依达拉奉对MPP~+所致星形胶质细胞损伤的保护作用
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摘要
依达拉奉(edaravone,Eda)是一种新型的神经保护剂,具有自由基清除作用,临床上主要用于急性脑梗塞的治疗。在体内,Eda通过转移一个电子给氧自由基或脂性自由基使其失活,自身形成无活性的Eda自由基,从而保护神经细胞免受自由基的损伤。近年来的相关研究显示,Eda具有确切的神经保护作用,可延迟神经元死亡,改善急性脑梗塞所致的神经症状,从而减轻神经功能障碍。然而,Eda发挥神经保护作用的机制尚缺乏深入研究。
星形胶质细胞是中枢神经系统中数量最多的细胞,在神经元存活、突触形成、神经再生和神经元修复等方面发挥重要作用。越来越多的证据显示胶质细胞塑造了神经网络。脑的病理学从广义上说就是胶质细胞的病理学,胶质细胞对神经元的存活及中枢神经系统的防御都至关重要。因此,维持星形胶质细胞的正常功能,抑制星形胶质细胞的凋亡,是神经保护的重要新策略。
氧化应激是指活性氧族(reactive oxygen species,ROS)生成与抗氧化防御系统之间的不平衡状态,可在ROS生成超过抗氧化防御系统时或者在抗氧化剂活性降低时发生,氧化应激和许多神经退行性疾病密切相关。星形胶质细胞在脑内ROS的清除过程中发挥着重要作用。而且,星形胶质细胞为神经元内谷胱甘肽(γ-L-glutamyl-L-cysteinyglycine,GSH)的合成提供前体物质。因此神经退行性病变中,星形胶质细胞抗氧化能力下降及其发生的氧化应激损伤,都会加剧病程的发展。
线粒体是ROS的主要来源,也是氧自由基损伤的主要目标。线粒体是细胞能量代谢的中心,还能调节细胞死亡,这是它第二个重要功能。近年来相关研究表明线粒体氧化应激与神经退行性疾病的神经元凋亡存在密切联系。过量ROS产生导致线粒体的膜系统损伤,激活线粒体通透性转换孔(mitochondrial permeability transition pore,PTP)开放,PTP的开放可释放促凋亡蛋白,继而引发线粒体途径的凋亡通路。线粒体在凋亡信号转导途径中起关键调节作用,线粒体功能障碍以及由线粒体介导的神经细胞凋亡在神经退行性疾病发生、发展中起了重要作用。针对线粒体功能的调节将有助于抑制ROS和引发的凋亡,发挥神经保护作用。
前期研究显示,Eda通过清除自由基保护神经元免受缺血再灌注引起的损伤。鉴于星形胶质细胞对降低脑氧化损伤程度以及神经元功能的恢复至关重要,我们推测Eda是否通过调节星形胶质细胞的功能来改善神经元的存活?目前尚没有相关研究报道。因此,本文工作的研究目的是探讨Eda对星形胶质细胞功能的调节作用。应用1-甲基,4-苯基吡啶离子(1-methyl-4-phenylpyridinium,MPP+)作为造模神经毒素,研究Eda对Mpp+诱导的星形胶质细胞凋亡和抗氧化能力的影响,以及对线粒体功能障碍的调节,探讨Eda调节星形胶质细胞功能的相关机制。
目的:研究、阐明Eda对MPP~+所致的星形胶质细胞损伤的调节作用及其机制。
方法:培养大鼠原代星形胶质细胞,应用Hoechst 33342荧光染色和LDH检测试剂盒检测细胞的凋亡;应用DCFH-DA荧光探针和GSH检测试剂盒检测细胞ROS水平、GSH含量;应用氧电极法、JC-1荧光探针检测线粒体呼吸功能和线粒体膜电位;应用半定量RT-PCR检测NADPH氧化酶亚基gp91、p47的表达变化;应用Western-blotting法检测AIF、cyto c的水平变化。
结果:1)MPP~+诱导星形胶质细胞凋亡和增加LDH的释放;预先给予Eda可以抑制MPP~+所致星形胶质细胞凋亡和LDH的释放,促进星形胶质细胞的存活。2)MPP~+降低星形胶质细胞内GSH的水平,诱导NADPH氧化酶激活;预先给予Eda增加星形胶质细胞内GSH的水平,同时抑制MPP~+所致NADPH氧化酶亚基gp91、p47表达增加的作用,从而抑制MPP~+诱导的星形胶质细胞ROS的增加。3)MPP~+诱导星形胶质细胞线粒体呼吸功能障碍;Eda(10μM)可以维持线粒体正常呼吸功能,改善MPP~+诱导的线粒体氧化损伤。4)MPP~+诱导星形胶质细胞△Ψ_m降低以及随后致凋亡因子(AIF和cyto c)的释放,导致细胞凋亡;Eda抑制MPP~+的上述作用,从而抑制星形胶质细胞凋亡。
结论:Eda通过抑制ROS生成、改善线粒体损伤、减少AIF和cvto c的释放,进而对抗MPP~+所致的星形胶质细胞凋亡。
本文研究工作的主要创新之处在于:
1.发现Eda通过调节星形胶质细胞功能发挥神经保护作用,其机制在于抑制MPP~+诱导的星形胶质细胞ROS的生成以及线粒体途径的凋亡通路,发挥神经保护作用。
2.揭示Eda通过抑制星形胶质细胞内NADPH氧化酶来源的ROS和线粒体来源的ROS,发挥其抗氧化作用。
Edaravone (Eda) is a potent radical scavenger, exerting multiple benefical effects on patients with acute ischemic stroke. Eda can efficiently scavenge free radicals via transfering an electron to oxygen free radicals or fat free radicals. Previouse researches revealed that Eda have potent antioxidant effects against ischemia-reperfusion-induced injury, delayed neuronal death and concomitant neurological deficits. These evidences also suggested that Eda provides neuroprotective effects via other mechanisms which have not been found.
Astrocytes, the most abundant glial cell type in the brain, provide metabolic and trophic support to neurons and modulate synaptic activity as well as survival of neurons. Increasing evidence indicates that glial cells form neural networks. The brain pathology is, in some sense, a pathology of glia. Glia cells are important for the survival of neurons and the defense of central nervous system. Therefore, modulation of astrocytic function may provide a novel therapeutic strategy for neurodegenerative disorders.
