Region- and Cell-Specific Vulnerability to ROS After Global Brain Ischemia-Reperfusion Injury: Molecular and Cellular...

Global brain ischemia-reperfusion (I/R) injury manifests as selective neuronal vulnerability rather than uniform tissue damage. Specific neuroanatomical regions-most notably the hippocampal cornu ammonis 1 (CA1) subfield, striatum, and cerebellum-exhibit a heightened susceptibility to oxidative stress-induced degeneration. This review consolidates current understanding regarding the region- and cell-specific vulnerability to reactive oxygen species (ROS) following global I/R, highlighting the molecular and cellular determinants that drive this selectivity. We examine the spatial distribution of ROS-generating systems, including NADPH oxidases (NOX2/NOX4) and mitochondrial complexes, alongside the divergent expression of antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase. Inherent neuronal properties, such as elevated synaptic activity, calcium permeability, and rigorous metabolic demands, further exacerbate oxidative injury. Additionally, we evaluate how astrocyte-neuron interactions and regional variations in blood-brain barrier (BBB) integrity modulate the severity and progression of ROS-induced damage. The roles of astrocytic endfoot polarization, aquaporin-4 (AQP4) localization, and Kir4.1-mediated potassium buffering in post-ischemic outcomes are also discussed. Furthermore, this review surveys emerging antioxidant-based therapies-ranging from edaravone and melatonin to selenium nanoparticles and miRNA-based interventions-while addressing translational hurdles like narrow therapeutic windows and inter-individual variability. By synthesizing experimental and translational evidence, this work provides a comprehensive framework for understanding oxidative stress-related vulnerability in I/R injury. Ultimately, it underscores the necessity for precision antioxidant strategies tailored to brain-region specificity, pathophysiological timing, and patient-specific factors to improve clinical outcomes.