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.