Kv1.3 as a therapeutic target for immunocytoprotection after reperfusion in ischemic stroke.

Abstract

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 hours after reperfusion dose-dependently reduces infarction and improves neurological deficit on day-8 after ischemic stroke. 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. We therefore tested whether Kv1.3 deletion or delayed pharmacological therapy would be beneficial in females and aged animals. Transient middle cerebral artery occlusion (tMCAO, 60-min) was induced in 16-week and 80-week-old male and female wild-type C57BL/6J and Kv1.3-/- mice. Stroke outcomes were assessed daily with the 14-score tactile and proprioceptive limp-placing test and on day-8 by T2-weighted MRI. Young and old female mice were treated twice daily with 40 mg/kg of the Kv1.3 blocker PAP-1 starting 12 hours after reperfusion. 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. PAP-1 treatment improved outcomes in both young and old females. In old females, Kv1.3 deletion and PAP-1 treatment significantly reduced microglia activation and T cell infiltration in the infarcted 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. Using young male rats, we further explored the treatment window for Kv1.3 inhibitors and found that PAP-1 treatment still provided benefit and reduced inflammatory marker expression in the brain when started 72 hours after reperfusion.