Scu对大鼠脑缺血再灌注损伤的保护作用及对PARP/AIF介导的细胞凋亡途径的抑制研究
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摘要
脑血管意外是一种常见疾病。根据发病原因的不同,可分为缺血性和出血性脑血管意外两大类。前者发病率远较后者为高,尤以65岁以上的老年人多见。脑血管意外具有高死亡率和高致残率的特点。据世界卫生组织调查表明,脑血管意外引起的死亡占所调查的57个国家死亡总人数的11.3%,仅次于癌症和心肌梗死。脑血管意外的患者约有1/3在发病后不久死亡,幸存者则由于偏瘫、失语等后遗症而致残,丧失工作能力,甚至丧失生活自理能力。随着人口老龄化程度的加剧,脑血管疾病已成为一个倍受社会关注的问题。脑缺血是脑血管疾病最主要的病种。在我国,其死亡率仅次于恶性肿瘤,严重危害人类健康。
大量文献报道,伴随着脑神经细胞缺血,机体的应激保护和缺血导致的损伤机制同时被激活,相关的细胞因子表达增高,信号通路被激活,最终导致神经细胞凋亡或坏死。因此,探寻缺血性脑血管疾病的有效治疗策略一直是世界医药学界共同关注的重大课题之一。灯盏花具有抗脑缺血、抗心肌缺血等药理作用。临床主要用于治疗心肌缺血损伤及脑血栓等引起的心脑血管疾病。灯盏花素是从灯盏花中提取的主要有效成分,是灯盏花甲素和灯盏花乙素(Scu)的混合物。其中Scu(黄芩素苷,scutellarin),即4, 5, 6-三羟基黄酮-7-葡糖醛酸苷,是灯盏花抗脑缺血损伤的主要有效成分。本研究采用大鼠局灶性脑缺血再灌注模型,旨在研究Scu对大鼠脑缺血再灌注过程中多聚ADP-核糖聚合酶(PARP) /凋亡诱导因子(AIF)介导的神经细胞凋亡途径的影响,为其在临床上防治脑血管疾病提供理论基础。
第一部分灯盏花乙素(Scu)对大鼠脑缺血再灌注脑损伤的保护作用
采用大脑中动脉阻塞(middle cerebral artery occulusion, MCAO)局灶性脑缺血再灌注模型,缺血前给予Scu25,50,75 mg·kg-1 7 d, ig。末次给药1 h后制备MCAO模型,缺血2 h,再灌注22 h后,分别用Longa’s法、TTC染色法来评价大鼠的神经功能状态及脑梗塞范围;用HE染色评价脑细胞损伤的程度。HE染色显示:模型组大鼠脑缺血再灌注后大鼠皮层和纹状体细胞排列紊乱,细胞间隙增宽,组织结构略显疏松,细胞形态异常,形状不规则,胞体缩小,胞质凝集,胞核固缩浓染,呈致密浓染块状或颗粒状,有的细胞界限不清,结构消失,并可见嗜神经现象;给予Scu50,75 mg·kg-1可明显减少MCAO后脑梗塞面积,改善神经功能症状,HE染色阳性染色细胞明显减少,与模型组比较,具有显著性差异(P<0.05)。
第二部分灯盏花乙素(Scu)对大鼠脑缺血再灌注脑损伤所致神经细胞凋亡的影响
大鼠在造模(MCAO)前1h给予7 d的Scu,ig。脑缺血2h再灌注22h后,用TUNEL法评价脑细胞凋亡的程度;用Western blot检测AIF蛋白在线粒体及细胞核中的表达水平,同时检测脑组织中NAD和PARP酶的活性。结果表明:模型组大鼠脑缺血再灌注后TUNEL阳性染色细胞明显增多(P<0.05,与伪手术组比较),脑组织中NAD水平明显降低,PARP酶过度活化,AIF在细胞核的表达明显增加。给予Scu(50,75 mg·kg-1)7 d后,TUNEL阳性染色细胞明显减少,凋亡程度减轻(P<0.05,与模型组比较);同时,Scu(50,75 mg·kg-1)能减少脑缺血再灌注损伤后大鼠脑组织中NAD的耗竭,抑制PARP酶的过度活化和AIF从线粒体向细胞核的易位效应。
结论:Scu作为灯盏花的有效成分,具有抗脑缺血再灌注损伤的保护作用,其抗神经细胞凋亡的作用之一是通过抑制脑缺血损伤引起的PARP酶的过度活化及AIF的易位而实现的。
Increasing evidence has shown that brain injury can develop as a result of cerebral ischemia-reperfusion due to stroke and other cardiovascular diseases. Cerebral ischemia/reperfusion(I/R) triggers a complex series of biochemical and molecular mechanisms that impairs neurological functions through breakdown of cellular integrity mediated by excitotoxic glutamatergic signaling, ionic imbalance, free-radical reactions.
Scutellarin (Scu) is the major active principle (flavonoid) extracted from Erigeron breviscapus. Hand.-Mazz, a Chinese herbal medicine, which is a Ca2+ channels blocking agent used in the clinical therapy of cerebrovascular disorders. Studies have shown the protective effects of Scu on brain injury induced by cerebral ischemia /reperfusion through interaction with a wide variety of targets because of its anti-oxidation, anti-inflammatory and attenuating neuronal damage. The aim of this study is to investigate the effects of Scu on brain injury through the inhibition of AIF-mediated apoptosis induced by transient focal brain ischemia in rats.
Part I The protective effects of Scu on cerebral injury induced by brain ischemia-reperfusion
Rats were pretreated with Scu 25, 50, 75 mg·kg-1 for 7 d and then subjected to cerebral ischemia/reperfusion injury induced by a middle cerebral artery occlusion (MCAO). After 2 h ischemia and 22 h reperfusion, the neurological outcome was evaluated by the Longa’s method; the infarct volume was assessed by TTC staining. Hematoxylin-Eosin (HE) staining was employed to determine the level of neuron damage. The results showed that Scu (50, 75mg·kg-1) significantly reduced the cerebral infarct volume and ameliorated the neurological deficit (P<0.05), and reduced the numbers of HE-positive staining cells after 22h reperfusion. These results showed that pretreatment with Scu could attenuate brain injury after cerebral ischemia/reperfusion.