Oxidative stress has been implicated in a range of degenerative diseases. Astrocytes play an important role in clearing production of reactive oxygen species (ROS) in the brain. Astrocytes may have a close relation with the selective vulnerability of neurons by scavenging ROS and releasing the precursor ofγ-L-glutamyl-L-cysteinyglycine (GSH) synthesis in neurons. Furthermore, alteration in astrocyte GSH level may be an important contributor to the pathogenesis of neurodegenerative disease.
Mitochondria are not only major source of ROS generation in aerobic cells, but they are also sensitive target for the damaging effects of oxygen radicals. Mitochondria participate in the regulation of both energy metabolism and cell death. Excessive ROS production impairs mitochondria membrane system and activates mitochondrial permeability transition pore (PTP), resulting in the release of pro-apoptotic proteins which subquently initiated mitochondrial apoptotic pathway. Mitochondria dysfunction is a prominent feature in apoptosis, and release of pro-apoptotic proteins from the mitochondrial intermembrane space has been considered to be a critical event that occurs during apoptosis. Restoring mitochondrial function helps to provide neuroprotective effects on neurodegenerative disorders
Previous studies demonstrated that Eda exerted neuroprotective effects by inhibiting endothelial injury and ameliorating neuronal damage after brain ischemia insult. As astrocytes play critical roles in decreasing the oxidative damage in the brain and restoring neuronal function, we hypothesized that Eda promotes the survival of neurons via regulating astrocytic function. The neurotoxin 1-methyl-4-phenylpyridinium (MPP~+) is a high affinity inhibitor of mitochondrial complex I and is commonly used as a neurotoxin to induce cellular injury. In the present study, we investigated the effect of Eda on the MPP~+-induced cytotoxicity and ROS production in rat primary cultured astrocytes, focusing on mitochondrial function.
AIM: To investigate the effects and possible mechanisms of Eda on MPP~+-induced cytotoxicity in rat primary cultured astrocytes.
METHODS: Astrocytic apoptosis was determined by staining with Hoechst 33324 staining and LDH assay. The production of ROS was measured by DCFH-DA probe. GSH assay was performed by test kits purchased from Jian Cheng Bioengineering Institute. Mitochondria respiratory function was measured by using a Clark Electrode provided by Hansatech. Molecular probe JC-1 was used to detect mitochondrial membrane potential (△Ψ_m). We observed changes in mRNA levels of gp91 and p47 by RT-PCR semi-quantitative analysis. We introduced Western-blotting for the analyses of AIF, cyto c.
RESULTS: 1) Treatment with MPP~+ (200μM) significantly induced astrocytic apoptosis and the release of LDH, Eda inhibited astrocytic apoptosis and reduced the LDH release induced by MPP~+; 2) Eda inhibited production of ROS through preventing GSH depletion and down-regulating mRNA expressions of NADPH Oxidase membrane subunit gp91 and membrane-translocated subunit p47 induced by MPP~+ (200μM); 3) Treatment with MPP~+ (50μM) significantly induced mitochondria oxidative respiratory dysfunction, Eda (1 and 10μM) prevented the decreases of ST3 and RCR induced by MPP~+ which inhibited ROS production of mitochondria source in astrocytes; 4) Eda protected astrocytes against MPP~+-induced apoptosis by inhibiting△Ψ_m loss and subsequently release of pro-apoptotic factors (cyto c and AIF) induced by MPP~+.
In the present study, we found that Eda inhibited astrocytic apoptosis and reduced the LDH release induced by MPP~+. Eda could inhibit production of ROS through preventing GSH depletion and down-regulating mRNA expressions of NADPH Oxidase membrane subunit gp91 and membrane-translocated subunit p47. Furthermore, Eda not only ameliorated mitochondrial respiratory function but also prevented△Ψ_m loss, thereby inhibiting subsequent release of cyto c and AIF. These findings reveal that Eda protects astrocytes against MPP~+-induced apoptosis via modulating ROS level and mitochondrial apoptotic pathway.
CONCLUSION: These results indicated that Eda could inhibit MPP~+-induced astrocytic apoptosis, the decrease of antioxidation and mitochondria dysfunction, suggesting that Eda may be a regulator of the astrocytic function.
In summary, the present study firstly reveals that Eda protects against MPP~+-induced cytotoxicity in astrocytes via decreasing ROS production and inhibiting mitochondria apoptotic pathways. These findings provide a new perspective for Eda used as a neuroprotective agent.
