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Endovascular thrombectomy and t-PA are the only current standard of care treatments for emergent large vessel occlusion (ELVO) stroke. Despite rising recanalization rates, stroke remains the leading cause of long-term disability worldwide suggesting that additional therapies are needed. Severe stroke morbidity may be due, in part, to the acute and sustained inflammatory stroke response. Preclinical research has supported anti-inflammatory agents in limiting brain injury and improving functional outcome; however, the post-stroke inflammatory cascade appears to have both beneficial and deleterious effects, necessitating careful therapeutic translation. We have recently demonstrated that delayed (3 day) post-stroke intravenous (IV) administration of the interleukin (IL)-1α (one of the two major isoforms of the pro-inflammatory family of cytokine IL-1), promoted, rather than suppressed, post-stroke angiogenesis in the transient middle cerebral artery occlusion (MCAo) mouse model. In this study, we aimed to show a therapeutic efficacy of IL-1α in neuroprotection. We investigated the potential for IL-1α, administered acutely IV or intra-arterial (IA) (n=5) after mouse MCAo, to also be neuroprotective. We noted that IV IL-1α (1 ng) is neuroprotective (as measured by cresyl violet stained infarct volumes) with mild, transient side effects (blunted hypertension and bradycardia) that were well tolerated, and with better functional recovery in free motion behavioral tests. IA IL-1α (0.1 ng) administration was even more neuroprotective without the systemic changes seen with IV treatment. Additionally, we noted that IL-1α is directly neuroprotective of primary mouse cortical neurons exposed to oxygen and glucose deprivation conditions in vitro. Taken together, these results suggest that IL-1α could be therapeutic after stroke when administered IV or IA, and the latter may eliminate potentially harmful hemodynamic side effects.