Part II The mechanism of Scu on apoptosis induced by transient focal cerebral ischemia in rats
Rats were pretreated with Scu for 7 d and then subjected to brain ischemia/reperfusion injury induced by a middle cerebral artery occlusion (MCAO). After 2 h ischemia and 22 h reperfusion, in situ end-labeling of nuclear DNA fragmentation (TUNEL) were employed to determine the level of neuron apoptosis.NAD content and PARP activity in brain homogenate were determined. The expression of AIF in the mitochondria and in the nucleus were analyzed by western blot. The data showed that The increase numbers of HE-positive staining cells were significantly observed at 22 h after reperfusion, whiles the immunoreactivity was inhibited by Scu (50, 75 mg·kg-1) (P<0.05,vs vehicle-treated). At the meantime, Scu (50, 75 mg·kg-1)-treatment reverse brain NAD depletion, and inhibited PARP over activation and AIF translocation from the mitochondria to the nucleus following cerebral I/R.
Conclusions:These findings suggested that the neuroprotective effects of Scu on brain ischemic injury-induced apoptosis were associated with inhibiting PARP-dependent mitochondrial dysfunction and subsequent translocation of AIF.
大量文献报道,伴随着脑神经细胞缺血,机体的应激保护和缺血导致的损伤机制同时被激活,相关的细胞因子表达增高,信号通路被激活,最终导致神经细胞凋亡或坏死。因此,探寻缺血性脑血管疾病的有效治疗策略一直是世界医药学界共同关注的重大课题之一。灯盏花具有抗脑缺血、抗心肌缺血等药理作用。临床主要用于治疗心肌缺血损伤及脑血栓等引起的心脑血管疾病。灯盏花素是从灯盏花中提取的主要有效成分,是灯盏花甲素和灯盏花乙素(Scu)的混合物。其中Scu(黄芩素苷,scutellarin),即4, 5, 6-三羟基黄酮-7-葡糖醛酸苷,是灯盏花抗脑缺血损伤的主要有效成分。本研究采用大鼠局灶性脑缺血再灌注模型,旨在研究Scu对大鼠脑缺血再灌注过程中多聚ADP-核糖聚合酶(PARP) /凋亡诱导因子(AIF)介导的神经细胞凋亡途径的影响,为其在临床上防治脑血管疾病提供理论基础。
第一部分灯盏花乙素(Scu)对大鼠脑缺血再灌注脑损伤的保护作用
采用大脑中动脉阻塞(middle cerebral artery occulusion, MCAO)局灶性脑缺血再灌注模型,缺血前给予Scu25,50,75 mg·kg-1 7 d, ig。末次给药1 h后制备MCAO模型,缺血2 h,再灌注22 h后,分别用Longa’s法、TTC染色法来评价大鼠的神经功能状态及脑梗塞范围;用HE染色评价脑细胞损伤的程度。HE染色显示:模型组大鼠脑缺血再灌注后大鼠皮层和纹状体细胞排列紊乱,细胞间隙增宽,组织结构略显疏松,细胞形态异常,形状不规则,胞体缩小,胞质凝集,胞核固缩浓染,呈致密浓染块状或颗粒状,有的细胞界限不清,结构消失,并可见嗜神经现象;给予Scu50,75 mg·kg-1可明显减少MCAO后脑梗塞面积,改善神经功能症状,HE染色阳性染色细胞明显减少,与模型组比较,具有显著性差异(P<0.05)。
第二部分灯盏花乙素(Scu)对大鼠脑缺血再灌注脑损伤所致神经细胞凋亡的影响
大鼠在造模(MCAO)前1h给予7 d的Scu,ig。脑缺血2h再灌注22h后,用TUNEL法评价脑细胞凋亡的程度;用Western blot检测AIF蛋白在线粒体及细胞核中的表达水平,同时检测脑组织中NAD和PARP酶的活性。结果表明:模型组大鼠脑缺血再灌注后TUNEL阳性染色细胞明显增多(P<0.05,与伪手术组比较),脑组织中NAD水平明显降低,PARP酶过度活化,AIF在细胞核的表达明显增加。给予Scu(50,75 mg·kg-1)7 d后,TUNEL阳性染色细胞明显减少,凋亡程度减轻(P<0.05,与模型组比较);同时,Scu(50,75 mg·kg-1)能减少脑缺血再灌注损伤后大鼠脑组织中NAD的耗竭,抑制PARP酶的过度活化和AIF从线粒体向细胞核的易位效应。
结论:Scu作为灯盏花的有效成分,具有抗脑缺血再灌注损伤的保护作用,其抗神经细胞凋亡的作用之一是通过抑制脑缺血损伤引起的PARP酶的过度活化及AIF的易位而实现的。
Increasing evidence has shown that brain injury can develop as a result of cerebral ischemia-reperfusion due to stroke and other cardiovascular diseases. Cerebral ischemia/reperfusion(I/R) triggers a complex series of biochemical and molecular mechanisms that impairs neurological functions through breakdown of cellular integrity mediated by excitotoxic glutamatergic signaling, ionic imbalance, free-radical reactions.
Scutellarin (Scu) is the major active principle (flavonoid) extracted from Erigeron breviscapus. Hand.-Mazz, a Chinese herbal medicine, which is a Ca2+ channels blocking agent used in the clinical therapy of cerebrovascular disorders. Studies have shown the protective effects of Scu on brain injury induced by cerebral ischemia /reperfusion through interaction with a wide variety of targets because of its anti-oxidation, anti-inflammatory and attenuating neuronal damage. The aim of this study is to investigate the effects of Scu on brain injury through the inhibition of AIF-mediated apoptosis induced by transient focal brain ischemia in rats.