星形胶质细胞是中枢神经系统中数量最多的细胞,在神经元存活、突触形成、神经再生和神经元修复等方面发挥重要作用。越来越多的证据显示胶质细胞塑造了神经网络。脑的病理学从广义上说就是胶质细胞的病理学,胶质细胞对神经元的存活及中枢神经系统的防御都至关重要。因此,维持星形胶质细胞的正常功能,抑制星形胶质细胞的凋亡,是神经保护的重要新策略。
氧化应激是指活性氧族(reactive oxygen species,ROS)生成与抗氧化防御系统之间的不平衡状态,可在ROS生成超过抗氧化防御系统时或者在抗氧化剂活性降低时发生,氧化应激和许多神经退行性疾病密切相关。星形胶质细胞在脑内ROS的清除过程中发挥着重要作用。而且,星形胶质细胞为神经元内谷胱甘肽(γ-L-glutamyl-L-cysteinyglycine,GSH)的合成提供前体物质。因此神经退行性病变中,星形胶质细胞抗氧化能力下降及其发生的氧化应激损伤,都会加剧病程的发展。
线粒体是ROS的主要来源,也是氧自由基损伤的主要目标。线粒体是细胞能量代谢的中心,还能调节细胞死亡,这是它第二个重要功能。近年来相关研究表明线粒体氧化应激与神经退行性疾病的神经元凋亡存在密切联系。过量ROS产生导致线粒体的膜系统损伤,激活线粒体通透性转换孔(mitochondrial permeability transition pore,PTP)开放,PTP的开放可释放促凋亡蛋白,继而引发线粒体途径的凋亡通路。线粒体在凋亡信号转导途径中起关键调节作用,线粒体功能障碍以及由线粒体介导的神经细胞凋亡在神经退行性疾病发生、发展中起了重要作用。针对线粒体功能的调节将有助于抑制ROS和引发的凋亡,发挥神经保护作用。
前期研究显示,Eda通过清除自由基保护神经元免受缺血再灌注引起的损伤。鉴于星形胶质细胞对降低脑氧化损伤程度以及神经元功能的恢复至关重要,我们推测Eda是否通过调节星形胶质细胞的功能来改善神经元的存活?目前尚没有相关研究报道。因此,本文工作的研究目的是探讨Eda对星形胶质细胞功能的调节作用。应用1-甲基,4-苯基吡啶离子(1-methyl-4-phenylpyridinium,MPP+)作为造模神经毒素,研究Eda对Mpp+诱导的星形胶质细胞凋亡和抗氧化能力的影响,以及对线粒体功能障碍的调节,探讨Eda调节星形胶质细胞功能的相关机制。
目的:研究、阐明Eda对MPP~+所致的星形胶质细胞损伤的调节作用及其机制。
方法:培养大鼠原代星形胶质细胞,应用Hoechst 33342荧光染色和LDH检测试剂盒检测细胞的凋亡;应用DCFH-DA荧光探针和GSH检测试剂盒检测细胞ROS水平、GSH含量;应用氧电极法、JC-1荧光探针检测线粒体呼吸功能和线粒体膜电位;应用半定量RT-PCR检测NADPH氧化酶亚基gp91、p47的表达变化;应用Western-blotting法检测AIF、cyto c的水平变化。
结果:1)MPP~+诱导星形胶质细胞凋亡和增加LDH的释放;预先给予Eda可以抑制MPP~+所致星形胶质细胞凋亡和LDH的释放,促进星形胶质细胞的存活。2)MPP~+降低星形胶质细胞内GSH的水平,诱导NADPH氧化酶激活;预先给予Eda增加星形胶质细胞内GSH的水平,同时抑制MPP~+所致NADPH氧化酶亚基gp91、p47表达增加的作用,从而抑制MPP~+诱导的星形胶质细胞ROS的增加。3)MPP~+诱导星形胶质细胞线粒体呼吸功能障碍;Eda(10μM)可以维持线粒体正常呼吸功能,改善MPP~+诱导的线粒体氧化损伤。4)MPP~+诱导星形胶质细胞△Ψ_m降低以及随后致凋亡因子(AIF和cyto c)的释放,导致细胞凋亡;Eda抑制MPP~+的上述作用,从而抑制星形胶质细胞凋亡。
结论:Eda通过抑制ROS生成、改善线粒体损伤、减少AIF和cvto c的释放,进而对抗MPP~+所致的星形胶质细胞凋亡。
本文研究工作的主要创新之处在于:
1.发现Eda通过调节星形胶质细胞功能发挥神经保护作用,其机制在于抑制MPP~+诱导的星形胶质细胞ROS的生成以及线粒体途径的凋亡通路,发挥神经保护作用。
2.揭示Eda通过抑制星形胶质细胞内NADPH氧化酶来源的ROS和线粒体来源的ROS,发挥其抗氧化作用。
Edaravone (Eda) is a potent radical scavenger, exerting multiple benefical effects on patients with acute ischemic stroke. Eda can efficiently scavenge free radicals via transfering an electron to oxygen free radicals or fat free radicals. Previouse researches revealed that Eda have potent antioxidant effects against ischemia-reperfusion-induced injury, delayed neuronal death and concomitant neurological deficits. These evidences also suggested that Eda provides neuroprotective effects via other mechanisms which have not been found.
Astrocytes, the most abundant glial cell type in the brain, provide metabolic and trophic support to neurons and modulate synaptic activity as well as survival of neurons. Increasing evidence indicates that glial cells form neural networks. The brain pathology is, in some sense, a pathology of glia. Glia cells are important for the survival of neurons and the defense of central nervous system. Therefore, modulation of astrocytic function may provide a novel therapeutic strategy for neurodegenerative disorders.
Oxidative stress has been implicated in a range of degenerative diseases. Astrocytes play an important role in clearing production of reactive oxygen species (ROS) in the brain. Astrocytes may have a close relation with the selective vulnerability of neurons by scavenging ROS and releasing the precursor ofγ-L-glutamyl-L-cysteinyglycine (GSH) synthesis in neurons. Furthermore, alteration in astrocyte GSH level may be an important contributor to the pathogenesis of neurodegenerative disease.
Mitochondria are not only major source of ROS generation in aerobic cells, but they are also sensitive target for the damaging effects of oxygen radicals. Mitochondria participate in the regulation of both energy metabolism and cell death. Excessive ROS production impairs mitochondria membrane system and activates mitochondrial permeability transition pore (PTP), resulting in the release of pro-apoptotic proteins which subquently initiated mitochondrial apoptotic pathway. Mitochondria dysfunction is a prominent feature in apoptosis, and release of pro-apoptotic proteins from the mitochondrial intermembrane space has been considered to be a critical event that occurs during apoptosis. Restoring mitochondrial function helps to provide neuroprotective effects on neurodegenerative disorders
Previous studies demonstrated that Eda exerted neuroprotective effects by inhibiting endothelial injury and ameliorating neuronal damage after brain ischemia insult. As astrocytes play critical roles in decreasing the oxidative damage in the brain and restoring neuronal function, we hypothesized that Eda promotes the survival of neurons via regulating astrocytic function. The neurotoxin 1-methyl-4-phenylpyridinium (MPP~+) is a high affinity inhibitor of mitochondrial complex I and is commonly used as a neurotoxin to induce cellular injury. In the present study, we investigated the effect of Eda on the MPP~+-induced cytotoxicity and ROS production in rat primary cultured astrocytes, focusing on mitochondrial function.
AIM: To investigate the effects and possible mechanisms of Eda on MPP~+-induced cytotoxicity in rat primary cultured astrocytes.
