Carriere Candace H, Kang Na Hyea, Niles Lennard P
Department of Psychiatry and Behavioural Neurosciences, Faculty of Health Sciences, McMaster University, HSC-4N77, 1200 Main Street West, Hamilton, ON, Canada L8N 3Z5.
Brain Res. 2016 Feb 15;1633:115-125. doi: 10.1016/j.brainres.2015.12.036. Epub 2015 Dec 29.
Parkinson's disease is a major neurodegenerative disorder which primarily involves the loss of dopaminergic neurons in the substantia nigra and related projections in the striatum. The pesticide/neurotoxin, rotenone, has been shown to cause systemic inhibition of mitochondrial complex I activity in nigral dopaminergic neurons, with consequent degeneration of the nigrostriatal pathway, as observed in Parkinson's disease. A novel intrastriatal rotenone model of Parkinson's disease was used to examine the neuroprotective effects of chronic low-dose treatment with the antioxidant indoleamine, melatonin, which can upregulate neurotrophic factors and other protective proteins in the brain. Sham or lesioned rats were treated with either vehicle (0.04% ethanol in drinking water) or melatonin at a dose of 4 µg/mL in drinking water. The right striatum was lesioned by stereotactic injection of rotenone at three sites (4 μg/site) along its rostrocaudal axis. Apomorphine administration to lesioned animals resulted in a significant (p<0.001) increase in ipsilateral rotations, which was suppressed by melatonin. Nine weeks post-surgery, animals were sacrificed by transcardial perfusion. Subsequent immunohistochemical examination revealed a decrease in tyrosine hydroxylase immunoreactivity within the striatum and substantia nigra of rotenone-lesioned animals. Melatonin treatment attenuated the decrease in tyrosine hydroxylase in the striatum and abolished it in the substantia nigra. Stereological cell counts indicated a significant (p<0.05) decrease in dopamine neurons in the substantia nigra of rotenone-lesioned animals, which was confirmed by Nissl staining. Importantly, chronic melatonin treatment blocked the loss of dopamine neurons in rotenone-lesioned animals. These findings strongly support the therapeutic potential of long-term and low-dose melatonin treatment in Parkinson's disease.
帕金森病是一种主要的神经退行性疾病，主要涉及黑质中多巴胺能神经元的丧失以及纹状体中相关投射的损伤。杀虫剂/神经毒素鱼藤酮已被证明会导致黑质多巴胺能神经元中线粒体复合物I活性的全身性抑制，随之而来的是黑质纹状体通路的退化，这与帕金森病中观察到的情况一致。一种新的帕金森病纹状体内鱼藤酮模型被用于研究抗氧化剂吲哚胺褪黑素进行慢性低剂量治疗的神经保护作用，褪黑素可以上调大脑中的神经营养因子和其他保护蛋白。假手术或造模大鼠分别接受载体（饮用水中的0.04%乙醇）或饮用水中剂量为4μg/mL的褪黑素治疗。通过立体定向在右侧纹状体沿其前后轴的三个部位（4μg/部位）注射鱼藤酮进行造模。对造模动物给予阿扑吗啡导致同侧旋转显著增加（p<0.001），而褪黑素可抑制这种增加。手术后9周，通过心脏灌注处死动物。随后的免疫组织化学检查显示，鱼藤酮造模动物的纹状体和黑质中酪氨酸羟化酶免疫反应性降低。褪黑素治疗减轻了纹状体中酪氨酸羟化酶的降低，并消除了黑质中的这种降低。体视学细胞计数表明，鱼藤酮造模动物黑质中的多巴胺能神经元显著减少（p<0.05），尼氏染色证实了这一点。重要的是，慢性褪黑素治疗阻止了鱼藤酮造模动物中多巴胺能神经元的损失。这些发现有力地支持了长期低剂量褪黑素治疗帕金森病的治疗潜力。
