The Effect Of Dexmedetomidine On GSDMD-induced Pyroptosis After Subarachnoid Hemorrhage In Rats And The Relevant Mechanism

Background:Subarachnoid hemorrhage(SAH)is life-threatening and leads to severe brain damage.Only nimodipine has proven effective in the treatment of SAH.Previous reports suggests that gasdermin D(GSDMD)-induced pyroptosis plays a critical role in early brain injury(EBI)after SAH.Dexmedetomidine(DEX)has been reported to reduce expression of GSDMD in a sepsis model but the underlying mechanisms remain unclear.Methods:In the present study,we used a rat model of SAH to investigate the effect of DEX on GSDMD-induced pyroptosis in EBI after SAH and to determine the mechanisms involved.After SAH,DEX was injected immediately to detect whether it could inhibit the apoptosis and whether pathway was activated.After intracerebroventricular injection of PI3K inhibitor LY294002,we detected whether the PI3K/AKT/GSK3p pathway was effectively inhibited,and whether the effect of DEX on pyroptosis after SAH was inhibited.We used neurological function score,brain edema,blood-brain barrier damage and FJC staining to evaluate the degree of brain injury.Pyroptosis proteins were detected by immunohistochemistry,immunofluorescence and Western blot.The release of pro-inflammatory factors and anti-inflammatory factors were detected by enzyme-linked immunosorbent assay.Results:GSDMD-induced pyroptosis caused the release of pro-inflammatory cytokines of interleukin-1β and interleukin-18 and subsequent EBI,which was attenuated by DEX.Furthermore,Dex-mediated PI3K/AKT/GSK3β pathway activation after SAH was inhibited by the PI3K inhibitor LY294002.Finally,DEX administration significantly reduced the high mortality rate and improved the neurological scores after SAH.Conclusions:our data demonstrated that DEX may reduce GSDMD-induced pyroptosis in EBI after SAH via activation of the PI3K/AKT/GSK3βpathway.