Neuroprotection during thrombectomy for acute ischemic stroke: a review of future therapies. Stroke is a major cause of death and disability globally. Endovascular thrombectomy has significantly reduced mortality, but functional outcomes remain suboptimal despite high recanalization rates. Adjunctive neuroprotective therapies are needed to improve outcomes. Recent preclinical studies have focused on preventing oxidative stress through antioxidant upregulation, with promising results. Various neuroprotective agents, including uric acid, activated protein C, nerinetide, otaplimastat, imatinib, verapamil, butylphthalide, edaravone, nelonemdaz, ApTOLL, regional hypothermia, remote ischemic conditioning, normobaric oxygen, and nuclear factor erythroid 2-related factor 2 (Nrf2), show potential for improving stroke care. Sedation and blood pressure management during thrombectomy also play crucial roles. A combined approach of endovascular therapy and neuroprotection may be key to reducing stroke-related disability. Stroke epidemiology and pathophysiology: Stroke risk factors are multifactorial, with non-modifiable factors including age, sex, ethnicity, and genetics, and modifiable factors including hypertension, hyperlipidemia, atrial fibrillation, cardiovascular disease, diabetes, and smoking. Aggressive management of modifiable risk factors reduces stroke risk. AIS occurs due to abrupt cessation of blood flow to the brain, leading to cell death. Large vessel occlusions (LVOs) are a major focus of reperfusion therapy, with 40% of AIS cases involving LVOs. Infarcted tissue experiences acidosis, inflammation, excitotoxicity, free radical toxicity, cytokine-mediated cytotoxicity, complement activation, oxidative stress, and BBB breakdown. These pro-inflammatory processes are central to neuroprotection research. Penumbra: The discovery of the ischemic core and penumbra has led to new treatment targets for salvageable ischemic tissue. Initial animal studies in the 1970s showed evidence of an irreversibly infarcted core surrounded by potentially recoverable tissue. Over decades, advances in AIS management have focused on penumbra detection and reperfusion therapies aimed at parenchymal salvage. Stroke and LVO detection: NCCTH is the first-line imaging modality for stroke evaluation, while MRI with DWI is the gold standard for stroke delineation. Multimodal protocols, including CTA or MRA, identify vaso-occlusive disease. MRI PWI and CTP are widely used for penumbra detection. Core-penumbra mismatch is associated with favorable outcomes. Current stroke treatment: LVO without revascularization results in severe disability and high mortality. The two mainstays of AIS treatment are IVT and EVT. IVT includes tPA and TNK, while EVT includes stent retrieNeuroprotection during thrombectomy for acute ischemic stroke: a review of future therapies. Stroke is a major cause of death and disability globally. Endovascular thrombectomy has significantly reduced mortality, but functional outcomes remain suboptimal despite high recanalization rates. Adjunctive neuroprotective therapies are needed to improve outcomes. Recent preclinical studies have focused on preventing oxidative stress through antioxidant upregulation, with promising results. Various neuroprotective agents, including uric acid, activated protein C, nerinetide, otaplimastat, imatinib, verapamil, butylphthalide, edaravone, nelonemdaz, ApTOLL, regional hypothermia, remote ischemic conditioning, normobaric oxygen, and nuclear factor erythroid 2-related factor 2 (Nrf2), show potential for improving stroke care. Sedation and blood pressure management during thrombectomy also play crucial roles. A combined approach of endovascular therapy and neuroprotection may be key to reducing stroke-related disability. Stroke epidemiology and pathophysiology: Stroke risk factors are multifactorial, with non-modifiable factors including age, sex, ethnicity, and genetics, and modifiable factors including hypertension, hyperlipidemia, atrial fibrillation, cardiovascular disease, diabetes, and smoking. Aggressive management of modifiable risk factors reduces stroke risk. AIS occurs due to abrupt cessation of blood flow to the brain, leading to cell death. Large vessel occlusions (LVOs) are a major focus of reperfusion therapy, with 40% of AIS cases involving LVOs. Infarcted tissue experiences acidosis, inflammation, excitotoxicity, free radical toxicity, cytokine-mediated cytotoxicity, complement activation, oxidative stress, and BBB breakdown. These pro-inflammatory processes are central to neuroprotection research. Penumbra: The discovery of the ischemic core and penumbra has led to new treatment targets for salvageable ischemic tissue. Initial animal studies in the 1970s showed evidence of an irreversibly infarcted core surrounded by potentially recoverable tissue. Over decades, advances in AIS management have focused on penumbra detection and reperfusion therapies aimed at parenchymal salvage. Stroke and LVO detection: NCCTH is the first-line imaging modality for stroke evaluation, while MRI with DWI is the gold standard for stroke delineation. Multimodal protocols, including CTA or MRA, identify vaso-occlusive disease. MRI PWI and CTP are widely used for penumbra detection. Core-penumbra mismatch is associated with favorable outcomes. Current stroke treatment: LVO without revascularization results in severe disability and high mortality. The two mainstays of AIS treatment are IVT and EVT. IVT includes tPA and TNK, while EVT includes stent retrie