Saravanan Karuppagounder S, Sindhu Kizhakke M, Senthilkumar Karuppagounder S, Mohanakumar Kochupurackal P
Division of Clinical and Experimental Neuroscience, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Calcutta 700032, India.
Neurochem Int. 2006 Jul;49(1):28-40. doi: 10.1016/j.neuint.2005.12.016. Epub 2006 Feb 21.
The present study investigated oxidative damage and neuroprotective effect of the antiparkinsonian drug, L-deprenyl in neuronal death produced by intranigral infusion of a potent mitochondrial complex-I inhibitor, rotenone in rats. Unilateral stereotaxic intranigral infusion of rotenone caused significant decrease of striatal dopamine levels as measured employing HPLC-electrochemistry, and loss of tyrosine hydroxylase immunoreactivity in the perikarya of ipsilateral substantia nigra (SN) neurons and their terminals in the striatum. Rotenone-induced increases in the salicylate hydroxylation products, 2,3- and 2,5-dihydroxybenzoic acid indicators of hydroxyl radials in mitochondrial P2 fraction were dose-dependently attenuated by L-deprenyl. L-deprenyl (0.1-10mg/kg; i.p.) treatment dose-dependently attenuated rotenone-induced reductions in complex-I activity and glutathione (GSH) levels in the SN, tyrosine hydroxylase immunoreactivity in the striatum or SN as well as striatal dopamine. Amphetamine-induced stereotypic rotations in these rats were also significantly inhibited by deprenyl administration. The rotenone-induced elevated activities of cytosolic antioxidant enzymes superoxide dismutase and catalase showed further significant increase following L-deprenyl. Our findings suggest that unilateral intranigral infusion of rotenone reproduces neurochemical, neuropathological and behavioral features of PD in rats and L-deprenyl can rescue the dopaminergic neurons from rotenone-mediated neurodegeneration in them. These results not only establish oxidative stress as one of the major causative factors underlying dopaminergic neurodegeneration as observed in Parkinson's disease, but also support the view that deprenyl is a potent free radical scavenger and an antioxidant.
本研究调查了抗帕金森病药物L-司来吉兰对大鼠黑质内注射强效线粒体复合体I抑制剂鱼藤酮所致神经元死亡的氧化损伤及神经保护作用。采用高效液相色谱-电化学法测定，单侧立体定向黑质内注射鱼藤酮导致纹状体多巴胺水平显著降低，同侧黑质（SN）神经元胞体及其在纹状体的终末酪氨酸羟化酶免疫反应性丧失。鱼藤酮诱导的线粒体P2组分中水杨酸羟化产物（羟基自由基指标2,3-二羟基苯甲酸和2,5-二羟基苯甲酸）增加，被L-司来吉兰剂量依赖性减弱。L-司来吉兰（0.1 - 10mg/kg；腹腔注射）治疗可剂量依赖性减弱鱼藤酮诱导的SN中复合体I活性和谷胱甘肽（GSH）水平降低、纹状体或SN中酪氨酸羟化酶免疫反应性以及纹状体多巴胺降低。给予司来吉兰也显著抑制了这些大鼠中苯丙胺诱导的刻板旋转。鱼藤酮诱导的胞质抗氧化酶超氧化物歧化酶和过氧化氢酶活性升高，在给予L-司来吉兰后进一步显著增加。我们的研究结果表明，单侧黑质内注射鱼藤酮可重现大鼠帕金森病的神经化学、神经病理学和行为特征，L-司来吉兰可使多巴胺能神经元免受鱼藤酮介导的神经退行性变。这些结果不仅确立了氧化应激是帕金森病中观察到的多巴胺能神经退行性变的主要致病因素之一，也支持了司来吉兰是一种有效的自由基清除剂和抗氧化剂的观点。
