Peroxisome proliferator-activated receptor-α activation attenuates 3-nitropropionic acid induced behavioral and biochemical alterations in rats: Possible neuroprotective mechanisms
Peroxisome proliferator-activated receptor-α activation attenuates 3-nitropropionic acid induced behavioral and biochemical alterations in rats: Possible neuroprotective mechanisms
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DOI：
10.1016/j.ejphar.2011.10.029
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发表时间：
2012-01-05
影响因子：
5
通讯作者：
Padi, Satyanarayana S. V.
中科院分区：
文献类型：
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作者：
Bhateja, Deepak Kumar;Dhull, Dinesh K.;Padi, Satyanarayana S. V.
过氧化物酶体增殖物激活受体被认为是控制各种神经退行性疾病的潜在治疗靶点。然而，没有一项研究阐明了它在治疗亨廷顿病中的作用。我们探讨了过氧化物酶体增殖物激活受体-a激动剂是否可以减弱全身给予3-硝基丙酸（3-NP）诱导的各种行为和生化改变，3-NP是公认的亨廷顿病表型的实验动物模型。腹膜内施用3-NP（20 mg/kg.，注射用）持续4天，大鼠产生运动功能减退、肌肉不协调和认知功能障碍。每日用非诺贝特（100或200 mg/kg.，p.o.），在3-NP给药前30分钟给药共4天，显著改善了3-NP诱导的运动和认知障碍。生化分析表明，系统3-NP管理显着增加氧化和亚硝化应激（增加脂质过氧化，蛋白质羰基和亚硝酸盐水平），乳酸脱氢酶活性，而降低过氧化氢酶，超氧化物歧化酶，还原型谷胱甘肽和琥珀酸脱氢酶的活性。非诺贝特治疗显著减轻脑组织中的氧化损伤、细胞因子和改善线粒体复合物酶活性。在本研究中，MK 886，过氧化物酶体增殖物激活受体-a的选择性抑制剂，通过受体依赖性或受体非依赖性的神经保护机制来阐明有益的效果。给予MK 886（lmg/kg，i. p.）在非诺贝特（200 mg/kg，p.o.）消除了非诺贝特的作用。结果表明，非诺贝特在3-NP给药大鼠中的受体依赖性神经保护作用为PPAR-a活化在神经保护中的作用提供了新的证据，该作用归因于调节氧化应激和炎症。(C)2011 Elsevier B. V.保留所有权利。
Peroxisome proliferators activated receptor is regarded as potential therapeutic targets to control various neurodegenerative disorders. However, none of the study has elucidated its effect in the treatment of Huntington's disease. We explored whether peroxisome proliferators activated receptor-a agonist may attenuate various behavioral and biochemical alterations induced by systemic administration of 3-nitropropionic acid (3-NP), an accepted experimental animal model of Huntington's disease phenotype. Intraperitoneal administration of 3-NP (20 mg/kg., i.p.) for 4 days in rats produced hypolocomotion, muscle incoordination, and cognitive dysfunction. Daily treatment with fenofibrate (100 or 200 mg/kg., p.o.), 30 min prior to 3-NP administration for a total of 4 days, significantly improved the 3-NP induced motor and cognitive impairment. Biochemical analysis revealed that systemic 3-NP administration significantly increased oxidative and nitrosative stress (increase lipid peroxidation, protein carbonyls and nitrite level), lactate dehydrogenase activity whereas, decreased the activities of catalase, superoxide dismutase, reduced glutathione, and succinate dehydrogenase. Fenofibrate treatment significantly attenuated oxidative damage, cytokines and improved mitochondrial complexes enzyme activity in brain. In the present study, MK886, a selective inhibitor of peroxisome proliferators activated receptor-a was employed to elucidate the beneficial effect through either receptor dependent or receptor independent neuroprotective mechanisms. Administration of MK886 (1 mg/kg, i.p.) prior to fenofibrate (200 mg/kg, p.o.) abolished the effect of fenofibrate. The results showed that receptor dependent neuroprotective effects of fenofibrate in 3-NP administered rats provide a new evidence for a role of PPAR-a activation in neuroprotection that is attributed by modulating oxidative stress and inflammation. (C) 2011 Elsevier B.V. All rights reserved.