银杏内酯B对外伤后神经细胞凋亡Omi/HtrA2信号通路影响的实验研究
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摘要
目的使用银杏内酯B (ginkgolide B,GB)治疗大鼠颅脑损伤,揭示其对Omi/Htr A2介导的神经细胞凋亡线粒体途径的影响。方法分设假手术组、脑外伤组和治疗组,30只大鼠随机分配,每组10只。脑外伤组和治疗组大鼠接受外力打击,假手术组大鼠不做外力打击。治疗组大鼠外伤后连续3天按照20mg/(kg·d)剂量腹腔注射GB,脑外伤组和假手术组大鼠连续3天腹腔注射1ml 0.9%氯化钠溶液。外伤后第3天,检测海马组织凋亡神经细胞及Omi/Htr A2、X染色体连锁凋亡抑制蛋白(X-linked inhibitor of apoptosis protein,XIAP)、pro-caspase-3、pro-caspase-9和剪切聚腺苷二磷酸-核糖多聚酶(poly ADP-ribose polymerase,PARP)蛋白表达和caspase-3和caspase-9蛋白活性。结果与假手术组比较,脑外伤组海马凋亡神经元比例、Omi/Htr A2、pro-caspase-3、pro-caspase-9和剪切PARP蛋白表达及caspase-3和caspase-9蛋白活性均显著升高(P<0.01),XIAP蛋白表达显著下降(P<0.01);与脑外伤组相比,治疗组海马凋亡神经元比例、Omi/Htr A2、pro-caspase-3、procaspase-9和剪切PARP蛋白表达及caspase-3和caspase-9蛋白活性均显著下降(P<0.01),XIAP蛋白表达显著升高(P<0.01)。结论 GB可能通过抑制Omi/Htr A2介导的线粒体途径从而降低颅脑损伤大鼠神经细胞凋亡。
Objective To utilize Ginkgolide B for treatment of rat craniocerebral injury and investigate its influence on Omi/HtrA2-mediated mitochondrial pathway implicated in neuronal apoptosis after rat craniocerebral injury.Methods Sham-operation group,brain trauma group and treatment group were formed.30 rats were randomly assigned and 10 rats were arranged in each group.Rats in brain trauma group and treatment group underwent external force hit,while rats in sham-operation group did not.Rats in treatment group were administrated intraperitoneally with 20 mg/(kg·d) Ginkgolide B daily for 3 days,while rats in sham-operation group and brain trauma group were given an intraperitoneal injection of 1 ml normal saline until completion of day 3.At post-traumatic day 3,apoptotic neuronal cells,expressions of Omi/HtrA2,X-linked inhibitor of apoptosis protein(XIAP),pro-caspase-3,pro-caspase-9 and cleaved poly ADP-ribose polymerase(PARP) and activities of caspase-3 and caspase-9 proteins were determined in hippocampus tissues.Results As compared with sham-operation group,percentage of apoptotic neurons,expressions of Omi/HtrA2,pro-caspase 3,pro-caspase 9 and cleaved PARP and activities of caspase-3 and caspase-9 proteins were significantly elevated(all P<0.01) and expression of XIAP was obviously decreased(P<0.01) in rat hippocampus tissues of brain trauma group.Percentage of apoptotic neurons,expressions of Omi/HtrA2,pro-caspase 3,pro-caspase 9 and cleaved PARP and activities of caspase-3 and caspase-9 proteins were significantly decreased(all P<0.01) and expression of XIAP was obviously elevated(P<0.01) in rat hippocampus tissues of treatment group when compared with brain trauma group(all P<0.01).Conclusion Ginkgolide B might depress neuronal cellular apoptosis of craniocerebral injury rats via inhibiting Omi/HtrA2 mediated mitochondrial pathway.
Objective To utilize Ginkgolide B for treatment of rat craniocerebral injury and investigate its influence on Omi/HtrA2-mediated mitochondrial pathway implicated in neuronal apoptosis after rat craniocerebral injury.Methods Sham-operation group,brain trauma group and treatment group were formed.30 rats were randomly assigned and 10 rats were arranged in each group.Rats in brain trauma group and treatment group underwent external force hit,while rats in sham-operation group did not.Rats in treatment group were administrated intraperitoneally with 20 mg/(kg·d) Ginkgolide B daily for 3 days,while rats in sham-operation group and brain trauma group were given an intraperitoneal injection of 1 ml normal saline until completion of day 3.At post-traumatic day 3,apoptotic neuronal cells,expressions of Omi/HtrA2,X-linked inhibitor of apoptosis protein(XIAP),pro-caspase-3,pro-caspase-9 and cleaved poly ADP-ribose polymerase(PARP) and activities of caspase-3 and caspase-9 proteins were determined in hippocampus tissues.Results As compared with sham-operation group,percentage of apoptotic neurons,expressions of Omi/HtrA2,pro-caspase 3,pro-caspase 9 and cleaved PARP and activities of caspase-3 and caspase-9 proteins were significantly elevated(all P<0.01) and expression of XIAP was obviously decreased(P<0.01) in rat hippocampus tissues of brain trauma group.Percentage of apoptotic neurons,expressions of Omi/HtrA2,pro-caspase 3,pro-caspase 9 and cleaved PARP and activities of caspase-3 and caspase-9 proteins were significantly decreased(all P<0.01) and expression of XIAP was obviously elevated(P<0.01) in rat hippocampus tissues of treatment group when compared with brain trauma group(all P<0.01).Conclusion Ginkgolide B might depress neuronal cellular apoptosis of craniocerebral injury rats via inhibiting Omi/HtrA2 mediated mitochondrial pathway.