Part I The protective effects of Scu on cerebral injury induced by brain ischemia-reperfusion
Rats were pretreated with Scu 25, 50, 75 mg·kg-1 for 7 d and then subjected to cerebral ischemia/reperfusion injury induced by a middle cerebral artery occlusion (MCAO). After 2 h ischemia and 22 h reperfusion, the neurological outcome was evaluated by the Longa’s method; the infarct volume was assessed by TTC staining. Hematoxylin-Eosin (HE) staining was employed to determine the level of neuron damage. The results showed that Scu (50, 75mg·kg-1) significantly reduced the cerebral infarct volume and ameliorated the neurological deficit (P<0.05), and reduced the numbers of HE-positive staining cells after 22h reperfusion. These results showed that pretreatment with Scu could attenuate brain injury after cerebral ischemia/reperfusion.
Part II The mechanism of Scu on apoptosis induced by transient focal cerebral ischemia in rats
Rats were pretreated with Scu for 7 d and then subjected to brain ischemia/reperfusion injury induced by a middle cerebral artery occlusion (MCAO). After 2 h ischemia and 22 h reperfusion, in situ end-labeling of nuclear DNA fragmentation (TUNEL) were employed to determine the level of neuron apoptosis.NAD content and PARP activity in brain homogenate were determined. The expression of AIF in the mitochondria and in the nucleus were analyzed by western blot. The data showed that The increase numbers of HE-positive staining cells were significantly observed at 22 h after reperfusion, whiles the immunoreactivity was inhibited by Scu (50, 75 mg·kg-1) (P<0.05,vs vehicle-treated). At the meantime, Scu (50, 75 mg·kg-1)-treatment reverse brain NAD depletion, and inhibited PARP over activation and AIF translocation from the mitochondria to the nucleus following cerebral I/R.
Conclusions:These findings suggested that the neuroprotective effects of Scu on brain ischemic injury-induced apoptosis were associated with inhibiting PARP-dependent mitochondrial dysfunction and subsequent translocation of AIF.
引文
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[1]Philip K Liu. Ischemia-reperfusion-related Repair Deficit after Oxidative Stress: Implications of Faulty Transcripts in Neuronal Sensitivity after Brain Injury. J Biomed Sci 2003; 10: 4-13.
[2] Hurn P.D., VannuccS.J. i and Hagberg H.. Adult or perinatal brain injury: does sex matter?. Stroke 2005; 36:193–5.
[3] Lennmyr F., Karlsson S., Gerwins P., Ata K.A. and Terent A.. Activation of mitogen-activated protein kinases in experimental cerebral ischemia. Acta Neurol Scand 2002; 106:333–40.
[4]Kao H, Takasawa R, Fukuda K, Shiokawa D, Sadanaga-Akiyoshi F, Ibayashi S. et al. DNA fragmentation in ischemic core and penumbra in focal cerebral ischemia in rats. Mol Brain Res 2001; 91:112-8.
[5] Chan P.H.. Reactive oxygen radicals in signaling and damage in the ischemic brain. J. Cereb. Blood Flow Metab 2001; 21:2–14.
[6] Yu S.W., Wang H., Poitras M.F., Coombs C., Bowers W.J., Federoff H.J. et al. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor.Science 2002; 297:259–63.
[7] Cipriani G., Rapizzi E., Vannacci A., Rizzuto R., Moroni F. and Chiarugi A.. Nuclear poly (ADP-ribose) polymerase-1 rapidly triggers mitochondrial dysfunction. J Biol Chem 2005; 280:17227–34.
[8] Ju B.G., Solum D., Song E.J., Lee K.J., Rose D.W., Glass C.K. et al. Activating the PARP-1 sensor component of the groucho/TLE1 corepressor complex mediates a CaMKinase IIdelta-dependent neurogenic gene activation pathway. Cell 2004; 119:815–29.
[9] Daugas E., Susin S.A., Zamzami N., Ferri K.F., Irinopoulou T., Larochette N. et al. Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J 2000;14:729–39.
[10] Cheung E.C., Melanson-Drapeau L., Cregan S.P., Vanderluit J.L., Ferguson K.L., McIntosh W.C. et al. Apoptosis-inducing factor is a key factor in neuronal cell death propagated by BAX-dependent and BAX-independent mechanisms. J Neurosci 2005; 25:1324–34.
[11] Plesnila N., Zhu C., Culmsee C., Groger M., Moskowitz M.A. and Blomgren K.. Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. J Cereb Blood Flow Metab2004; 24: 458–66.
[12] Culmsee C., Zhu C., Landshamer S., Becattini B., Wagner E., Pellechia M. et al. Apoptosis-inducing factor triggered by poly (ADP-ribose) polymerase and Bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia. J Neurosci 2005; 25:10262–72.
[13] Liu H, Yang XL, Wang Y, Tang XQ, Jiang DY, Xu HB. Protective effects of scutellarin on superoxide-induced oxidative stress in rat cortical synaptosomes.Acta Pharmacol Sin 2003; 24(11):1113-7.
[14] Yang XF, He W, Lu WH, Zeng FD. Effects of scutellarin on liver function after brain I/R in rats. Acta Pharmacol Sin 2003; 24(11): 1118-24.
[15] HU Xia-min, Mi-mei ZHOU, Xian-min HU, Fan-dian ZENG. Neuroprotective effects of scutellarin on rat neuronal damage induced by cerebral ischemia/reperfusion. Acta Pharmacol Sin 2005; 26(12): 1454–9.
[16] Zea Longa E, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniotomy in rats. Stroke 1989, 20: 84 91.
[17] Nisselbaum J.S. and Green S.. A simple ultramicro method for determination of pyridine nucleotides in tissues. Anal Biochem 1969; 27:212–7.
