Inhibition of ASIC1a improves behavioral recovery after stroke.

Stroke continues to be a leading cause of death and long-term disabilities worldwide, despite extensive research efforts. The failure of multiple clinical trials raises the need for continued study of brain injury mechanisms and novel therapeutic strategies for ischemic stroke. The contribution of acid-sensing ion channel 1a (ASIC1a) to neuronal injury during the acute phase of stroke has been well studied, however, the long-term impact of ASIC1a inhibition on stroke recovery has not been established. The present study sought to bridge part of the translational gap by focusing on long-term behavioral recovery after a 30-minute stroke in mice that had ASIC1a knocked out or inhibited by PcTX1. The neurological consequences of stroke in mice were evaluated before and after the stroke using neurological deficit score, open field, and corner turn test over a 28-day period. ASIC1a knocked out and inhibited mice showed improved neurological scores more quickly than wild-type control and vehicle-injected mice after the stroke. ASIC1a knockout mice also recovered from mobility deficits in the open field test more quickly than wild-type mice, while PcTX1-injected mice did not experience significant mobility deficits at all after the stroke. In contrast to vehicle-injected mice which showed clear sidedness bias in corner turn test after stroke, PcTX1-injected mice never experienced significant sidedness bias at all. This study supports and extends previous work demonstrating ASIC1a as a potential therapeutic target for the treatment of ischemic stroke. Significance Statement The contribution of acid-sensing ion channels to neuronal injury is well studied; however, most work focuses on acute-phase molecular and histological endpoints. Here we begin to bridge the bench-to-bedside translational gap by using clinically relevant endpoints in our preclinical model. We show for the first time that both genetic knockout and acute pharmacological inhibition of ASIC1a improve long-term behavioral recovery after stroke. By performing neurological and behavioral tests over 28 days we found that deletion or inhibition of ASIC1a resulted in faster recovery of focal and general neurological deficits and mobility. This work is an important translational step in the identification of ASIC1a as a potential therapeutic target for stroke.