Sevoflurane reduces brain edema and improves blood-brain barrier by downregulating CaMKII to inhibit TMEM16A after cerebral ischemia injury both in vivo and in vitro.

This study aimed to investigate whether sevoflurane could reduce brain edema and protect blood-brain barrier (BBB) after cerebral-ischemia injury in vivo and in vitro via calmodulin-dependent protein kinase II (CaMKII)/ transmembrane protein 16A (TMEM16A) pathway. Adult male Sprague-Dawley rats and the brain slices were respectively subjected to middle cerebral artery occlusion (MCAO) in vivo and oxygen-glucose deprivation (OGD) in vitro. Sevoflurane was intervened through a combination of pre-treatment and post-treatment in entire process. TMEM16A overexpression and knockdown was performed by adeno-associated virus. And using agonist and inhibitor affected CaMKII. Neurologic function, ultrastructure, brain water content and the integrity of blood-brain barrier were assessed. Protein levels were investigated by immunofluorescence and western blot. TMEM16A and AQP4 levels, brain water content, leakage of BBB increased in MCAO group. Claudin5 and ZO-1 levels decreased and neurological damage was aggravated after MCAO injury. Sevoflurane reduced brain edema, improved neurological function and protected BBB after MCAO by increasing Claudin5 and ZO-1 levels and decreasing TMEM16A and AQP4 levels. The effect of sevoflurane was weakened by overexpression of TMEM16A and enhanced by knockout of its expression. And when using the inhibitor KN-93, CaMKII level increased while TMEM16A level decreased, enhancing the neuroprotective effect of sevoflurane. Conversely, the effect of sevoflurane was weakened after using the agonist CALP1. Similarly, these manifestations were also observed after OGD injury. In brief, our findings suggest sevoflurane could reduce brain edema, and protect the BBB after cerebral ischemia-reperfusion injury which are related to the downregulation of CaMKII to inhibit TMEM16A.