METHODS: Astrocytic apoptosis was determined by staining with Hoechst 33324 staining and LDH assay. The production of ROS was measured by DCFH-DA probe. GSH assay was performed by test kits purchased from Jian Cheng Bioengineering Institute. Mitochondria respiratory function was measured by using a Clark Electrode provided by Hansatech. Molecular probe JC-1 was used to detect mitochondrial membrane potential (△Ψ_m). We observed changes in mRNA levels of gp91 and p47 by RT-PCR semi-quantitative analysis. We introduced Western-blotting for the analyses of AIF, cyto c.
RESULTS: 1) Treatment with MPP~+ (200μM) significantly induced astrocytic apoptosis and the release of LDH, Eda inhibited astrocytic apoptosis and reduced the LDH release induced by MPP~+; 2) Eda inhibited production of ROS through preventing GSH depletion and down-regulating mRNA expressions of NADPH Oxidase membrane subunit gp91 and membrane-translocated subunit p47 induced by MPP~+ (200μM); 3) Treatment with MPP~+ (50μM) significantly induced mitochondria oxidative respiratory dysfunction, Eda (1 and 10μM) prevented the decreases of ST3 and RCR induced by MPP~+ which inhibited ROS production of mitochondria source in astrocytes; 4) Eda protected astrocytes against MPP~+-induced apoptosis by inhibiting△Ψ_m loss and subsequently release of pro-apoptotic factors (cyto c and AIF) induced by MPP~+.
In the present study, we found that Eda inhibited astrocytic apoptosis and reduced the LDH release induced by MPP~+. Eda could inhibit production of ROS through preventing GSH depletion and down-regulating mRNA expressions of NADPH Oxidase membrane subunit gp91 and membrane-translocated subunit p47. Furthermore, Eda not only ameliorated mitochondrial respiratory function but also prevented△Ψ_m loss, thereby inhibiting subsequent release of cyto c and AIF. These findings reveal that Eda protects astrocytes against MPP~+-induced apoptosis via modulating ROS level and mitochondrial apoptotic pathway.
CONCLUSION: These results indicated that Eda could inhibit MPP~+-induced astrocytic apoptosis, the decrease of antioxidation and mitochondria dysfunction, suggesting that Eda may be a regulator of the astrocytic function.
In summary, the present study firstly reveals that Eda protects against MPP~+-induced cytotoxicity in astrocytes via decreasing ROS production and inhibiting mitochondria apoptotic pathways. These findings provide a new perspective for Eda used as a neuroprotective agent.
引文
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26. Hansson, E. & Ronnback, L. Glial neuronal signaling in the central nervous system. FASEB J 17, 341-348 (2003).
27. Giaume, C, Kirchhoff, F., Matute, C., Reichenbach, A. & Verkhratsky, A. Glia: the fulcrum of brain diseases. Cell Death Differ 14, 1324-1335 (2007).
28. Magistretti, P.J. Neuron-glia metabolic coupling and plasticity. J Exp Biol 209, 2304-2311(2006).
29. Pekny, M. & Nilsson, M. Astrocyte activation and reactive gliosis. Glia 50, 427-434 (2005).
30. Chen, Y. & Swanson, R.A. Astrocytes and brain injury. J Cereb Blood Flow Metab 23, 137-149 (2003).
31. Nicotera, P., Bellomo, G. & Orrenius, S. Calcium-mediated mechanisms in chemically induced cell death. Annu Rev Pharmacol Toxicol 32, 449-470 (1992).
32. Hu, X., Ge, Q.F., Zhang, L., Lu, Y.B. & Wei, E.Q. [Homeostatic conditions affect the protective effect of edaravone on ischemic injury in neurons]. Zhejiang Da Xue Xue Bao Yi Xue Ban 35,147-153 (2006).
33. Miyamoto, R., Shimakawa, S., Suzuki, S., Ogihara, T. & Tamai, H. Edaravone prevents kainic acid-induced neuronal death. Brain Res (2008).
34. Otani, H., et al. Temporal effects of edaravone, a free radical scavenger, on transient ischemia-induced neuronal dysfunction in the rat hippocampus. Eur J Pharmacol 512, 129-137 (2005).
35. Ishikawa, A., et al. Edaravone inhibits the expression of vascular endothelial growth factor in human astrocytes exposed to hypoxia. Neurosci Res 59,406-412 (2007).
36. Kawasaki, T., et al. Nitric oxide-induced apoptosis in cultured rat astrocytes: protection by edaravone, a radical scavenger. Glia 55,1325-1333 (2007).
37. D'Autreaux, B. & Toledano, M.B. ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 8, 813-824 (2007).
38. Simon, H.U., Haj-Yehia, A. & Levi-Schaffer, F. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 5,415-418 (2000).
39. Li, J.M. & Shah, A.M. Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 287, R1014-1030 (2004).
40. Liu, Q., Kang, J.H. & Zheng, R.L. NADPH oxidase produces reactive oxygen species and maintains survival of rat astrocytes. Cell Biochem Funct 23, 93-100 (2005).
41. Kahles, T., et al. NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke. Stroke 38, 3000-3006 (2007).
42. Wang, Q., et al. Ethanol preconditioning protects against ischemia/reperfusion-induced brain damage: role of NADPH oxidase-derived ROS. Free Radic Biol Med 43, 1048-1060 (2007).
43. Scherz-Shouval, R. & Elazar, Z. ROS, mitochondria and the regulation of autophagy. Trends Cell Biol 17, 422-427 (2007).
44. Indo, H.P., et al. Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage. Mitochondrion 7, 106-118 (2007).
45. Arvelo, F. [Mitochondria and apoptosis]. Acta Cient Venez 53, 297-306 (2002).
46. Orrenius, S., Gogvadze, V. & Zhivotovsky, B. Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol 47, 143-183 (2007).
47. Ott, M., Gogvadze, V., Orrenius, S. & Zhivotovsky, B. Mitochondria, oxidative stress and cell death. Apoptosis 12, 913-922 (2007).
48. Lee, H.C. & Wei, Y.H. Oxidative stress, mitochondrial DNA mutation, and apoptosis in aging. Exp Biol Med (Maywood) 232, 592-606 (2007).
