Beyond Ischemic Duration: Mechanistic Determinants of Neuronal Vulnerability in Global Brain Ischemia–Reperfusion Versus Cardiac Arrest (CA/ROSC)

Global cerebral ischemia remains a major cause of neurological morbidity and mortality, yet effective neuroprotective strategies have shown limited translational success. Experimental studies frequently rely on ischemic duration as a primary determinant of injury severity, implicitly assuming equivalence across global brain ischemia-reperfusion (IR) and cardiac arrest with return of spontaneous circulation (CA/ROSC) models. However, increasing experimental evidence indicates that identical ischemic durations can lead to substantially different neuronal outcomes depending on the physiological and systemic context of ischemia. In brain-restricted global IR models, partial preservation of systemic circulation allows residual metabolic activity, delayed stress responses, and region-specific neuronal vulnerability, most notably delayed neuronal death in the hippocampal cornu ammonis 1 region. By contrast, CA/ROSC is characterized by complete systemic circulatory arrest followed by a biologically hostile reperfusion phase that includes profound mitochondrial dysfunction, heterogeneous reperfusion, blood-brain barrier disruption, and amplification of systemic inflammatory responses. As a result, these qualitative differences shift ischemic injury thresholds toward earlier onset and broader neuronal damage in CA/ROSC, even when ischemic durations are nominally comparable. This review integrates experimental evidence from rat models to examine how energy failure, reperfusion biology, proteostasis disruption, and brain-body interactions collectively determine neuronal vulnerability beyond ischemic duration alone. Through direct comparison of global IR and CA/ROSC paradigms, we highlight limitations of duration-centric interpretations and outline implications for experimental design and translational neuroprotection. Recognition of context-dependent ischemic mechanisms is essential for improving model selection and advancing therapeutic strategies for global cerebral ischemia.