[18] Cao G., Pei,W. Ge H., Liang Q., Luo Y., Sharp F.R. et al. In vivo delivery of a Bcl-xL fusion protein containing the TAT protein transduction domain protects against ischemic brain injury and neuronal apoptosis. J Neurosci 2002; 22 : 5423–31.
[19] Wang H., Yu S.W., Koh D.W., Lew J., Coombs C., Bowers W. et al. Apoptosis-inducing factor substitutes for caspase executioners in NMDA-triggered excitotoxic neuronal death. J Neurosci 2004; 24:10963–73.
[20] Nakajima H., Kakui N., Ohkuma K., Ishikawa M. and Hasegawa T.. A newly synthesized poly (ADP-ribose) polymerase inhibitor, 2-methyl-3, 5, 7, 8-tetrahydrothiopyrano [4, 3-d] pyrimidine-4-one (DR2313): pharmacological profiles, neuroprotective effects and therapeutic time window in cerebral ischemia in rats.Journal of Pharmacology and Experimental Therapeutics 2004; 1:472–81.
[21] LaPlaca M.C., Zhang J., Raghupathi R., Li J.H., Smith F., Bareyre F.M. et al. Pharmacologic inhibition of poly (ADP-ribose) polymerase is neuroprotective following traumatic brain injury in rats. J Neurotrauma 2001; 18:369–76.
[22] Hong S.J., Dawson T.M. and Dawson V.L.. Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling.Trends Pharmacol Sci 2004; 25:259–64.
[23] Li X., Nemoto M., Xu Z., Yu S.-W., Shimoji M., Andrabi S.A. et al. Influence of duration of focal cerebral ischemia and neuronal nitric oxide synthase on translocation of apoptosis-inducing factor to the nucleus. Cellular neuroscience 2007;144(1): 56-65.
[24]Chiarugi. Poly (ADP-ribosyl)ation and stroke. Pharmacological Research 2005; 52:15–24.
[25] Ye H., Cande C., Stephanou N.C., Jiang S., Gurbuxani S., Larochette N. et al. DNA bindingis required for the apoptogenic action of apoptosis inducing factor. Nature Structural & Molecular Biology 2002; 9: 680–4.
1 刘静,唐兆新.线粒体在细胞凋亡中的作用[J].动物医学进展, 2006, 27 (6):43.
2 Takashi M. Caspases involved in ER stress - mediated cell death[J]. J Chemical Neuroanatomy, 2004, 28:101-5.
3 Finkel E.The mitochondrion: is it central to apoptosis?[J]. Science, 2001, 292:624-6.
4 Desagher S, Martinou JC. Mitochondria as the central controlpoint of apoptosis[J]. Trends Cell Biol, 2000, 10:369-77.
5 Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW. Three dimensional structure of the apoptosome:implications for assembly, proCaspase-9 binding, and activation[J]. Mol Cell, 2002,9:423-32.
6 Shi Y. Apoptosome: the cellular engine for the activation of Caspase-9[J]. Structure ( Camb ), 2002, 10:285-8.
7 RaffM. Cell suicide for beginners. Nature, 1998, 396:119-22.
8Céline C, Isabelle C, Eric D, et a.l Apoptosis-inducing factor (AIF): a novel Caspase-independent death effector released from mitochondria[ J]. Biochimie, 2002, 84(2-3): 215-22.
9 Cookson MR, Inc PG, Usher PA. Poly ADP-ribose) polymerase is found in both the nucleus and cytoplasm of human CNS neurons. [J].BrainRes,1999, 834(1-2):182-5.
10 Aoufouchi S, Shall S. Regulation by phosphorylation of Xenopus laevis poly (ADP-ribose) polymerase enzyme activity during oocytc maturation. Biochem [J].1997, 325:543-51.
11 Kato N, Morita H, Sugiyama T. Evalration of the poly(ADP-ribose) polymerase gene in human stroke[J].Atherosclerosis,1999,148(2):345-52.
12 Szabo C, Dawson VL. Role of poly(ADP-Ribose) synthetase in inflammation and ischemia-reperfusion[J]. Trends pharmacol Sci,1998,19(7):287-98.
13 Davidovic L,Vodenicharov M,Afar EB. et al. Importance of Poly (ADP-ribose) glycohydrolase in the control of poly (ADP-ribose)metabolism[J]. Exp Cell Res, 2001, 268(1):7-13.
14 Bums TF,Bernhard EJ,EI-Deity WS.Tissre specific expression of p53 target genes suggests a key role for KILLER/DR in p53-dependent apoptosis in vivo[J]. Oncogene, 2000, 113(pt6):955-961.
15 KimJ W, Won J, SohnS, et al. DNA-binding activity of the N-terminal cleavage product of poly (ADP-ribose)polymerase is required for UV mediated apoptosis[J]. J cell sci, 2000,113(pt6):955-961.
16 Le Rhun Y Celluar responses to DNA damage in the absence of Poly(ADP-ribose) polymerase[J].Biochem Biophys. Res Commun,1998, 245:1-10.
17 Griffin RJ.The role of inhibitors of Poly(ADP-ribose)polymerase as resistanc modifying agents in cancer therapy[J].Biochimie, 1995, 77:408-422
18 Jackson SP. The recognition of DNA damage[J]. Curr Opin Genet Dev, 1996, 6:19-25.
19 毛力真. PARP与缺血性神经元损伤后DNA的修复[J].中国临床神经科学, 1999, 4 (7): 246-8.
20 Zhang J, Dawson TM, Snyder SH. Nitric oxide activation of poly (ADP-ribose) synthetase in neurotoxiciy [J]. Science,1994, 263(514):687-689.
21 罗玉敏,Chen Jun,秦震等. 脑缺血与 DNA 损伤.国外医学脑血管疾病分册, 2002, 5 (8): 259-61.
22 YU SW, WANG H, Poitrasm F. Mediation of poly(ADP-ribose)polymerase-1 dependent cell death by apoptosis-inducingfactor[J]. Science, 2002, 297(5579): 259-63.
