5-(4-phenylbutoxy)psoralen and Infarction--Middle-Cerebral-Artery

The voltage-gated potassium channel Kv1.3, which is expressed on activated, disease-associated microglia and memory T cells, constitutes an attractive target for immunocytoprotection after endovascular thrombectomy (EVT). Using young male mice and rats we previously demonstrated that the Kv1.3 blocker PAP-1 when started 12 h after reperfusion dose-dependently reduces infarction and improves neurological deficit on day 8. However, these proof-of-concept findings are of limited translational value because the majority of strokes occur in patients over 65 and, when considering overall lifetime risk, in females. Here, we therefore tested whether Kv1.3 deletion or delayed pharmacological therapy would be beneficial in females and aged animals.. Kv1.3 deletion provided no significant benefit in young females but improved outcomes in young males, old males, and old females compared with wild-type controls of the same sex. Delayed PAP-1 treatment improved outcomes in both young and old females. In old females, Kv1.3 deletion and PAP-1 treatment significantly reduced Iba-1 and CD3 staining intensity in the ipsilateral hemisphere.. Our preclinical studies using aged and female mice further validate Kv1.3 inhibitors as potential adjunctive treatments for reperfusion therapy in stroke by providing both genetic and pharmacological verification.

Topics: Age Factors; Animals; Combined Modality Therapy; Disease Models, Animal; Female; Ficusin; Infarction, Middle Cerebral Artery; Kv1.3 Potassium Channel; Male; Mice; Mice, Inbred C57BL; Reperfusion; Stroke