Astrocytic BEST1 can serve as a target for functional recovery after ischemic stroke.

Abstract

Solid evidence from animal experiments supported the concept of peri-infarct tonic inhibition. Related drug targets have the potential to be translated for clinical stroke treatment. Recently, we reported the contribution of neuronal bestrophin-1 (BEST1)-mediated glutamate release to acute ischemic damage exacerbation in rodents. Now, we found a switch of abnormal BEST1 expression and function from neurons to astrocytes in the peri-infarct cortex following astrocytic activation. Excessive GABA was released through astrocytic BEST1 channel during the subacute phase of stroke, leading to sustained tonic inhibition. Astrocyte-specific knockdown of BEST1 promoted motor functional recovery, depending on reduced tonic inhibition. Moreover, we prepared self-assembled nanoparticles encapsulating siBest1 (SNP-siBest1), which displayed high brain accumulation and long circulation and knocked down astrocytic BEST1 effectively and safely. Systemic treatment with SNP-siBest1 after ischemic stroke showed a therapeutic effect in mice. Therefore, BEST1 is a potential target for stroke therapy from acute to subacute phase, and selective BEST1 blockers beyond nanoparticles are worth developing.