NMDA Receptor-Targeted Neuroprotection in Ischemic Stroke: The 3S Framework Integrating Spatiotemporal Dynamics, Subtype Selectivity, and Signaling Pathways

Ischemic stroke remains a leading cause of death and disability worldwide, yet therapeutic options beyond thrombolysis are limited. A central paradox in stroke neuropharmacology lies in why complete NMDA receptor (NMDAR) blockade has repeatedly failed in clinical trials, while more targeted interventions retain therapeutic promise. To address this paradox, we propose a "Spatiotemporal-Subtype-Signaling (3S)" framework that integrates three interrelated dimensions: (1) spatiotemporal dynamics, in which receptor expression, phosphorylation, and subcellular localization shift across the transition from acute energy failure to delayed neurodegeneration; (2) subtype selectivity, in which distinct NMDAR subtypes exert opposing effects on neuronal fate, with GluN2A promoting survival via the PI3K-Akt-FOXO/GSK3β and ERK-CREB-BDNF pathways, GluN2B mediating excitotoxicity through p38 MAPK, JNK, and PSD-95-nNOS coupling, and GluN2C/GluN2D contributing through context-dependent mechanisms; and (3) signaling pathway selectivity, defined by the differential coupling of receptor subtypes to pro-survival versus pro-death cascades. Recent work further highlights NMDAR-ferroptosis crosstalk and sexual dimorphism: males rely predominantly on non-ionotropic GluN2B signaling, whereas females depend on estrogen receptor α (ERα) and G protein-coupled receptor 30 (GPR30)-mediated pathways. Translational efforts include subtype-selective antagonists (e.g., NP10679, a pH-sensitive GluN2B inhibitor) and disruptors of pathological protein-protein interactions (e.g., nerinetide, which targets the PSD-95-nNOS interface), while remote ischemic postconditioning has shown encouraging clinical results. Although these mechanisms remain primarily supported by preclinical evidence, they extend the scope of the framework. Collectively, the 3S framework clarifies why complete receptor blockade fails while precision interventions may succeed, and identifies priorities for sex-specific, subtype-targeted neuroprotective strategies in ischemic stroke.