| BackgroundStroke is one of the high incidence diseases worldwide,and it is the primary cause of death and disability in China.Ischemic stroke is the main type of stroke.In clinic,some operations may cause perioperative ischemic stroke,such as neurosurgery and cardiac macro vascular surgery.After ischemic stroke,the recovery of blood flow will cause ischemia-reperfusion injury.Diabetes increases the risk of perioperative stroke and worsens the severity of neurological impairment after stroke.Therefore,the choice of anesthetics for patients with diabetes mellitus during perioperative period has clinical significance.Isoflurane is one of the commonly used inhalation anesthetics in clinic.It has the effects of neuroprotection and anti-neuroinflammatory response.Our previous studies have shown that isoflurane pretreatment has neuroprotective effects in diabetic stroke,and its mechanism is related to inhibiting the activity of NLRP3(NLR family pyrin domain containing 3)inflammasome.However,the further mechanism is not clear.At the same time,some studies have shown that autophagy is also involved in the process of stroke.The activation of Toll like receptor-4(TLR4)plays a very important role in neuroinflammatory response mediated by microglia.Studies have shown that when the body is stimulated by endogenous and exogenous danger signals,TLR4 is activated by activating its downstream nuclear factor NF-κB.Promoting Interleukin-1(3 matures and releases and participates in the process of inflammatory response.In addition,TLR4 is also a receptor of autophagy and plays an important role in the process of autophagy.In conclusion,we speculate that the neuroprotective effect of isoflurane is related to TLR4 mediated inflammatory response and autophagy.Our study provides an important basis for the protection of diabetic cranial nerves during perioperative period.ObjectivesInvestigate the neuroprotective effect of isoflurane on diabetic stroke combined with ischemic stroke and its relationship with TLR4 mediated inflammatory response and autophagy.Methods1.The model of type 2 diabetes(T2DM)mice was established.To compare the difference of nerve function damage after middle cerebral artery occlusion(MCAO)in diabetes and non-diabetes mice.2.Diabetes mice were pretreated with 1.5%isoflurane to observe the neurological damage after MCAO and the changes of TLR4 activity,inflammatory response and autophagy in brain tissue.3.Finally,CRX-527,TLR4 specific agonist,was administered after isoflurane pretreatment of MCAO.Then detect the volume of cerebral infarction,neurological injury score,TLR4 in brain tissue and the expression levels of inflammatory response and autophagy related proteins.ResultsCompared with non-diabetes mice,diabetes mice had more severe cerebral infarction volume(p<0.05)and neurobehavioral score(p<0.05)24 hours after MCAO.Isoflurane pretreatment decreased the cerebral infarct volume(p<0.05)and neurobehavioral score(p<0.05)in diabetes mice 24h after MCAO,and inhibited the activities of TLR4,NLRP3 and other inflammatory proteins in microglia of ischemic penumbra(p<0.001),and the expression of autophagy related proteins(p<0.001).After pretreatment with isoflurane,CRX-527 aggravated cerebral infarction volume(p<0.05)and neurobehavioral score(p<0.05),and activated microglia TLR4,NLRP3 and autophagy(p<0.001).Conclusion1.Diabetes aggravates cerebral ischemia-reperfusion injury,increases the recruitment of microglia in the ischemic penumbra and activates its TLR4 signaling pathway.2.Isoflurane preconditioning has neuroprotective effect by inhibiting TLR4 pathway of microglia and reducing inflammatory response and autophagy induced by ischemia-reperfusion injury. |
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