Neuroprotective Effects, Mechanisms of Action and Therapeutic Potential of the Kv7/KCNQ Channel Opener QO-83 in Ischemic Stroke.

Abstract

Ischemic stroke is a worldwide disease with high mortality and morbidity. Kv7/KCNQ channels are key modulators of neuronal excitability and microglia function, and activation of Kv7/KCNQ channels has emerged as a potential therapeutic avenue for ischemic stroke. In the present study, we focused on a new Kv7/KCNQ channel opener QO-83 on the stroke outcomes and its therapeutic potential. Transient or distal middle cerebral artery occlusion model was established with C57 mouse to evaluate the role of QO-83. Solitary dose of QO-83 contributes to the microglia inhibition and fibrotic scar mitigation post stroke. QO83 shows prominent effect on reducing infarction area, alleviating cerebral edema, maintaining blood-brain barrier integrity, and enhancing neurogenesis. Single-nucleus RNA sequencing unveils neuroprotection and specific microglial subclusters influenced by QO-83. More importantly, QO83 shows promise in enhancing survival rates with dose dependence. Notably, these protective effects extend beyond the 4-6 h post-reperfusion window. Additionally, continuous dosing of QO-83 correlates with enhanced cognition. In conclusion, this study highlights QO-83 as a protective agent against ischemic brain injury, showcasing its multifaceted effects and potential as a therapeutic strategy.