2-Hydroxypropyl-β-Cyclodextrin Accesses Acute and Subacute Infarcts in a Mouse Model of Ischemic Stroke

Ischemic stroke is a leading cause of mortality and long-term disability worldwide, with limited pharmacological interventions available. 2-hydroxypropyl-β-cyclodextrin (HPβCD), a cyclic oligosaccharide approved for the treatment of Niemann-Pick disease type C, has demonstrated therapeutic potential in preclinical models of ischemic stroke by attenuating immune cell and lipid droplet accumulation in infarcts. However, the ability of HPβCD to penetrate ischemic brain tissues remains a critical determinant of its efficacy. The present study aimed to (1) assess the penetration and distribution of FITC-HPβCD within acute and subacute infarcts, which are sites of persisting blood-brain barrier (BBB) impairment, and (2) validate the accumulation of FITC-HPβCD in previously identified target organs, including the kidneys, liver, and spleen, using an aged (15-month-old) male mouse model of ischemic stroke induced by distal middle cerebral artery occlusion. We determined that FITC-HPβCD exhibits widespread systemic dissemination within 30 minutes after subcutaneous administration and is primarily eliminated via renal excretion. Notably, FITC-HPβCD selectively accumulated in the ipsilateral (i.e., infarcted) hemisphere 24 hours and 1 week after ischemic stroke, indicating that ischemia enhances the penetration of FITC-HPβCD into the brain. These results provide valuable insights into the therapeutic potential of HPβCD as a treatment for ischemic stroke and inform strategies for optimizing drug delivery to the brain in cerebrovascular diseases.