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

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.