49. Mignotte, B. & Vayssiere, J.L. Mitochondria and apoptosis. Eur J Biochem 252, 1-15 (1998).
50. Beal, M.F. Mitochondria and neurodegeneration. Novartis Found Symp 287, 183-192; discussion 192-186 (2007).
51. Brady, N.R., Hamacher-Brady, A., Westerhoff, H.V. & Gottlieb, R.A. A wave of reactive oxygen species (ROS)-induced ROS release in a sea of excitable mitochondria. Antioxid Redox Signal 8, 1651-1665 (2006).
52. Desagher, S. & Martinou, J.C. Mitochondria as the central control point of apoptosis. Trends Cell Biol 10, 369-377 (2000).
53. Panov, A., et al. Species- and tissue-specific relationships between mitochondrial permeability transition and generation of ROS in brain and liver mitochondria of rats and mice. Am J Physiol Cell Physiol 292, C708-718 (2007).
54. Yel, L., Brown, L.E., Su, K., Gollapudi, S. & Gupta, S. Thimerosal induces neuronal cell apoptosis by causing cytochrome c and apoptosis-inducing factor release from mitochondria. Int J Mol Med 16, 971-977 (2005).
55. Gogvadze, V., Orrenius, S. & Zhivotovsky, B. Multiple pathways of cytochrome c release from mitochondria in apoptosis. Biochim Biophys Acta 1757, 639-647 (2006).
56. Cande, C., et al. Apoptosis-inducing factor (AIF): a novel caspase-independent death effector released from mitochondria. Biochimie 84, 215-222 (2002).
57. Piantadosi, C.A., Carraway, M.S., Haden, D.W. & Suliman, H.B. Protecting the permeability pore and mitochondrial biogenesis. Novartis Found Symp 280, 266-276; discussion 276-280 (2007).
58. Di Monte, D.A., Wu, E.Y. & Langston, J.W. Role of astrocytes in MPTP metabolism and toxicity. Ann NY Acad Sci 648,219-228 (1992).
59. Dubin, M. & Stoppani, A.O. [Programmed cell death and apoptosis. The role of mitochondria]. Medicina (B Aires) 60, 375-386 (2000).
60. Hughes, G., Murphy, M.P. & Ledgerwood, E.C. Mitochondrial reactive oxygen species regulate the temporal activation of nuclear factor kappaB to modulate tumour necrosis factor-induced apoptosis: evidence from mitochondria-targeted antioxidants. Biochem J 389, 83-89 (2005).
61. Watanabe, T., Tanaka, M., Watanabe, K., Takamatsu, Y. & Tobe, A. [Research and development of the free radical scavenger edaravone as a neuroprotectant]. Yakugaku Zasshi 124, 99-111(2004).
62. Mueller, C.F., Laude, K., McNally, J.S. & Harrison, D.G. ATVB in focus: redox mechanisms in blood vessels. Arterioscler Thromb Vasc Biol 25, 274-278 (2005).
63. Bedard, K. & Krause, K.H. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87, 245-313 (2007).
64. Mytilineou, C, Kramer, B.C. & Yabut, J.A. Glutathione depletion and oxidative stress. Parkinsonism Relat Disord 8, 385-387 (2002).
65. Jenner, P. & Olanow, C.W. Understanding cell death in Parkinson's disease. Ann Neurol 44, S72-84 (1998).
66. Orrenius, S., Gogvadze, V. & Zhivotovsky, B. Mitochondrial oxidative stress: implications for cell death. Annual Review Of Pharmacology And Toxicology 47, 143-183 (2007).
67. Bayir, H., et al. Apoptotic interactions of cytochrome c: redox flirting with anionic phospholipids within and outside of mitochondria. Biochim Biophys Acta 1757, 648-659 (2006).
1.Oishi,R.,et al.Effect of MCI-186 on ischemia-induced changes in monoamine metabolism in rat brain.Stroke 20,1557-1564(1989).
2.Nishi,H.,Watanabe,T.,Sakurai,H.,Yuki,S.& Ishibashi,A.Effect of MCI-186on brain edema in rats.Stroke 20,1236-1240(1989).
3.Abe,K.[Edaravone].Nippon Rinsho 64 Suppl7,548-553(2006).
4.Mehta,S.L.,Manhas,N.& Raghubir,R.Molecular targets in cerebral ischemia for developing novel therapeutics.Brain Res Rev 54,34-66(2007).
5.Nakagomi,T.,Yamakawa,K.,Sasaki,T.,Saito,I.& Takakura,K.Effect of edaravone on cerebral vasospasm following experimental subarachnoid hemorrhage.J Stroke Cerebrovasc Dis 12,17-21(2003).
6.Yoshino,H.& Kimura,A.Investigation of the therapeutic effects of edaravone,a free radical scavenger,on amyotrophic lateral sclerosis(Phase Ⅱ study).Amyotroph Lateral Scler 7,241-245(2006).
7.Foner,S.N.Free Radicals and Unstable Molecules.Science 143,441-450(1964).
8.Margaill,I.,Plotkine,M.& Lerouet,D.Antioxidant strategies in the treatment of stroke.Free Radic Biol Med 39,429-443(2005).
9.Orrenius,S.,Gogvadze,V.& Zhivotovsky,B.Mitochondrial oxidative stress:implications for cell death.Annu Rev Pharmacol Toxicol 47,143-183(2007).
10.Simon,H.U.,Haj-Yehia,A.& Levi-Schaffer,F.Role of reactive oxygen species (ROS)in apoptosis induction.Apoptosis 5,415-418(2000).
11.Gonzalez,C.,et al.Significance of ROS in oxygen sensing in cell systems with sensitivity to physiological hypoxia.Respir Physiol Neurobiol 132,17-41 (2002).
12. Prabhakar, N.R., Kumar, G.K., Nanduri, J. & Semenza, G.L. ROS signaling in systemic and cellular responses to chronic intermittent hypoxia. Antioxid Redox Signal 9, 1397-1403(2007).
13. Indo, H.P., et al. Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage. Mitochondrion 7, 106-118 (2007).
14. Alexandrova, M.L., et al. Oxidative stress in the chronic phase after stroke. Redox Rep 8, 169-176 (2003).
15. Tabrizchi, R. Edaravone Mitsubishi-Tokyo. Curr Opin Investig Drugs 1, 347-354 (2000).
16. Mizuno, A., Umemura, K. & Nakashima, M. Inhibitory effect of MCI-186, a free radical scavenger, on cerebral ischemia following rat middle cerebral artery occlusion. Gen Pharmacol 30, 575-578 (1998).
