Neuroprotection by YZG-331 in postoperative cognitive dysfunction via Mg²⁺-dependent blockade of NMDA receptors.

Authors

Han Guo, Jiaojiao Zhao, Keying Tian, Qinghui Guo, Siruan Chen, Yuhan Ge, Wenyan Guo, Xingchen Lin, Hui Bai, Lei Yang, Lei Yang, Xia Qin, Panpan Zhang, Zhanfeng Jia, Ruifang Zheng, Zuxiao Yang, Yun Stone Shi, Dezhi Kong, Tengfei Ji, Wei Zhang

Published in

Acta pharmaceutica Sinica. B. Volume 16. Issue 9. Pages 5995-6012. Epub Jul 20, 2026.

Abstract

Postoperative cognitive dysfunction (POCD) is a debilitating neurological complication that occurs following surgery, for which no effective interventions are currently available. Here, we identified YZG-331, a novel adenosine analog, as a promising neuroprotective agent that rescues cognitive deficits and mitigates dendritic spine loss in a murine POCD model. Integrated proteomic profiling and bioinformatics pathway analysis revealed that YZG-331 selectively targets NMDA receptor (NMDAR) signaling. Electrophysiological recordings and living-cell calcium imaging demonstrated that YZG-331 suppressed NMDAR-mediated currents and calcium influx in a dose-dependent manner. Furthermore, Mg²⁺ is required for YZG-331 to inhibit NMDAR activity. YZG-331 disrupts the formation of NMDAR condensates in the presence of Mg²⁺, thereby attenuating NMDAR-mediated excitotoxicity. Our findings establish YZG-331 as a prospective therapeutic candidate for POCD and reveal Mg²⁺-dependent receptor modulation as a novel pharmacological strategy for targeting NMDAR-associated neuropathologies.

PMID:
42764912
Bibliographic data and abstract were imported from PubMed on 21 Sep 2026.

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