摘要
目的过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activatedreceptor gamma，PPARγ)是一种能够调节多种炎性介质表达的核转录因子，激活后对于脑外器官的缺血再灌注损伤具有保护作用。我们的实验观察PPARγ激动剂是否对小鼠局灶性脑缺血再灌注损伤具有保护的作用，并对其机制进行初步探讨。
方法制作小鼠大脑中动脉阻塞再灌注模型(MCAO／R)，缺血前1 h给予PPARγ激动剂罗格列酮(Rosiglitazone)干预，依据干预剂量的不同，随机分为0mg／kg(对照组)、3mg/kg组、6mg／kg组以及12mg/kg组，每组10只。分别采用3％氯化三苯四唑(2，3，5-triphenyltetrazolium，TTC)染色法、神经功能缺损评分法，观察PPARγ激动剂罗格列酮对小鼠脑梗死体积及行为学的影响，初步筛查最适干预剂量。然后应用该剂量对MCAO／R模型进行不同时间点干预，依据不同干预时间点，即缺血前1 h、缺血同时、缺血后1 h、缺血后2 h以及缺血后3 h，随机分组。采用TIC染色法检测各组小鼠脑梗死体积；Zea-Longa评分法对各组小鼠进行动物行为学评估；紫外分光光度法检测脑组织髓过氧化物酶(myeloperoxidase，MPO)活性；RT-PCR检测炎性因子(ICAM-1、IL-1β、COX-2)mRNA表达水平；免疫组化、Western-blot法观察上述炎性因子蛋白表达变化。
结果(1)与脑梗死对照组相比，PPARγ激动剂罗格列酮3mg／kg干预组、6mg／kg干预组以及12mg／kg干预组小鼠脑梗死体积明显减小(F=65．551，P＜0．01)；行为学评分显示，与脑梗死对照组相比，PPARγ激动剂罗格列酮3mg/kg干预组、6mg／kg干预组以及12mg／kg干预组小鼠运动评分明显减少(F=6．451，P＜0．01)。其中罗格列酮6mg/kg干预组、12mg／kg干预组脑梗死体积及行为学评分作用优于3mg／kg干预组，均有统计学差异(P＜0．05)，而6mg／kg干预组和12mg／kg干预组两组之间未显示明显差异(P＞0．05)；(2)选取6mg／kg剂量，以不同时间点分组给药干预(其中A组为对照组、B组为缺血前1 h给药组、C组为缺血同时给药组、D组为缺血后1 h给药组、E组为缺血后2 h给药组、F组为缺血后3 h给药组)，结果显示：①脑梗死体积：与A组相比，B组和C组均能够显著降低小鼠脑梗死体积(F=23．407，P＜0．01)，D、E、F组则均无统计学差异；②行为学评分：与A组相比，B组和C组均能够显著降低小鼠行为学评分(F=8．355，P＜0．01)，D、E、F组则均无统计学差异；③MPO值：与A组相比，B组和C组小鼠缺血脑组织MPO活性明显降低(F=20．907，P＜0．01)，D、E、F组均无统计学差异；④炎性因子ICAM-1、IL-1β和COX-2 mRNA表达：与A组相比，B组和C组缺血脑组织上述炎性因子基因表达水平均显著降低(F值分别为15．907、12．354、16．282，P＜0．01)，而D、E、F组均无统计学差异；⑤炎性因子ICAM-1、IL-1β和COX-2蛋白表达水平：与A组相比，B组和C组缺血脑组织上述炎性因子蛋白表达水平均显著降低(F值分别为33．561、22．304、19．207，P＜0．01)，而D、E、F组均无统计学差异。
结论(1)PPARγ激动剂对小鼠脑缺血再灌注损伤具有保护作用。(2)PPARγ激动剂对小鼠脑缺血再灌注损伤的保护机制与抑制缺血脑组织的炎症反应有关。(3)PPARγ激动剂应在脑缺血再灌注损伤早期应用。
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.
引文
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