17. Shichinohe, H., et al. Neuroprotective effects of the free radical scavenger Edaravone (MCI-186) in mice permanent focal brain ischemia. Brain Res 1029, 200-206 (2004).
18. Uno, M., et al. Inhibition of brain damage by edaravone, a free radical scavenger, can be monitored by plasma biomarkers that detect oxidative and astrocyte damage in patients with acute cerebral infarction. Free Radic Biol Med 39, 1109-1116(2005).
19. Ogasawara, K., et al. Pretreatment with the free radical scavenger edaravone prevents cerebral hyperperfusion after carotid endarterectomy. Neurosurgery 55, 1060-1067(2004).
20. Mitsumori, K., Sakuragi, M. & Kitami, K. The effect MCI — 186 on regional cerebral blood flow in patients with acute cerebral irfarction—A Sequential SPECT study. Ther Res 19, 1333-1345 (1998).
21. Otani, H., et al. Temporal effects of edaravone, a free radical scavenger, on transient ischemia-induced neuronal dysfunction in the rat hippocampus. Eur J Pharmacol 512, 129-137 (2005).
22. Qi, X., Okuma, Y, Hosoi, T. & Nomura, Y. Edaravone protects against hypoxia/ischemia-induced endoplasmic reticulum dysfunction. J Pharmacol Exp Ther 311, 388-393 (2004).
23. Amemiya, S., et al. Anti-apoptotic and neuroprotective effects of edaravone following transient focal ischemia in rats. Eur J Pharmacol 516, 125-130 (2005).
24. Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc Dis 15, 222-229 (2003).
25. Song, Y, Li, M., Li, J.C. & Wei, E.Q. Edaravone protects PC12 cells from ischemic-like injury via attenuating the damage to mitochondria. J Zhejiang Univ Sci B 7, 749-756 (2006).
26. Yasuoka, N., Nakajima, W., Ishida, A. & Takada, G. Neuroprotection of edaravone on hypoxic-ischemic brain injury in neonatal rats. Brain Res Dev Brain Res 151,129-139 (2004).
27. Wen, J., et al Edaravone inhibits JNK-c-Jun pathway and restores anti-oxidative defense after ischemia-reperfusion injury in aged rats. Biol Pharm Bull 29, 713-718(2006).
28. Kawasaki, T., et al. Nitric oxide-induced apoptosis in cultured rat astrocytes: protection by edaravone, a radical scavenger. Glia 55,1325-1333 (2007).
29. Kawasaki, T., Ishihara, K., Ago, Y, Baba, A. & Matsuda, T. Edaravone (3-methyl-l-phenyl-2-pyrazolin-5-one), a radical scavenger, prevents l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in the substantia nigra but not the striatum. J Pharmacol Exp Ther 322, 274-281 (2007).
30. Banno, M., et al. The radical scavenger edaravone prevents oxidative neurotoxicity induced by peroxynitrite and activated microglia. Neuropharmacology 48, 283-290 (2005).
31. Kawasaki, T., et al. Protective effect of the radical scavenger edaravone against methamphetamine-induced dopaminergic neurotoxicity in mouse striatum. Eur J Pharmacol 542, 92-99 (2006).
32. Nakano-Okuda, Y, et al. Effects of edaravone on N-methyl-D-aspartate (NMDA)-mediated cytochrome c release and apoptosis in neonatal rat cerebrocortical slices. Int J Dev Neurosci 24, 349-356 (2006).
33. Strijbos, P.J. Nitric oxide in cerebral ischemic neurodegeneration and excitotoxicity. Crit Rev Neurobiol 12, 223-243 (1998).
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35. Duncan, A.J. & Heales, S.J. Nitric oxide and neurological disorders. Mol Aspects Med 26, 67-96 (2005).
36. Yoshida, H., et al. Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury. CNS Drug Rev 12, 9-20 (2006).
37. Zhang, N., et al. Edaravone reduces early accumulation of oxidative products and sequential inflammatory responses after transient focal ischemia in mice brain. Stroke 36, 2220-2225 (2005).
38. Okatani, Y, Wakatsuki, A., Enzan, H. & Miyahara, Y. Edaravone protects against ischemia/reperfusion-induced oxidative damage to mitochondria in rat liver. Eur J Pharmacol 465,163-170 (2003).
39. Takayasu, Y, et al. Edaravone, a radical scavenger, inhibits mitochondrial permeability transition pore in rat brain. J Pharmacol Sci 103,434-437 (2007).
2.Nishi,H.,Watanabe,T.,Sakurai,H.,Yuki,S.& Ishibashi,A.Effect of MCI-186 on brain edema in rats.Stroke 20,1236-1240(1989).
3.Oishi,R.,et al.Effect of MCI-186 on ischemia-induced changes in monoamine metabolism in rat brain.Stroke 20,1557-1564(1989).
4.Watanabe,T.,Yuki,S.,Egawa,M.& Nishi,H.Protective effects of MCI-186 on cerebral ischemia:possible involvement of free radical scavenging and antioxidant actions.J Pharmacol Exp Ther 268,1597-1604(1994).
5.Green,A.R.& Shuaib,A.Therapeutic strategies for the treatment of stroke.Drug Discov Today 11,681-693(2006).
6.Alexandrova,M.L.,et al.Oxidative stress in the chronic phase after stroke.Redox Rep 8,169-176(2003).
7.Love,S.Oxidative stress in brain ischemia.Brain Pathol 9,119-131(1999).
8.White,B.C.,et al.Brain ischemia and reperfusion:molecular mechanisms of neuronal injury.J Neurol Sci 179,1-33(2000).
9.Wang,C.X.& Shuaib,A.Neuroprotective effects of free radical scavengers in stroke.Drugs Aging 24,537-546(2007).
10.Abe,K.[Edaravone].Nippon Rinsho 64 Suppl7,548-553(2006).