引文
1万芬,唐金荣.银杏内酯B对缺血性脑卒中的研究进展[J].医学综述,2016,22(23):4667-4671
2 Gu JH,Ge JB,Li M,et al.Inhibition of NF-κB activation is associated with anti-inflammatory and anti-apoptotic effects of Ginkgolide B in a mouse model of cerebral ischemia/reperfusion injury[J].Eur J Pharm Sci,2012,47(4):652-660
3 Dan HC,Sun M,Kaneko S,et al.Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein(XIAP)[J].J Biol Chem,2016,291(43):22846
4 Han J,Liu Z,Wang N,et al.Micro RNA-874 inhibits growth,induces apoptosis and reverses chemoresistance in colorectal cancer by targeting X-linked inhibitor of apoptosis protein[J].Oncol Rep,2016,36(1):542-550
5 Xu Y,Yang W,Shi J,et al.Prohibitin 1 regulates tumor cell apoptosis via the interaction with X-linked inhibitor of apoptosis protein[J].J Mol Cell Biol,2016,8(3):282-285
6 Li H,He F,Zhao X,et al.YAP inhibits the apoptosis and migration of human rectal cancer cells via suppression of JNK-Drp1-Mitochondrial fission-Htr A2/Omi pathways[J].Cell Physiol Biochem,2017,44(5):2073-2089
7 Hu Y,Huang M,Wang P,et al.Ucf-101 protects against cerebral oxidative injury and cognitive impairment in septic rat[J].Int Immunopharmacol,2013,16(1):108-113
8 Su D,Ma J,Zhang Z,et al.Protective effects of UCF-101 on cerebral ischemia-reperfusion(CIR)is depended on the MAPK/p38/ERK signaling pathway[J].Cell Mol Neurobiol,2016,36(6):907-914
9 Su D,Su Z,Wang J,et al.UCF-101,a novel Omi/Htr A2 inhibitor,protects against cerebral ischemia/reperfusion injury in rats[J].Anat Rec(Hoboken),2009,292(6):854-861
10 Simon DW,Mc Geachy MJ,Bayir H,et al.The far-reaching scope of neuroinflammation after traumatic brain injury[J].Nat Rev Neurol,2017,13(3):171-191
11 Russo MV,Mc Gavern DB.Inflammatory neuroprotection following traumatic brain injury[J].Science,2016,353(6301):783-785
12 Pearn ML,Niesman IR,Egawa J,et al.Pathophysiology associated with traumatic brain injury:current treatments and potential novel therapeutics[J].Cell Mol Neurobiol,2017,37(4):571-585
13 Joseph B,Haider A,Rhee P.Traumatic brain injury advancements[J].Curr Opin Crit Care,2015,21(6):506-511
14 Kuhn H,Nieuwenhuijsen H,Karthe B,et al.Stretch-induced apoptosis in rat alveolar epithelial cells is mediated by the intrinsic mitochondrial pathway[J].Exp Lung Res,2017,43(1):49-56
15 Hu J,Yan Q,Shi C,et al.BMSC paracrine activity attenuates interleukin-1β-induced inflammation and apoptosis in rat AF cells via inhibiting relative NF-κB signaling and the mitochondrial pathway[J].Am J Transl Res,2017,9(1):79-89
16 Lin M,Tang S,Zhang C,et al.Euphorbia factor L2 induces apoptosis in A549 cells through the mitochondrial pathway[J].Acta Pharm Sin B,2017,7(1):59-64
17 Xue Z,Song Z,Wan Y,et al.Calcium-sensing receptor antagonist NPS2390 attenuates neuronal apoptosis though intrinsic pathway following traumatic brain injury in rats[J].Biochem Biophys Res Commun,2017,486(2):589-594
18 Miao Q,Ge M,Huang L.Up-regulation of GBP2 is associated with neuronal apoptosis in rat brain cortex following traumatic brain injury[J].Neurochem Res,2017,42(5):1515-1523
19 Gao Y,Zhuang Z,Gao S,et al.Tetrahydrocurcumin reduces oxidative stress-induced apoptosis via the mitochondrial apoptotic pathway by modulating autophagy in rats after traumatic brain injury[J].Am J Transl Res,2017,9(3):887-899
20陈坤,张明,陈北冬,等.银杏内酯B抑制高糖诱导内皮细胞凋亡及机制研究[J].中国药理学通报,2017,33(3):378-383
21 Yu WH,Dong XQ,Hu YY,et al.Ginkgolide B reduces neuronal cell apoptosis in the traumatic rat brain:possible involvement of tolllike receptor 4 and nuclear factor kappa B pathway[J].Phytother Res,2012,26(12):1838-1844
22 Hu YY,Huang M,Dong XQ,et al.Ginkgolide B reduces neuronal cell apoptosis in the hemorrhagic rat brain:possible involvement of Toll-like receptor 4/nuclear factor-kappa B pathway[J].J Ethnopharmacol,2011,137(3):1462-1468
