Sharma Rohita, McMillan Catherine R, Tenn Catherine C, Niles Lennard P
Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5.
Brain Res. 2006 Jan 12;1068(1):230-6. doi: 10.1016/j.brainres.2005.10.084. Epub 2005 Dec 20.
There is considerable evidence that pharmacological doses of the pineal hormone, melatonin, are neuroprotective in diverse models of neurodegeneration including Parkinson's disease. However, there is limited information about the effects of physiological doses of this hormone in similar models. In this study, rats were chronically treated with melatonin via drinking water following partial 6-hydroxydopamine lesioning in the striatum. The two doses of melatonin (0.4 microg/ml and 4.0 microg/ml) were within the reported physiological concentrations present in the serum and cerebrospinal fluid respectively. At 2 weeks after surgery, the higher dose of melatonin significantly attenuated rotational behavior in hemi-parkinsonian rats compared to similarly lesioned animals receiving either vehicle (P < 0.001) or the lower dose of melatonin (P < 0.01). Animals were perfused or sacrificed 10 weeks after commencing melatonin treatment for immunohistochemical or mRNA studies. Animals treated with 4.0 microg/ml melatonin exhibited normal tyrosine hydroxylase (TH) immunoreactivity in the lesioned striatum, whereas little or no TH immunofluorescence was visible in similarly lesioned animals receiving vehicle. In contrast, semiquantitative RT-PCR analysis revealed no group differences in TH mRNA, suggesting spontaneous recovery of this transcript as observed previously in partially lesioned animals. There were no significant differences in striatal GDNF mRNA levels between sham and lesioned animals. However, there was a significant (P < 0.01) increase in GDNF mRNA expression in the intact contralateral striata of lesioned animals treated with vehicle. Interestingly, melatonin treatment attenuated this novel compensatory contralateral increase in striatal GDNF expression, presumably due to its neuroprotective effect. These findings support a physiological role for melatonin in protecting against parkinsonian neurodegeneration in the nigrostriatal system.
有大量证据表明，松果体激素褪黑素的药理剂量在包括帕金森病在内的多种神经退行性疾病模型中具有神经保护作用。然而，关于该激素生理剂量在类似模型中的作用信息有限。在本研究中，大鼠纹状体经部分6-羟基多巴胺损伤后，通过饮水长期给予褪黑素。两种褪黑素剂量（0.4微克/毫升和4.0微克/毫升）分别处于血清和脑脊液中报道的生理浓度范围内。术后2周，与接受溶剂或低剂量褪黑素的类似损伤动物相比，高剂量褪黑素显著减轻了半帕金森病大鼠的旋转行为（P < 0.001）（P < 0.01）。在开始褪黑素治疗10周后，对动物进行灌注或处死，以进行免疫组织化学或mRNA研究。用4.0微克/毫升褪黑素处理的动物在损伤的纹状体中表现出正常的酪氨酸羟化酶（TH）免疫反应性，而在接受溶剂的类似损伤动物中几乎没有或没有可见的TH免疫荧光。相比之下，半定量RT-PCR分析显示TH mRNA在各组间无差异，表明该转录本如先前在部分损伤动物中观察到的那样自发恢复。假手术组和损伤组动物纹状体GDNF mRNA水平无显著差异。然而，接受溶剂处理的损伤动物完整的对侧纹状体中GDNF mRNA表达显著增加（P < 0.01）。有趣的是，褪黑素治疗减弱了纹状体GDNF表达这种新的对侧代偿性增加，推测是由于其神经保护作用。这些发现支持了褪黑素在保护黑质纹状体系统免受帕金森病神经退行性变方面的生理作用。