23 王昌正,陈东立,曹诚等. 凋亡诱导因子与非受体酪氨酸激酶 C-Abl 的相互作用[J]. 生物技术通讯, 2006, 17(2): 152.
24 Otera H, Ohsakaya S, Nagaura. Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space[J]. J EMBO, 2005, 24 ( 7 ):1375-86.
25 Ishitsuka K, Hidesshima T, Hamasaki M. Novel inosine monophosphate dehydrogenase inhibitor VX-944 induces apoptosis in multi plemyeloma cells primarily via Caspase-independent AIF/Endo G pathway[J]. Oncogene, 2005, 24 (38 ):5888-96.
26 Panka D J, Wang W, Atkinsn B. The Raf inhibitor BAY 43-9006 (Sorafenib ) induces Caspase-independent apoptosis in melanoma cells[J]. CancerRes, 2006, 66 ( 3) :1611-9.
27 Tanaka S, Takehashi M, Iida S. Mitochondrial impairment induced by poly (ADP-ribose ) polymerase-1 activation in cortical neurons after oxygen and glucose deprivation[J]. Neurochem, 2005, 95( 1 ): 179-90.
28 Ye H, Cande C, Stephanou N C. DNA binding as a structural requirement for the apoptogenic action of AIF[J ]. Nat Struct Biol, 2002, 9:680-4.
29 Lorenzo HK, Susin SA, Penninger J, et al. Apoptosis inducingfactor (AIF): a phylogenetically old Caspase- independent effector of cell death[J]. Cell Death Differ, 1999, 6: 516-24.
30 Park S Y, Cho S J, Kwon H C. Caspase-independent cell death by allicin in human epithelial carcinoma cells: involvement of PKA[J]. Cancer Lett. 2005, 224 (1): 123-32.
31 Susin S A, Lorenzo H K, Zamzami N. Molecular characterization of mitochondrial apoptosis-inducing factor[J ]. Nature, 1999, 397( 6718):387-9.
32 Gurbuxani S, Schmitt E, Cande C, et al. Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor[J]. Oncogene, 2003, 22 ( 43) :6669-78.
33 Lipton S A ,Wetzel B E. Dueling activities of AIF in cell death versus survival : DNA binding and redox activity [J]. Journal of Cell , 2002,111(2): 147-50.
34 Klein J A, Guess L C M, Rossmann M P, et al. The harlequin mouse mutation downregulatesapoptosis-inducing factor[J].Nature, 2002, 419:367-74.
35 Lipton S A, Ella B W. Dueling activities of AIF in cell death versus survival: DNA binding and redox activity[J]. Cell, 2002, 111:147-50.
36 DU L, Zhang X, Han Y Y, et al. Intra-mitochondrial poly (ADP-ribosylation) contributes to NAD + depletion and celldeath induced by oxidative stress[J]. J Biol Chem, 2003, 278(20):18426-33.
37 Yu SW, Andrabis S A, Wang H, et al. Apoptosis-inducing factormediates poly (ADP-ribose)(PAR) polymer-induced cell death[J]. Proc Natl Acad Sci USA, 2006, 103(48):18314-19.
38 Ying W, Garnier P, Swanson R, et al. NAD+ repletion prevents PARP-1-induced glycolytic blockade and cell death in cultured mouse astrocytes[J]. Biochem Biophys Res Commun, 2003, 308(4): 809-13.
39 Rapizzi E, Fossati S, Moroni F, et al. Inhibition of poly (ADP-ribose) glycohydrolase by gallotannin selectively up-regulates expression of proinflammatory genes[J]. Mol Pharmacol, 2004, 66 (4): 890-8.
2 Saito A,Maier CM, Narasimhan P, et al. Oxidative stress and neuronal death/survival signaling in cerebral ischemia. Mol Neurobiol, 2005,31(1-3):105-16.
3 Zhang F, Yin W, Chen J. Apoptosis in cerebral ischemia: executional and regulatory signaling mechanisms[J]. Neurol Res, 2004,26(8):835-45.
4 Johnson MV.Excitotoxicity in perinatal brain injury[J]. Brain Pathol, 2005, 15(3):234-40.
5 Ferrer I, Planas, AM. Signaling of cell death and cell survival following focal cerebral ischemia:life and death struggle in the penumbral[J]. J Neuropathol Exp Neurol, 2003, 62(4):329-9.
6 Philip K Liu. Ischemia-reperfusion-related Repair Deficit after Oxidative Stress: Implications of Faulty Transcripts in Neuronal Sensitivity after Brain Injury[J]. J Biomed Sci 2003;10: 4-13.
7 Suresh L. Mehta, Namratta Manhas and Ram Raghubir. Molecular targets in cerebral ischemia for developing novel therapeutics[J].Brain Research Reviews, 2007,54(1): 34-66.
8 National Institute of Neurological Disorder and Stroke Study Group:Tissue plasminogen activator for acute ischemic stroke[J]. N Engl J Med,1995, 999:1581-7.
9 Cipriani G., Rapizzi E., Vannacci A., Rizzuto R., Moroni F. and Chiarugi A.. Nuclear poly (ADP-ribose) polymerase-1 rapidly triggers mitochondrial dysfunction[J]. J Biol Chem 2005; 280:17227–34.
10 Ju B.G., Solum D., Song E.J., Lee K.J., Rose D.W., Glass C.K. et al. Activating the PARP-1 sensor component of the groucho/TLE1 corepressor complex mediates a CaM Kinase II delta-dependent neurogenic gene activation pathway. Cell 2004; 119:815–29.
11 Yu S.W., Wang H., Poitras M.F., Coombs C., Bowers W.J., Federoff H.J. et al. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor[J].Science 2002; 297:259–63.