11.Yoshida,H.,et al.Neuroprotective effects of edaravone:a novel free radical scavenger in cerebrovascular injury.CNS Drug Rev 12,9-20(2006).
12.Alexandrova,M.,et al.Dynamics of free radical processes in acute ischemic stroke:influence on neurological status and outcome.J Clin Neurosci 11,501-506(2004).
13.Nishikawa,M.& Inoue,M.[Oxidative stress and tissue injury].Masui 57,321-326(2008).
14.Nakamoto,N.,et al.A free radical scavenger,edaravone,attenuates steatosis and cell death via reducing inflammatory cytokine production in rat acute liver injury.Free Radic Res 37,849-859(2003).
15.Wang,L.F.& Zhang,H.Y.A theoretical investigation on DPPH radical-scavenging mechanism of edaravone.Bioorg Med Chem Lett 13,3789-3792(2003).
16. Tabrizchi, R. Edaravone Mitsubishi-Tokyo. Curr Opin Investig Drugs 1, 347-354 (2000).
17. Dervan, A.G., et al. Astroglial plasticity and glutamate function in a chronic mouse model of Parkinson's disease. Exp Neurol 190, 145-156 (2004).
18. Volterra, A. & Meldolesi, J. Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 6, 626-640 (2005).
19. Seifert, G., Schilling, K. & Steinhauser, C. Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci 7,194-206 (2006).
20. Dong, Y. & Benveniste, E.N. Immune function of astrocytes. Glia 36,180-190 (2001).
21. Fellin, T., D'Ascenzo, M. & Haydon, P.G. Astrocytes control neuronal excitability in the nucleus accumbens. Scientific WorldJournal 7, 89-97 (2007).
22. Takano, T., et al. Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 9, 260-267 (2006).
23. Peuchen, S., et al. Interrelationships between astrocyte function, oxidative stress and antioxidant status within the central nervous system. Prog Neurobiol 52, 261-281 (1997).
24. Aschner, M. Neuron-astrocyte interactions: implications for cellular energetics and antioxidant levels. Neurotoxicology 21, 1101-1107 (2000).
25. Haydon, P.G. & Carmignoto, G. Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev 86, 1009-1031 (2006).
26. Hansson, E. & Ronnback, L. Glial neuronal signaling in the central nervous system. FASEB J 17, 341-348 (2003).
27. Giaume, C, Kirchhoff, F., Matute, C., Reichenbach, A. & Verkhratsky, A. Glia: the fulcrum of brain diseases. Cell Death Differ 14, 1324-1335 (2007).
28. Magistretti, P.J. Neuron-glia metabolic coupling and plasticity. J Exp Biol 209, 2304-2311(2006).
29. Pekny, M. & Nilsson, M. Astrocyte activation and reactive gliosis. Glia 50, 427-434 (2005).
30. Chen, Y. & Swanson, R.A. Astrocytes and brain injury. J Cereb Blood Flow Metab 23, 137-149 (2003).
31. Nicotera, P., Bellomo, G. & Orrenius, S. Calcium-mediated mechanisms in chemically induced cell death. Annu Rev Pharmacol Toxicol 32, 449-470 (1992).
32. Hu, X., Ge, Q.F., Zhang, L., Lu, Y.B. & Wei, E.Q. [Homeostatic conditions affect the protective effect of edaravone on ischemic injury in neurons]. Zhejiang Da Xue Xue Bao Yi Xue Ban 35,147-153 (2006).
33. Miyamoto, R., Shimakawa, S., Suzuki, S., Ogihara, T. & Tamai, H. Edaravone prevents kainic acid-induced neuronal death. Brain Res (2008).
34. Otani, H., et al. Temporal effects of edaravone, a free radical scavenger, on transient ischemia-induced neuronal dysfunction in the rat hippocampus. Eur J Pharmacol 512, 129-137 (2005).
35. Ishikawa, A., et al. Edaravone inhibits the expression of vascular endothelial growth factor in human astrocytes exposed to hypoxia. Neurosci Res 59,406-412 (2007).
36. Kawasaki, T., et al. Nitric oxide-induced apoptosis in cultured rat astrocytes: protection by edaravone, a radical scavenger. Glia 55,1325-1333 (2007).
37. D'Autreaux, B. & Toledano, M.B. ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 8, 813-824 (2007).
38. Simon, H.U., Haj-Yehia, A. & Levi-Schaffer, F. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 5,415-418 (2000).
39. Li, J.M. & Shah, A.M. Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 287, R1014-1030 (2004).
40. Liu, Q., Kang, J.H. & Zheng, R.L. NADPH oxidase produces reactive oxygen species and maintains survival of rat astrocytes. Cell Biochem Funct 23, 93-100 (2005).
41. Kahles, T., et al. NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke. Stroke 38, 3000-3006 (2007).
42. Wang, Q., et al. Ethanol preconditioning protects against ischemia/reperfusion-induced brain damage: role of NADPH oxidase-derived ROS. Free Radic Biol Med 43, 1048-1060 (2007).
43. Scherz-Shouval, R. & Elazar, Z. ROS, mitochondria and the regulation of autophagy. Trends Cell Biol 17, 422-427 (2007).
44. Indo, H.P., et al. Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage. Mitochondrion 7, 106-118 (2007).
45. Arvelo, F. [Mitochondria and apoptosis]. Acta Cient Venez 53, 297-306 (2002).
46. Orrenius, S., Gogvadze, V. & Zhivotovsky, B. Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol 47, 143-183 (2007).
47. Ott, M., Gogvadze, V., Orrenius, S. & Zhivotovsky, B. Mitochondria, oxidative stress and cell death. Apoptosis 12, 913-922 (2007).
48. Lee, H.C. & Wei, Y.H. Oxidative stress, mitochondrial DNA mutation, and apoptosis in aging. Exp Biol Med (Maywood) 232, 592-606 (2007).
49. Mignotte, B. & Vayssiere, J.L. Mitochondria and apoptosis. Eur J Biochem 252, 1-15 (1998).
50. Beal, M.F. Mitochondria and neurodegeneration. Novartis Found Symp 287, 183-192; discussion 192-186 (2007).
51. Brady, N.R., Hamacher-Brady, A., Westerhoff, H.V. & Gottlieb, R.A. A wave of reactive oxygen species (ROS)-induced ROS release in a sea of excitable mitochondria. Antioxid Redox Signal 8, 1651-1665 (2006).