2 Gu JH,Ge JB,Li M,et al.Inhibition of NF-κB activation is associated with anti-inflammatory and anti-apoptotic effects of Ginkgolide B in a mouse model of cerebral ischemia/reperfusion injury[J].Eur J Pharm Sci,2012,47(4):652-660
3 Dan HC,Sun M,Kaneko S,et al.Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein(XIAP)[J].J Biol Chem,2016,291(43):22846
4 Han J,Liu Z,Wang N,et al.Micro RNA-874 inhibits growth,induces apoptosis and reverses chemoresistance in colorectal cancer by targeting X-linked inhibitor of apoptosis protein[J].Oncol Rep,2016,36(1):542-550
5 Xu Y,Yang W,Shi J,et al.Prohibitin 1 regulates tumor cell apoptosis via the interaction with X-linked inhibitor of apoptosis protein[J].J Mol Cell Biol,2016,8(3):282-285
6 Li H,He F,Zhao X,et al.YAP inhibits the apoptosis and migration of human rectal cancer cells via suppression of JNK-Drp1-Mitochondrial fission-Htr A2/Omi pathways[J].Cell Physiol Biochem,2017,44(5):2073-2089
7 Hu Y,Huang M,Wang P,et al.Ucf-101 protects against cerebral oxidative injury and cognitive impairment in septic rat[J].Int Immunopharmacol,2013,16(1):108-113
8 Su D,Ma J,Zhang Z,et al.Protective effects of UCF-101 on cerebral ischemia-reperfusion(CIR)is depended on the MAPK/p38/ERK signaling pathway[J].Cell Mol Neurobiol,2016,36(6):907-914
9 Su D,Su Z,Wang J,et al.UCF-101,a novel Omi/Htr A2 inhibitor,protects against cerebral ischemia/reperfusion injury in rats[J].Anat Rec(Hoboken),2009,292(6):854-861
10 Simon DW,Mc Geachy MJ,Bayir H,et al.The far-reaching scope of neuroinflammation after traumatic brain injury[J].Nat Rev Neurol,2017,13(3):171-191
11 Russo MV,Mc Gavern DB.Inflammatory neuroprotection following traumatic brain injury[J].Science,2016,353(6301):783-785
12 Pearn ML,Niesman IR,Egawa J,et al.Pathophysiology associated with traumatic brain injury:current treatments and potential novel therapeutics[J].Cell Mol Neurobiol,2017,37(4):571-585
13 Joseph B,Haider A,Rhee P.Traumatic brain injury advancements[J].Curr Opin Crit Care,2015,21(6):506-511
14 Kuhn H,Nieuwenhuijsen H,Karthe B,et al.Stretch-induced apoptosis in rat alveolar epithelial cells is mediated by the intrinsic mitochondrial pathway[J].Exp Lung Res,2017,43(1):49-56
15 Hu J,Yan Q,Shi C,et al.BMSC paracrine activity attenuates interleukin-1β-induced inflammation and apoptosis in rat AF cells via inhibiting relative NF-κB signaling and the mitochondrial pathway[J].Am J Transl Res,2017,9(1):79-89
16 Lin M,Tang S,Zhang C,et al.Euphorbia factor L2 induces apoptosis in A549 cells through the mitochondrial pathway[J].Acta Pharm Sin B,2017,7(1):59-64
17 Xue Z,Song Z,Wan Y,et al.Calcium-sensing receptor antagonist NPS2390 attenuates neuronal apoptosis though intrinsic pathway following traumatic brain injury in rats[J].Biochem Biophys Res Commun,2017,486(2):589-594
18 Miao Q,Ge M,Huang L.Up-regulation of GBP2 is associated with neuronal apoptosis in rat brain cortex following traumatic brain injury[J].Neurochem Res,2017,42(5):1515-1523
19 Gao Y,Zhuang Z,Gao S,et al.Tetrahydrocurcumin reduces oxidative stress-induced apoptosis via the mitochondrial apoptotic pathway by modulating autophagy in rats after traumatic brain injury[J].Am J Transl Res,2017,9(3):887-899
20陈坤,张明,陈北冬,等.银杏内酯B抑制高糖诱导内皮细胞凋亡及机制研究[J].中国药理学通报,2017,33(3):378-383
21 Yu WH,Dong XQ,Hu YY,et al.Ginkgolide B reduces neuronal cell apoptosis in the traumatic rat brain:possible involvement of tolllike receptor 4 and nuclear factor kappa B pathway[J].Phytother Res,2012,26(12):1838-1844
22 Hu YY,Huang M,Dong XQ,et al.Ginkgolide B reduces neuronal cell apoptosis in the hemorrhagic rat brain:possible involvement of Toll-like receptor 4/nuclear factor-kappa B pathway[J].J Ethnopharmacol,2011,137(3):1462-1468
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