12 Cheung E.C., Melanson-Drapeau L., Cregan S.P., Vanderluit J.L., Ferguson K.L., McIntosh W.C. et al. Apoptosis-inducing factor is a key factor in neuronal cell death propagated by BAX-dependent and BAX-independent mechanisms[J]. J Neurosci 2005; 25:1324–34.
13 Daugas E., Susin S.A., Zamzami N., Ferri K.F., Irinopoulou T., Larochette N. et al. Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis[J]. FASEB J 2000;14:729–39.
14 Ishitsuka K, Hidesshima T, Hamasakim. Novel inosine monophosphate dehydrogenase inhibitor VX-944 induces apoptosis in multi plemyeloma cells primarily via Caspase-independent AIF/Endo G pathway[J]. Oncogene, 2005, 24 (38 ):5888-96.
15 Lorenzo HK, Susin SA, Penninger J, et al. Apoptosis inducingfactor (AIF):a phylogenetically old Caspase- independent effector of cell death[J].Cell Death Differ, 1999, 6: 516-24.
16 Plesnila N., Zhu C., Culmsee C., Groger M., Moskowitz M.A. and Blomgren K.. Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia[J]. J Cereb Blood Flow Metab2004; 24: 458–66.
17 Chiarugi. Poly (ADP-ribosyl)ation and stroke[J]. Pharmacological Research 2005; 52:15–24.
18 Huang H B,Bao W F,Yang F F,et al. A study on chemical consitituents of Erigeron breviscapus(Vant.)Hand.-Mazz.[J]. J Shenyang Pham Univ,2005,26(11):1323-5.
19 石森林,徐莲英,吕圭源. 灯盏花的药理学研究进展[J]. 浙江中医学院学报,2004, 28(4):87-8.
20 Yang XF, He W, Lu WH, Zeng FD. Effects of scutellarin on liver function after brain I/R in rats[J]. Acta Pharmacol Sin 2003; 24(11): 1118-24.
21 HU Xia-min, Mi-mei ZHOU, Xian-min HU, Fan-dian ZENG. Neuroprotective effects of scutellarin on rat neuronal damage induced by cerebral ischemia/reperfusion[J]. Acta Pharmacol Sin 2005; 26(12): 1454–9.
1 Longa EZ, Weinsfein PR. Carlson S. Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats[J]. Stroke 1989; 20:84-91.
2 Kato H, Kogure K. Biochemical and molecular characteristics of the brain with developing cerebral infarction[J].Cell Mol Neurobilo, 1999, 19(1): 93~108.
3 Hou ST, MacManus JP. Molecular mechanisms of cerebral ischemia-induced neuronal death. Int Rev Cytol, 2002, 221:93~148.
4 Hurn P.D., VannuccS.J. i and Hagberg H.. Adult or perinatal brain injury: does sex matter? [J]. Stroke 2005; 36:193–5.
5 Lennmyr F., Karlsson S., Gerwins P., Ata K.A. and Terent A.. Activation of mitogen-activated protein kinases in experimental cerebral ischemia[J]. Acta Neurol Scand 2002; 106:333–40.
1 Kao H, Takasawa R, Fukuda K, Shiokawa D, Sadanaga-Akiyoshi F, Ibayashi S. et al. DNA fragmentation in ischemic core and penumbra in focal cerebral ischemia in rats[J]. Mol Brain Res 2001; 91:112-8.
2 Saito A,Maier CM, Narasimhan P, et al. Oxidative stress and neuronal death/survival signaling in cerebral ischemia[J]. Mol Neurobiol, 2005, 31 (1-3): 105-16.
3 Zhang F, Yin W, Chen J. Apoptosis in cerebral ischemia: executional and regulatory signaling mechanisms[J]. Neurol Res, 2004,26(8):835-45.
4 Desagher S, Martinou JC. Mitochondria as the central controlpoint of apoptosis[J]. TrendsCellBiol, 2000, 10:369-77.
5 Céline C, Isabelle C, Eric D, et al. Apoptosis-inducing factor (AIF): a novel Caspase-independent death effector released from mitochondria[J]. Biochimie, 2002, 84(2-3): 215-22.
6 Aoufouchi S, Shall S. Regulation by phosphorylation of Xenopus laevis poly(ADP-ribose) polymerase enzyme activity during oocytc maturation[J]. J Biochem,1997, 325:543-51.
7 Le Rhun Y. Celluar responses to DNA damage in the absence of Poly(ADP-ribose) polymerase[J].Biochem Biophys. Res Commun,1998, 245:1-10.
8 Griffin RJ.The role of inhibitors of Poly(ADP-ribose)polymerase as resistanc modifying agents in cancer therapy.Biochimie,1995,77:408-422.
9 Cookson MR, Inc PG, Usher PA. Poly ADP-ribose) polymerase is found in both the nucleus and cytoplasm of human CNS neurons [J]. BrainRes,1999, 834(1-2):182-5.
10 Aoufouchi S, Shall S. Regulation by phosphorylation of Xenopus laevis poly(ADP-ribose) polymerase enzyme activity during oocytc maturation[J]. J Biochem,1997,325:543-51.
11 Conde C, Mark M, Oliver FJ. Loss of poly(ADP-ribose)poly-merasel causes increased tumor latency in p53-deficient mice[J]. J EMBO, 2001, 20(13):3535-43.
12 Djordjevic VB.Free radicals in cell biology[J]. Int Rev Cytol, 2004, 237:57-89.
[1]Philip K Liu. Ischemia-reperfusion-related Repair Deficit after Oxidative Stress: Implications of Faulty Transcripts in Neuronal Sensitivity after Brain Injury. J Biomed Sci 2003; 10: 4-13.
[2] Hurn P.D., VannuccS.J. i and Hagberg H.. Adult or perinatal brain injury: does sex matter?. Stroke 2005; 36:193–5.
[3] Lennmyr F., Karlsson S., Gerwins P., Ata K.A. and Terent A.. Activation of mitogen-activated protein kinases in experimental cerebral ischemia. Acta Neurol Scand 2002; 106:333–40.