52. Desagher, S. & Martinou, J.C. Mitochondria as the central control point of apoptosis. Trends Cell Biol 10, 369-377 (2000).
53. Panov, A., et al. Species- and tissue-specific relationships between mitochondrial permeability transition and generation of ROS in brain and liver mitochondria of rats and mice. Am J Physiol Cell Physiol 292, C708-718 (2007).
54. Yel, L., Brown, L.E., Su, K., Gollapudi, S. & Gupta, S. Thimerosal induces neuronal cell apoptosis by causing cytochrome c and apoptosis-inducing factor release from mitochondria. Int J Mol Med 16, 971-977 (2005).
55. Gogvadze, V., Orrenius, S. & Zhivotovsky, B. Multiple pathways of cytochrome c release from mitochondria in apoptosis. Biochim Biophys Acta 1757, 639-647 (2006).
56. Cande, C., et al. Apoptosis-inducing factor (AIF): a novel caspase-independent death effector released from mitochondria. Biochimie 84, 215-222 (2002).
57. Piantadosi, C.A., Carraway, M.S., Haden, D.W. & Suliman, H.B. Protecting the permeability pore and mitochondrial biogenesis. Novartis Found Symp 280, 266-276; discussion 276-280 (2007).
58. Di Monte, D.A., Wu, E.Y. & Langston, J.W. Role of astrocytes in MPTP metabolism and toxicity. Ann NY Acad Sci 648,219-228 (1992).
59. Dubin, M. & Stoppani, A.O. [Programmed cell death and apoptosis. The role of mitochondria]. Medicina (B Aires) 60, 375-386 (2000).
60. Hughes, G., Murphy, M.P. & Ledgerwood, E.C. Mitochondrial reactive oxygen species regulate the temporal activation of nuclear factor kappaB to modulate tumour necrosis factor-induced apoptosis: evidence from mitochondria-targeted antioxidants. Biochem J 389, 83-89 (2005).
61. Watanabe, T., Tanaka, M., Watanabe, K., Takamatsu, Y. & Tobe, A. [Research and development of the free radical scavenger edaravone as a neuroprotectant]. Yakugaku Zasshi 124, 99-111(2004).
62. Mueller, C.F., Laude, K., McNally, J.S. & Harrison, D.G. ATVB in focus: redox mechanisms in blood vessels. Arterioscler Thromb Vasc Biol 25, 274-278 (2005).
63. Bedard, K. & Krause, K.H. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87, 245-313 (2007).
64. Mytilineou, C, Kramer, B.C. & Yabut, J.A. Glutathione depletion and oxidative stress. Parkinsonism Relat Disord 8, 385-387 (2002).
65. Jenner, P. & Olanow, C.W. Understanding cell death in Parkinson's disease. Ann Neurol 44, S72-84 (1998).
66. Orrenius, S., Gogvadze, V. & Zhivotovsky, B. Mitochondrial oxidative stress: implications for cell death. Annual Review Of Pharmacology And Toxicology 47, 143-183 (2007).
67. Bayir, H., et al. Apoptotic interactions of cytochrome c: redox flirting with anionic phospholipids within and outside of mitochondria. Biochim Biophys Acta 1757, 648-659 (2006).
1.Oishi,R.,et al.Effect of MCI-186 on ischemia-induced changes in monoamine metabolism in rat brain.Stroke 20,1557-1564(1989).
2.Nishi,H.,Watanabe,T.,Sakurai,H.,Yuki,S.& Ishibashi,A.Effect of MCI-186on brain edema in rats.Stroke 20,1236-1240(1989).
3.Abe,K.[Edaravone].Nippon Rinsho 64 Suppl7,548-553(2006).
4.Mehta,S.L.,Manhas,N.& Raghubir,R.Molecular targets in cerebral ischemia for developing novel therapeutics.Brain Res Rev 54,34-66(2007).
5.Nakagomi,T.,Yamakawa,K.,Sasaki,T.,Saito,I.& Takakura,K.Effect of edaravone on cerebral vasospasm following experimental subarachnoid hemorrhage.J Stroke Cerebrovasc Dis 12,17-21(2003).
6.Yoshino,H.& Kimura,A.Investigation of the therapeutic effects of edaravone,a free radical scavenger,on amyotrophic lateral sclerosis(Phase Ⅱ study).Amyotroph Lateral Scler 7,241-245(2006).
7.Foner,S.N.Free Radicals and Unstable Molecules.Science 143,441-450(1964).
8.Margaill,I.,Plotkine,M.& Lerouet,D.Antioxidant strategies in the treatment of stroke.Free Radic Biol Med 39,429-443(2005).
9.Orrenius,S.,Gogvadze,V.& Zhivotovsky,B.Mitochondrial oxidative stress:implications for cell death.Annu Rev Pharmacol Toxicol 47,143-183(2007).
10.Simon,H.U.,Haj-Yehia,A.& Levi-Schaffer,F.Role of reactive oxygen species (ROS)in apoptosis induction.Apoptosis 5,415-418(2000).
11.Gonzalez,C.,et al.Significance of ROS in oxygen sensing in cell systems with sensitivity to physiological hypoxia.Respir Physiol Neurobiol 132,17-41 (2002).
12. Prabhakar, N.R., Kumar, G.K., Nanduri, J. & Semenza, G.L. ROS signaling in systemic and cellular responses to chronic intermittent hypoxia. Antioxid Redox Signal 9, 1397-1403(2007).
13. Indo, H.P., et al. Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage. Mitochondrion 7, 106-118 (2007).
14. Alexandrova, M.L., et al. Oxidative stress in the chronic phase after stroke. Redox Rep 8, 169-176 (2003).
15. Tabrizchi, R. Edaravone Mitsubishi-Tokyo. Curr Opin Investig Drugs 1, 347-354 (2000).
16. Mizuno, A., Umemura, K. & Nakashima, M. Inhibitory effect of MCI-186, a free radical scavenger, on cerebral ischemia following rat middle cerebral artery occlusion. Gen Pharmacol 30, 575-578 (1998).
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