Esketamine Enhances Post-Stroke Microglial Proliferation and Attenuates Neuroinflammation by Disrupting the Src-Pannexin1 Interaction

Previous research has suggested the potential of esketamine in alleviating post-stroke neuroinflammation, yet the underlying mechanism remained elusive. In our research, we have observed that esketamine increased the number of M2 anti-inflammatory phenotype microglia in the infarcted area after stroke, and this phenomenon is partly associated with the suppression of Panx1. Further research revealed that esketamine suppresses the phosphorylation of sarcoma kinase (Src) at the tyrosine 416 (Y416) site and inhibits the interaction between Src and Panx1, ultimately suppressing the function of Panx1. However, we found esketamine's inhibitory effect on post-stroke Panx1 activation is the underlying mechanism driving the increase in unactivated microglia, yet esketamine's influence on microglial polarization is mediated through a mechanism independent of Panx1.Our research suggests that esketamine, as a drug already used in clinical anesthesia, could potentially provide a solution during the periprocedural period to mitigate the damage caused by aseptic inflammation post-stroke. To further explore the reasons behind the increase in Src following Panx1 inhibition, we subjected the BV2 microglial cell line to glucose-oxygen deprivation and inhibited Panx1 using 10panx1.By comparing the RNA-seq results of the group subjected solely to glucose-oxygen deprivation with those of the 10panx1+ glucose-oxygen deprivation group, we were able to identify pathways related to changes in Src.