Mild hypercapnia before reperfusion reduces ischemia-reperfusion injury in hyperacute ischemic stroke rat model

Endovascular thrombectomy has a recanalization rate over 80%; however, approximately 50% of ischemic stroke patients still experience dependency or mortality. Recently, clinical trials demonstrated the benefits of administering neuroprotective agents prior to endovascular thrombectomy. Additionally, recent studies showed neuroprotective effects of mild hypercapnia in patients resuscitated after cardiac arrest. However, its efficacy in ischemic stroke remains unclear. We aimed to investigate whether carbon dioxide (CO 2 ) per-conditioning has neuroprotective effects in rat models with middle cerebral artery occlusion (MCAO). Rat models received intermittent inhalation of mixed gas during the MCAO period. After surgery, behavioral assessments, infarct size measurement, immunohistochemistry, and western blot analysis were performed. We found CO 2 per-conditioning reduced infarct size and neurological deficit. The number of 8-hydroxy-2-deoxyguanosine (8-OHdG) positive cells and matrix metalloproteinase 9 (MMP-9)/platelet derived growth factor receptor beta (PDGFRβ) double positive cells were significantly decreased after CO 2 per-conditioning. The expressions of tight junction protein and pericytes survival were preserved. This study underscores mild hypercapnia before reperfusion not only reduces neurologic deficit and infarct size, but also maintains the integrity of the blood-brain barrier and neurovascular unit, alongside mitigating oxidative stress in hyperacute stroke rat models. Therapeutic mild hypercapnia before reperfusion is promising and requires further clinical application.