The Protection Of Peroxisome Proliferators Activated Receptor-gamma Agonist Against Focal Cerebral Ischemia-reperfusion Injury In Mice

Objectives Peroxisome proliferator-activated receptor gamma (PPARγ)is anuclear membrane-associated transcription factor that governs the expression ofvarious inflammatory genes.PPARγagonists protect peripheral organs from ischemicinjury.In the present study,we investigated whether the PPARγagonist rosiglitazoneis neuroprotective against focal cerebral ischemia-reperfusion injury.Methods The Kunming mice underwent 2-h middle cerebral artery occlusionfollowed by a 22-hour reperfusion (MCAO/R),and received either vehicle orrosiglitazone treatment of 3,6 or 12 mg/kg (n=10 per group)when 1 h beforeischemia.TTC staining was adopted to determine the volume of cerebral infarction.The neurological scores were made on Zea Longa scale.Then with a different timewindow at the optimal dose,including 1 h before ischemia,when ischemia,1 h afterischemia,2 h after ischemia and 3 h after ischemia,mice was randomly divided intodifferent groups.Cerebral infarct volume and neurological function were assessed;Myeloperoxidase (MPO)activity was measured in brain tissue as an index ofneutrophil accumulation;RT-PCR,immunohistochemistry and Western blotting wereperformed to examine the mRNA and protein expression of pro-inflammatorymediators (ICAM-1,IL-1βand COX-2).Results (1)Compared with those in vehicle group,cerebral infarct volume andneurological function were significantly decreased in rosiglitazone-treated groupswith 3,6 and 12 mg/kg (F=65.551,P＜0.01;F=6.451,P＜0.01,respectively).Thevolume of cerebral infarct and neurological scores in 6mg/kg-treated group and12mg/kg-treated group were lower than those in 3mg/kg-treated group (P<0.05),butthere were not significantly different between in 6mg/kg-treated group and12mg/kg-treated group (P＞0.05).(2)With 6mg/kg-treated in different groups (Agroup without rosiglitazone-treated,B group treated when 1 h before ischemia,Cgroup treated when ischemia,D group treated when 1 h after ischemia,E grouptreated when 2 h after ischemia and F group treated when 3 h after ischemia),thestudy shows①Compared with those in A group,Ischemic size and neurologicalfunction of mice in B group and C group were decreased significantly (F=23.407,P ＜0.01;F=8.355,P＜0.01,respectively),and they were not significiantly different inD,E and F groups (P＞0.05).②MPO activity in the B group and C group weresignificantly lower than that in A group (F=20.907,P＜0.01),which in D,E and Fgroups were not significiantly different from that in A group.③Consistently,themRNA and protein expression of pro-inflammatory mediators (ICAM-1,IL-1βandCOX-2)in the B group and C group were also significantly downregulated than thosein A group,as determined by RT-PCR (F=15.907,12.354,16.282,P＜0.01,respectively)and Western-blot (F =33.561,22.304,19.207,P＜0.01,respectively),and they were not significiantly different in D,E and F groups from in A group.Conclusions (1)The present study shows that PPARγagonist,rosiglitazone,hasneuroprotective role against focal cerebral ischemia-reperfusion injury in mice.(2)The neuroprotective properties of PPARγagonist are at least partially mediated viaanti-inflammatory actions.(3)PPARγagonist should be applied during focal cerebralischemia-reperfusion injury early.