[4]Kao H, Takasawa R, Fukuda K, Shiokawa D, Sadanaga-Akiyoshi F, Ibayashi S. et al. DNA fragmentation in ischemic core and penumbra in focal cerebral ischemia in rats. Mol Brain Res 2001; 91:112-8.
[5] Chan P.H.. Reactive oxygen radicals in signaling and damage in the ischemic brain. J. Cereb. Blood Flow Metab 2001; 21:2–14.
[6] Yu S.W., Wang H., Poitras M.F., Coombs C., Bowers W.J., Federoff H.J. et al. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor.Science 2002; 297:259–63.
[7] Cipriani G., Rapizzi E., Vannacci A., Rizzuto R., Moroni F. and Chiarugi A.. Nuclear poly (ADP-ribose) polymerase-1 rapidly triggers mitochondrial dysfunction. J Biol Chem 2005; 280:17227–34.
[8] Ju B.G., Solum D., Song E.J., Lee K.J., Rose D.W., Glass C.K. et al. Activating the PARP-1 sensor component of the groucho/TLE1 corepressor complex mediates a CaMKinase IIdelta-dependent neurogenic gene activation pathway. Cell 2004; 119:815–29.
[9] Daugas E., Susin S.A., Zamzami N., Ferri K.F., Irinopoulou T., Larochette N. et al. Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J 2000;14:729–39.
[10] Cheung E.C., Melanson-Drapeau L., Cregan S.P., Vanderluit J.L., Ferguson K.L., McIntosh W.C. et al. Apoptosis-inducing factor is a key factor in neuronal cell death propagated by BAX-dependent and BAX-independent mechanisms. J Neurosci 2005; 25:1324–34.
[11] Plesnila N., Zhu C., Culmsee C., Groger M., Moskowitz M.A. and Blomgren K.. Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. J Cereb Blood Flow Metab2004; 24: 458–66.
[12] Culmsee C., Zhu C., Landshamer S., Becattini B., Wagner E., Pellechia M. et al. Apoptosis-inducing factor triggered by poly (ADP-ribose) polymerase and Bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia. J Neurosci 2005; 25:10262–72.
[13] Liu H, Yang XL, Wang Y, Tang XQ, Jiang DY, Xu HB. Protective effects of scutellarin on superoxide-induced oxidative stress in rat cortical synaptosomes.Acta Pharmacol Sin 2003; 24(11):1113-7.
[14] Yang XF, He W, Lu WH, Zeng FD. Effects of scutellarin on liver function after brain I/R in rats. Acta Pharmacol Sin 2003; 24(11): 1118-24.
[15] HU Xia-min, Mi-mei ZHOU, Xian-min HU, Fan-dian ZENG. Neuroprotective effects of scutellarin on rat neuronal damage induced by cerebral ischemia/reperfusion. Acta Pharmacol Sin 2005; 26(12): 1454–9.
[16] Zea Longa E, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniotomy in rats. Stroke 1989, 20: 84 91.
[17] Nisselbaum J.S. and Green S.. A simple ultramicro method for determination of pyridine nucleotides in tissues. Anal Biochem 1969; 27:212–7.
[18] Cao G., Pei,W. Ge H., Liang Q., Luo Y., Sharp F.R. et al. In vivo delivery of a Bcl-xL fusion protein containing the TAT protein transduction domain protects against ischemic brain injury and neuronal apoptosis. J Neurosci 2002; 22 : 5423–31.
[19] Wang H., Yu S.W., Koh D.W., Lew J., Coombs C., Bowers W. et al. Apoptosis-inducing factor substitutes for caspase executioners in NMDA-triggered excitotoxic neuronal death. J Neurosci 2004; 24:10963–73.
[20] Nakajima H., Kakui N., Ohkuma K., Ishikawa M. and Hasegawa T.. A newly synthesized poly (ADP-ribose) polymerase inhibitor, 2-methyl-3, 5, 7, 8-tetrahydrothiopyrano [4, 3-d] pyrimidine-4-one (DR2313): pharmacological profiles, neuroprotective effects and therapeutic time window in cerebral ischemia in rats.Journal of Pharmacology and Experimental Therapeutics 2004; 1:472–81.
[21] LaPlaca M.C., Zhang J., Raghupathi R., Li J.H., Smith F., Bareyre F.M. et al. Pharmacologic inhibition of poly (ADP-ribose) polymerase is neuroprotective following traumatic brain injury in rats. J Neurotrauma 2001; 18:369–76.
[22] Hong S.J., Dawson T.M. and Dawson V.L.. Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling.Trends Pharmacol Sci 2004; 25:259–64.
[23] Li X., Nemoto M., Xu Z., Yu S.-W., Shimoji M., Andrabi S.A. et al. Influence of duration of focal cerebral ischemia and neuronal nitric oxide synthase on translocation of apoptosis-inducing factor to the nucleus. Cellular neuroscience 2007;144(1): 56-65.
[24]Chiarugi. Poly (ADP-ribosyl)ation and stroke. Pharmacological Research 2005; 52:15–24.
[25] Ye H., Cande C., Stephanou N.C., Jiang S., Gurbuxani S., Larochette N. et al. DNA bindingis required for the apoptogenic action of apoptosis inducing factor. Nature Structural & Molecular Biology 2002; 9: 680–4.
1 刘静,唐兆新.线粒体在细胞凋亡中的作用[J].动物医学进展, 2006, 27 (6):43.
2 Takashi M. Caspases involved in ER stress - mediated cell death[J]. J Chemical Neuroanatomy, 2004, 28:101-5.
3 Finkel E.The mitochondrion: is it central to apoptosis?[J]. Science, 2001, 292:624-6.
4 Desagher S, Martinou JC. Mitochondria as the central controlpoint of apoptosis[J]. Trends Cell Biol, 2000, 10:369-77.
5 Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW. Three dimensional structure of the apoptosome:implications for assembly, proCaspase-9 binding, and activation[J]. Mol Cell, 2002,9:423-32.
