Mechanisms Underlying Region-Specific Vulnerability and Resistance to Ischemia-Reperfusion Injury in the Central Nervous System

Selective neuronal vulnerability is a hallmark of ischemic injury in the central nervous system (CNS), yet the mechanisms underlying regional differences in neuronal survival and degeneration remain incompletely understood. Cerebral ischemia from ischemic stroke or cardiac arrest triggers a complex cascade of metabolic failure, excitotoxic signaling, oxidative stress, and neuroinflammatory responses that collectively determine neuronal fate. Notably, neuronal degeneration follows highly specific anatomical patterns rather than uniformly throughout the CNS. Classical experimental studies have shown that hippocampal cornu ammonis 1 (CA1) pyramidal neurons undergo delayed neuronal death after transient global ischemia, whereas neighboring CA3 neurons remain relatively resistant. Similar heterogeneity is observed in other regions, including the olfactory bulb and spinal cord, where mitral cells and dorsal horn neurons exhibit relative resistance to ischemic injury. Accumulating evidence indicates that selective vulnerability arises from the interplay of multiple molecular and cellular mechanisms, including excitotoxic glutamatergic signaling, mitochondrial dysfunction, oxidative stress, neurovascular unit dysfunction, and neuroinflammatory responses. In addition, structural and circuit-level determinants such as hippocampal connectivity and regional neurovascular organization further influence neuronal susceptibility to ischemic stress. This review integrates evidence from experimental and clinical studies to examine the mechanisms underlying neuronal vulnerability and resistance across the CNS. Particular emphasis is placed on the interplay between neuronal metabolism, glial responses, and neurovascular regulation in shaping regional injury patterns. Understanding these mechanisms may provide important insights for the development of mechanism-based neuroprotective strategies targeting selectively vulnerable neuronal populations.