The Modulation Of Akt-GSK3β-AMPA Receptor GluR2Activity In Long-term Neuroprotection Induced By Propofbl Post-conditioning In A Rat Model Of Focal Cerebral Ischemia/Reperfusion Injury

Objiective:Perioperative stroke significantly increases perioperative morbidity and mortality. The most common type of perioperative stroke is ischemia, as hemorrhagic stroke accounts for<1%of perioperative stroke. Therefore, it is essential to choose anesthetic agents during perioperative. Propofol can reduce intracranial pressure and cerebral metabolic rate, which is one of the most commonly used intravenous anesthetics during neurologic surgery. Our precious studies show that propofol postconditioning reduced cerebral ischemia/reperfusion injury and provided the long-term brain protection effect, which may be related to inhibit the internalization of AMPA receptor GluR2subunit in hippocampus. But the upregulator of AMPA receptor GluR2subunit is not known. Moreover, we further explored whether Akt-GSK3β pathway involved in the modulation of AMPA receptor GluR2subunit activity. Therefore, it provides a theoretical basis to reasonable choose anesthetic agents for clinical perioperative cerebral ischemic patients.Methods:The rat model of cerebral ischemia-reperfusion injury was established by middle cerebral artery occlusion.216male SD rats (250-280g) were randomly divided into4groups with54rats in each group, including sham operation (S) group, ischemia-reperfusion (IR) group, ischemia-reperfusion+intralipid (I) group and ischemia-reperfusion+propofol (P) group. The neurological deficit score、 cerebral infarct volume and Y-maze test were evaluated at days3,7,14,28after MCAO. Neurogenesis was detected at days10,14,28after MCAO. The effect of propofol post-conditioning on pAkt/Akt, pGSK3β/GSK3β and pGluR2expression in hippocampus was assayed by Western blotting at days3,7,14,28after MCAO. Results:Compared with group S, group I/R and P increased neurological deficit score, neurogenesis and cerebral infarct volume(P<0.05), decreased long-term cognitive function (P<0.05), improved phosphorylation of AMPA receptor GluR2at Ser880(P<0.05).Compared with group S, the phosphorylation levels of Akt and GSK3β decreased at3d, but increased at7,14,28d in group I/R, the phosphorylation levels of Akt and GSK30increased at ays3,7,14,28in group P. Compared with group I/R, propofol postconditioning decreased neurological deficit score and cerebral infarct volume(P<0.05), enhanced long-term cognitive function and neurogenesis(P<0.05). Moreover, propofol postconditioning decreased phosphorylation of AMPA receptor GluR2at Ser880and increased phosphorylation of Akt (Ser473) and GSK3β(Ser9)(P<0.05).Conclusion:Propofol post-conditioning at dose of20mg·kg-1·h-1provides a sustained brain protective effect, which can last for at least28days and regulation of Akt-GSK3β-AMPA receptor GluR2activity may contribute to this long-term brain protection.