gupta,Gary J. Iacobucci,Wenjun Zheng & Gabriela K. Popescu
Molecular Psychiatry  Published:05 September 2024
DOI:https://doi.org/10.1038/s41380-024-02729-9

重症うつ病の「救命」薬、低用量ケタミンはなぜ数時間で症状を緩和できるのか?(How can low-dose ketamine, a ‘lifesaving’ drug for major depression, alleviate symptoms within hours? UB research reveals how)

Abstract

Ketamine, a general anesthetic, has rapid and sustained antidepressant effects when administered at lower doses. Anesthetic levels of ketamine reduce excitatory transmission by binding deep into the pore of NMDA receptors where it blocks current influx. In contrast, the molecular targets responsible for antidepressant levels of ketamine remain controversial. We used electrophysiology, structure-based mutagenesis, and molecular and kinetic modeling to investigate the effects of ketamine on NMDA receptors across an extended range of concentrations. We report functional and structural evidence that, at nanomolar concentrations, ketamine interacts with membrane-accessible hydrophobic sites on NMDA receptors, which are distinct from the established pore-blocking site. These interactions stabilize receptors in pre-open states and produce an incomplete, voltage- and pH-dependent reduction in receptor gating. Notably, this allosteric inhibitory mechanism spares brief synaptic-like receptor activations and preferentially reduces currents from receptors activated tonically by ambient levels of neurotransmitters. We propose that the hydrophobic sites we describe here account for clinical effects of ketamine not shared by other NMDA receptor open-channel blockers such as memantine and represent promising targets for developing safe and effective neuroactive therapeutics.

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