Strokes constitute over 50% of all neurological diseases, standing as the foremost cause of physical and mental disability. Currently, there are no widely accepted gold standard treatments for ischemic strokes beyond intravenous thrombolysis and mechanical thrombectomy applied during the acute therapeutic window. Therefore, the need for novel treatments targeting crucial signaling mediators involved in ischemic stroke is of utmost importance. The sigma-1 receptor (S1R), a molecular chaperone located at mitochondria-associated endoplasmic reticulum membranes (MAM), has exhibited neuroprotective effects when modulated by synthetic and endogenous agents across various cerebrovascular diseases. In this review, we describe the emerging therapeutic role of S1R agonists and antagonists in regulating blood-brain barrier (BBB) dysfunction, neuroinflammation, and neurocognitive impairment following ischemic stroke.
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