6 Shi Y. Apoptosome: the cellular engine for the activation of Caspase-9[J]. Structure ( Camb ), 2002, 10:285-8.
7 RaffM. Cell suicide for beginners. Nature, 1998, 396:119-22.
8Céline C, Isabelle C, Eric D, et a.l Apoptosis-inducing factor (AIF): a novel Caspase-independent death effector released from mitochondria[ J]. Biochimie, 2002, 84(2-3): 215-22.
9 Cookson MR, Inc PG, Usher PA. Poly ADP-ribose) polymerase is found in both the nucleus and cytoplasm of human CNS neurons. [J].BrainRes,1999, 834(1-2):182-5.
10 Aoufouchi S, Shall S. Regulation by phosphorylation of Xenopus laevis poly (ADP-ribose) polymerase enzyme activity during oocytc maturation. Biochem [J].1997, 325:543-51.
11 Kato N, Morita H, Sugiyama T. Evalration of the poly(ADP-ribose) polymerase gene in human stroke[J].Atherosclerosis,1999,148(2):345-52.
12 Szabo C, Dawson VL. Role of poly(ADP-Ribose) synthetase in inflammation and ischemia-reperfusion[J]. Trends pharmacol Sci,1998,19(7):287-98.
13 Davidovic L,Vodenicharov M,Afar EB. et al. Importance of Poly (ADP-ribose) glycohydrolase in the control of poly (ADP-ribose)metabolism[J]. Exp Cell Res, 2001, 268(1):7-13.
14 Bums TF,Bernhard EJ,EI-Deity WS.Tissre specific expression of p53 target genes suggests a key role for KILLER/DR in p53-dependent apoptosis in vivo[J]. Oncogene, 2000, 113(pt6):955-961.
15 KimJ W, Won J, SohnS, et al. DNA-binding activity of the N-terminal cleavage product of poly (ADP-ribose)polymerase is required for UV mediated apoptosis[J]. J cell sci, 2000,113(pt6):955-961.
16 Le Rhun Y Celluar responses to DNA damage in the absence of Poly(ADP-ribose) polymerase[J].Biochem Biophys. Res Commun,1998, 245:1-10.
17 Griffin RJ.The role of inhibitors of Poly(ADP-ribose)polymerase as resistanc modifying agents in cancer therapy[J].Biochimie, 1995, 77:408-422
18 Jackson SP. The recognition of DNA damage[J]. Curr Opin Genet Dev, 1996, 6:19-25.
19 毛力真. PARP与缺血性神经元损伤后DNA的修复[J].中国临床神经科学, 1999, 4 (7): 246-8.
20 Zhang J, Dawson TM, Snyder SH. Nitric oxide activation of poly (ADP-ribose) synthetase in neurotoxiciy [J]. Science,1994, 263(514):687-689.
21 罗玉敏,Chen Jun,秦震等. 脑缺血与 DNA 损伤.国外医学脑血管疾病分册, 2002, 5 (8): 259-61.
22 YU SW, WANG H, Poitrasm F. Mediation of poly(ADP-ribose)polymerase-1 dependent cell death by apoptosis-inducingfactor[J]. Science, 2002, 297(5579): 259-63.
23 王昌正,陈东立,曹诚等. 凋亡诱导因子与非受体酪氨酸激酶 C-Abl 的相互作用[J]. 生物技术通讯, 2006, 17(2): 152.
24 Otera H, Ohsakaya S, Nagaura. Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space[J]. J EMBO, 2005, 24 ( 7 ):1375-86.
25 Ishitsuka K, Hidesshima T, Hamasaki M. Novel inosine monophosphate dehydrogenase inhibitor VX-944 induces apoptosis in multi plemyeloma cells primarily via Caspase-independent AIF/Endo G pathway[J]. Oncogene, 2005, 24 (38 ):5888-96.
26 Panka D J, Wang W, Atkinsn B. The Raf inhibitor BAY 43-9006 (Sorafenib ) induces Caspase-independent apoptosis in melanoma cells[J]. CancerRes, 2006, 66 ( 3) :1611-9.
27 Tanaka S, Takehashi M, Iida S. Mitochondrial impairment induced by poly (ADP-ribose ) polymerase-1 activation in cortical neurons after oxygen and glucose deprivation[J]. Neurochem, 2005, 95( 1 ): 179-90.
28 Ye H, Cande C, Stephanou N C. DNA binding as a structural requirement for the apoptogenic action of AIF[J ]. Nat Struct Biol, 2002, 9:680-4.
29 Lorenzo HK, Susin SA, Penninger J, et al. Apoptosis inducingfactor (AIF): a phylogenetically old Caspase- independent effector of cell death[J]. Cell Death Differ, 1999, 6: 516-24.
30 Park S Y, Cho S J, Kwon H C. Caspase-independent cell death by allicin in human epithelial carcinoma cells: involvement of PKA[J]. Cancer Lett. 2005, 224 (1): 123-32.
31 Susin S A, Lorenzo H K, Zamzami N. Molecular characterization of mitochondrial apoptosis-inducing factor[J ]. Nature, 1999, 397( 6718):387-9.
32 Gurbuxani S, Schmitt E, Cande C, et al. Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor[J]. Oncogene, 2003, 22 ( 43) :6669-78.
33 Lipton S A ,Wetzel B E. Dueling activities of AIF in cell death versus survival : DNA binding and redox activity [J]. Journal of Cell , 2002,111(2): 147-50.
34 Klein J A, Guess L C M, Rossmann M P, et al. The harlequin mouse mutation downregulatesapoptosis-inducing factor[J].Nature, 2002, 419:367-74.
35 Lipton S A, Ella B W. Dueling activities of AIF in cell death versus survival: DNA binding and redox activity[J]. Cell, 2002, 111:147-50.
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