Chemical Mechanisms of Cerebral Ischemia–Reperfusion Injury and Neuroprotection in the Thrombectomy Era

Mechanical thrombectomy has significantly improved outcomes for patients with large-vessel occlusion stroke. However, restoring the artery does not always re-establish full microvascular blood flow, tissue rescue, or a good neurological outcome. Ischemia–reperfusion injury varies over time, with distinct biochemical mechanisms dominating during ischemia, early reperfusion, and the subsequent hours. During ischemia, factors like adenosine triphosphate (ATP) depletion, ionic imbalance, calcium overload, mitochondrial dysfunction, acidosis, and metabolic changes such as succinate build-up render brain tissue highly vulnerable. When blood flow resumes, oxygen delivery to this stressed tissue can induce rapid mitochondrial redox shifts, electron leakage, reactive oxygen and nitrogen species formation, iron-dependent radical generation, and lipid peroxidation. Damage may then persist for hours through ongoing mitochondrial dysfunction, phospholipid hydroperoxide accumulation, reactive aldehydes, ferroptosis, blood–brain barrier breakdown, microvascular issues, and inflammation. Much of the mechanistic evidence supporting these processes derives from experimental studies, and their relevance to clinical outcomes after thrombectomy requires further validation. This narrative review tracks these chemical changes across the main phases of cerebral ischemia–reperfusion injury and connects them to modern thrombectomy practices. It also explores how the timing of each process may inform neuroprotective strategies, drug delivery methods, patient selection via imaging, and future clinical trial approaches.