Altered peroxisome proliferator-activated receptor isotypes expression after focal cerebral ischemia-reperfusion in rats

Abstract

Objective To examine peroxisome proliferator-activated receptor(PPAR)isotypes (PPARα,PPARδ/βand PPARγ)expression in rats after cerebral ischemia-reperfusion(I/R)and I/R in combination with pan-PPAR co-agonist,and to explore the effect of altered PPAR expressions in brain injury.Methods Adult male SD rats underwent 2-hour middle cerebral artery occlusion followed by a 22-hour reperfusion(MCAO/R).One hour before the operation,the mice received either vehicle(I/R-group)or bezafibrate(6 mg/kg)treatment(Beza-group).TTC(2,3,5-triphenyhetrazolium)staining was adopted to determine the volume of cerebral infarction.The expressions of PPAR isotypes were characterized by immunohistochemical staining(IHC)and Western blot.Furthermore,the spatial localizations of PPAR isotypes were analyzed with respect to ipsilateral ischemic(core and penumbra)and contralateral nonischemic hemisphere.Results Compared with sham-group,2 h ischemia and 22 h reperfusion caused(1) 44.30%infarct volume in average in ipsilateral hemisphere;(2)Marked increased PPAR expression in all three isotypes evaluated by IHC(t=8.63,9.29,13.62,P:0.000)and Western blot(PPARot by 1.47-fold,PPARδ/β by 3.52-fold,and PPARγ by 2.25-fold;t=8.16,9.24,6.43;P=0.000);(3)Marked increagc in PPAR staining in the ischemia-affected region of the ipsilateral MCA territory,in particular in the ischemic itmnumbra.No detectable increase in number and intensity was observed in the contralateral(nonischemic)hemisphere.The pan-PPAR co-agonists bezafibrate can activate all 3 subtypes of the receptor.Compared with I/R-group,(1)Ischemic size in bezafibrate-group rats was significantly decreased than that in I/R group(20.22±6.18 versus 44.30±4.54,t=7.69,P=0.000).(2)Bezafibrate treatment further increased the alterations of all PPAR expression,which were induced by the exposure of I/R,as determined by IHC(t=7.36,5.64,10.50,and P=0.000)and Western blot(PPARα by 95.45%,PPARS/β by 183.47%,and PPARγ by 224.61%;t=13.02,17.52,13.64,and P=0.000).(3)The PPAR immunoreactive expressions were observed in not only the ipsilateral but the contralateral hemisphere of bezafibrate-group.Conclusions Cerebral I/R injury increases the expression of all three PPAR isotypes and activation of PPAR by pan-PPAR agonist not only reduces ischemic size but further enhances the alteration of PPAR The up-regulation of PPAR expression may represent the compensatory self-protection against brain I/R injury. Key words: Brain ischemia; Reperfusion injury; PPAR alpha; PPAR beta; PPAR delta; PPAR gamma