PPARδ激动剂GW501516通过调节线粒体生物合成对大鼠I/R后神经损伤的保护作用  

Protective effect of PPARδagonist GW501516 on neural injury after ischemia/reperfusion in rats by regulating mitochondrial biosynthesis

作　　者：李咏 刘立[1] 徐隽 王为 LI Yong;LIU Li;XU Jun;WANG Wei(Department of Pharmacy,Wuhan Fourth Hospital,Wuhan 430033,China)

机构地区：[1]武汉市第四医院药学部,湖北武汉430033

出　　处：《西部医学》2023年第10期1459-1464,共6页Medical Journal of West China

基　　金：武汉市卫健委医学科研项目(WXZ20B05)。

摘　　要：目的探讨过氧化物酶体增殖物激活受体δ(PPARδ)激动剂GW501516对大鼠脑缺血/再灌注(I/R)后神经损伤的影响及其机制。方法采用双侧颈总动脉夹闭合并低血压的方法来建立大鼠I/R模型,分为模型组(Model)、PPARδ激动剂GW501516干预组(GW组,5 mg/kg)、GW501516+过氧化物酶体增殖物激活受体-γ共激活因子-1α(PGC-1α)抑制剂SR-18292组(GW+SR-18292组,5 mg/kg GW501516联合30 mg/kg SR-18292),另设置假手术组(sham),每组12只。于造模前30 min开始腹腔注射相应药物进行干预,1次/d,连续干预7 d。采用Zea-Longa评分法评估大鼠神经功能;HE染色观察大鼠海马组织病理学变化;TUNEL染色检测大鼠海马组织细胞凋亡情况;生化检测大鼠海马组织中MDA含量及SOD活性;qRT-PCR检测大鼠海马组织线粒体DNA(mtDNA)拷贝数;Western blot检测海马组织中PPARδ、PGC-1α、核呼吸因子1(NRF-1)和线粒体转录因子A(TFAM)蛋白表达水平。结果与sham组比较,Model组大鼠神经损伤严重,海马组织细胞凋亡率及MDA含量显著增加(P<0.05),SOD活性、mtDNA拷贝数及PPARδ、PGC-1α、NRF-1和TFAM等蛋白表达水平显著减低(均P<0.05)。与Model组比较,GW501516组大鼠神经损伤有所改善,海马组织细胞凋亡率、MDA含量显著降低(P<0.05),而SOD活性、mtDNA拷贝数及PPARδ、PGC-1α、NRF-1和TFAM蛋白表达水平显著升高(P<0.05);然而,SR-18292联合干预可显著抑制GW501516对I/R大鼠神经损伤的改善作用。结论PPARδ激动剂GW501516通过上调PGC-1α表达,促进线粒体生物合成,降低氧化应激损伤,抑制细胞凋亡,进而改善大鼠脑缺血/再灌注后神经损伤。Objective To investigate the effect of peroxisome proliferators activate receptorδ(PPARδ)agonist GW501516 on nerve injury after ischemia/reperfusion(I/R)in rats and its mechanism.Methods A rat model of I/R was established by bilateral common carotid artery clipping combined with hypotension.All rats were divided into Model group(Model)and PPARδagonist GW501516 intervention group(GW,5 mg/kg),GW501516+Peroxisome proliferators activate receptor-γcoactivator-1α(PGC-1α)inhibitor SR-18292 group(GW+SR-18292,5 mg/kg GW501516 combined with 30 mg/kg SR-18292),and sham-operated group(sham),12 rats in each group.Corresponding drugs were intraperitoneally injected 30 min before modeling,once a day,for 7 consecutive days.Zea-longa score was used to evaluate the neurological function of rats.HE staining was used to observe the histopathological changes of hippocampus.TUNEL staining was used to detect the apoptosis of cells in hippocampal tissue.The content of MDA and the activity of SOD in hippocampus were detected by biochemical method.The copy number of mitochondrial DNA(mtDNA)in hippocampus was detected by qRT-PCR.The protein expressions of PPARδ,PGC-1α,nuclear respiratory factor-1(NRF-1)and mitochondrial transcription factor A(TFAM)in hippocampus were detected by Western blot.Results Compared with sham group,the Model group rats had severe nerve injury,the apoptosis rate and MDA content of hippocampal tissue were significantly increased(P<0.05),while SOD activity,mtDNA copy number and protein expression levels of PPARδ,PGC-1α,NRF-1 and TFAM were significantly decreased(P<0.05).Compared with Model group,the nerve injury of rats in GW501516 group was improved,the apoptosis rate and MDA content of hippocampal tissue were significantly decreased(P<0.05),while the SOD activity,mtDNA copy number and the protein expression levels of PPARδ,PGC-1α,NRF-1 and TFAM were significantly increased(P<0.05).However,SR-18292 combined intervention can significantly inhibit the ameliorative effect of GW501516 on nerve injury in I/R

关 键 词：脑缺血/再灌注 GW501516 过氧化物酶体增殖物激活受体Δ 线粒体生物合成 氧化应激 

分 类 号：R743.31[医药卫生—神经病学与精神病学]