| Objective:Propofol is one of the most popular agents used for clinical anesthesia. It has been suggestted that propofol is an ideal anesthetic for neurosurgery because of its presumed beneficial effects on cerebral physiology (reduction in cerebral metabolic rate and cerebral blood flow, brain relaxation). Our previous research demonstrated that propofol at dose of20mg-kg-1-h"1infused at the onset of reperfusion for30min could provide neuroprotection to rats which had undergone2h of middle cerebral artery occlusion (MCAO) followed by22h of reperfusion. In addition, the protection provided by propofol postcondioning can be contributed to the stabilization of GluR2subunit of AMPA receptors which play a critical role in central nervous system ischemic insults and activation of phosphoinositide-3-kinase (PI3K)/Akt pathway Howerer, the relationship between GluR2and PI3K during postconditioning as well as the regulation of up and downstream was still unclear. The aim of this study was to investigate role of PI3K-AMPA receptor glutamate receptor2subunit trafficking and the regulation of PI3K in propofol-induced postconditioning against focal cerebral ischemia-reperfusion injury in rats.Methods:168male SD rats (250-280g) were randomly divided into6groups with28rats in each group, including sham operation (S) group, ischemia-reperfusion (IR) group, propofol (P) group, and wortmannin+Sham (W+S) group, wortmannin+ischemia-reperfusion (W+IR) group, wortmannin+propofol (W+P) group. Middle cerebral artery occlusion (MCAO) model was to establish the rat model of cerebral ischemia-reperfusion injury. Cerebral ischemia was induced by60min of middle cerebral artery occlusion followed by23h reperfusion. Rats in group P were treated with propofol20mg·kg-1·h-1at the onset of reperfusion for2h, while in groups with wortmannin received wortmannin0.6mg-kg-130min before reperfusion.In the following23h, the mNSS(modified neurological severity score), the percentage of cerebral infarct volume. The activation of PI3K in the following23h was detected by ELISA, as well as the expression of the percentage of pGluR2and PI3K-AMPAR GluR2submit complex substance were measured by western blot and co-immunoprecipitation methods, while immunogold silver staining was used to invest the trafficking of GluR2of AMPA receptor.Results:After a24h observation, comparing with IR group, rats in Group P were lower in the neurological behavioral scores and the cerebral infarct volume (P<0.01). Additionally, in Group P the activity of PI3K was increased while the expression of PI3K-AMPAR GluR2subunit complex was found up-regulated significantly (P<0.01) compared with Group IR. When it comes to the trafficking of AMPAR GluR2, electron microscopy results showed that the percentages of GluR2on the postsynaptic membrane were promoted in Group P(P<0.01). The pGluR2was reduced compared with Group IR (P<0.01) at each time points. However there was no significant difference between IR group and W+IR group in these indexes (P>0.05). Furthermore, compared with Group P, the mNSS scores and the volumes of cerebral infarction increased at any time point in Group W+P. The activity of PI3K, the complex of PI3K-AMPAR GluR2and GluR2in postsynaptic membrane decreased, while the expression of pGluR2was up-regulated (P<0.05or P<0.01).Conclusion:Propofol post-conditioning at dose of20mg-kg-1-h-1for2h provides a neuroprotective effect. The mechanism may be up-regulation activity of PI3K and made it connect with AMPA receptors, which will cause increasing expression of PI3K-AMPA GluR2subunits complex in the ipsilateral hippocampus of rats’brain and depress the internalization and phosphorylation of GluR2subunits. The progress above is one of the mechanisms of propofol post-conditioning. |
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