Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India; Department of Zoology, Pandit Deendayal Upadhyaya Adarsha Mahavidyalaya (PDUAM), Eraligool 788723, Karimganj, Assam, India.
Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India.
Neuroscience. 2018 Sep 15;388:347-356. doi: 10.1016/j.neuroscience.2018.07.041. Epub 2018 Aug 1.
Elevated levels of cholesterol (hypercholesterolemia) and homocysteine (hyperhomocysteinemia, HHcy) in blood have been linked with the pathology of Parkinson's disease. However, the impact of their combined effect on brain is unknown. The present study aims to investigate the effect of HHcy on dopaminergic neurons in brain of mice with hypercholesterolemia. Mice were subjected to a high-cholesterol diet for 12 weeks to develop hypercholesterolemia, and were administered with homocysteine (250 mg/kg, b.w., i.p., 60 days) daily starting from 24th day of the high-cholesterol diet for induction of HHcy. The animals were subjected to Parkinsonian motor behavioral tests and sacrificed to estimate the levels of cholesterol, homocysteine and dopamine in brain, and to assess dopaminergic neuronal status. There occurred elevation in cholesterol and homocysteine levels in nigrostriatum of hypercholesterolemic animals with HHcy. Injection of homocysteine in hypercholesterolemic mice exacerbated the motor abnormalities as well as caused depletion of striatal dopamine level significantly, which was supported by a significant decrease in tyrosine hydroxylase (TH) immunoreactivity in striatum. While neither hypercholesterolemia nor HHcy caused significant changes in the number of TH-positive neurons, hypercholesterolemia in combination with HHcy resulted in a significant loss of nigral TH-positive neurons. The results highlighted the involvement of mitochondrial complex-I dysfunction with subsequent generation of hydroxyl radicals for the observed loss of midbrain dopamine neurons in animals receiving the combined treatment. Thus, the findings of the present study pointed out the combined effect of homocysteine and cholesterol toward dopamine neuronal dysfunctions, which has substantial relevance to Parkinson's disease.
血液中胆固醇（高胆固醇血症）和同型半胱氨酸（高同型半胱氨酸血症，HHcy）水平升高与帕金森病的病理学有关。然而，它们联合作用对大脑的影响尚不清楚。本研究旨在探讨 HHcy 对高胆固醇血症小鼠大脑多巴胺能神经元的影响。小鼠接受高胆固醇饮食 12 周以发展为高胆固醇血症，并从高胆固醇饮食的第 24 天开始每天给予同型半胱氨酸（250mg/kg，体重，腹腔注射，60 天）以诱导 HHcy。动物接受帕金森运动行为测试后处死，以估计大脑中的胆固醇、同型半胱氨酸和多巴胺水平，并评估多巴胺能神经元状态。在有 HHcy 的高胆固醇血症动物的黑质纹状体中，胆固醇和同型半胱氨酸水平升高。同型半胱氨酸注射到高胆固醇血症小鼠中加剧了运动异常，并显著导致纹状体多巴胺水平耗竭，这得到了纹状体酪氨酸羟化酶（TH）免疫反应性显著降低的支持。虽然高胆固醇血症或 HHcy 都没有导致 TH 阳性神经元数量发生显著变化，但高胆固醇血症与 HHcy 联合作用导致黑质中 TH 阳性神经元明显丢失。这些结果强调了线粒体复合物-I 功能障碍的参与，随后产生羟基自由基，导致接受联合治疗的动物中中脑多巴胺神经元丢失。因此，本研究的结果指出了同型半胱氨酸和胆固醇对多巴胺能神经元功能障碍的联合作用，这与帕金森病有实质性的相关性。
