免疫调节药物可减轻帕金森病大鼠模型中 l-多巴诱导的运动障碍。
Immunomodulatory drugs alleviate l-dopa-induced dyskinesia in a rat model of Parkinson's disease.
机构信息
Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
CNR Institute of Neuroscience, Cagliari, Cagliari, Italy.
出版信息
Mov Disord. 2019 Dec;34(12):1818-1830. doi: 10.1002/mds.27799. Epub 2019 Jul 23.
BACKGROUND
Thalidomide and closely related analogues are used clinically for their immunomodulatory and antiangiogenic properties mediated by the inhibition of the proinflammatory cytokine tumor necrosis factor α. Neuroinflammation and angiogenesis contribute to classical neuronal mechanisms underpinning the pathophysiology of l-dopa-induced dyskinesia, a motor complication associated with l-dopa therapy in Parkinson's disease. The efficacy of thalidomide and the more potent derivative 3,6'-dithiothalidomide on dyskinesia was tested in the 6-hydroxydopamine Parkinson's disease model.
METHODS
Three weeks after 6-hydroxydopamine infusion, rats received 10 days of treatment with l-dopa plus benserazide (6 mg/kg each) and thalidomide (70 mg/kg) or 3,6'-dithiothalidomide (56 mg/kg), and dyskinesia and contralateral turning were recorded daily. Rats were euthanized 1 hour after the last l-dopa injection, and levels of tumor necrosis factor-α, interleukin-10, OX-42, vimentin, and vascular endothelial growth factor immunoreactivity were measured in their striatum and substantia nigra reticulata to evaluate neuroinflammation and angiogenesis. Striatal levels of GLUR1 were measured as a l-dopa-induced postsynaptic change that is under tumor necrosis factor-α control.
RESULTS
Thalidomide and 3,6'-dithiothalidomide significantly attenuated the severity of l-dopa-induced dyskinesia while not affecting contralateral turning. Moreover, both compounds inhibited the l-dopa-induced microgliosis and excessive tumor necrosis factor-α in the striatum and substantia nigra reticulata, while restoring physiological levels of the anti-inflammatory cytokine interleukin-10. l-Dopa-induced angiogenesis was inhibited in both basal ganglia nuclei, and l-dopa-induced GLUR1 overexpression in the dorsolateral striatum was restored to normal levels.
CONCLUSIONS
These data suggest that decreasing tumor necrosis factor-α levels may be useful to reduce the appearance of dyskinesia, and thalidomide, and more potent derivatives may provide an effective therapeutic approach to dyskinesia. © 2019 International Parkinson and Movement Disorder Society.
背景
沙利度胺及其密切相关的类似物通过抑制促炎细胞因子肿瘤坏死因子 α 发挥其免疫调节和抗血管生成特性，临床上用于治疗。神经炎症和血管生成有助于经典的神经元机制，这些机制是左旋多巴诱导的运动障碍的病理生理学基础，左旋多巴诱导的运动障碍是帕金森病中与左旋多巴治疗相关的运动并发症。在 6-羟多巴胺帕金森病模型中测试了沙利度胺和更有效的衍生物 3,6'-二硫代沙利度胺对运动障碍的疗效。
方法
在 6-羟多巴胺输注后 3 周，大鼠接受了 10 天的治疗，给予左旋多巴加苯丝肼（各 6mg/kg）和沙利度胺（70mg/kg）或 3,6'-二硫代沙利度胺（56mg/kg），每天记录运动障碍和对侧转动。最后一次左旋多巴注射后 1 小时处死大鼠，测量其纹状体和黑质网状部的肿瘤坏死因子-α、白细胞介素-10、OX-42、波形蛋白和血管内皮生长因子免疫反应性，以评估神经炎症和血管生成。测量纹状体 GLUR1 水平作为受肿瘤坏死因子-α控制的左旋多巴诱导的突触后变化。
结果
沙利度胺和 3,6'-二硫代沙利度胺显著减轻了左旋多巴诱导的运动障碍的严重程度，而不影响对侧转动。此外，两种化合物均抑制了纹状体和黑质网状部的左旋多巴诱导的小胶质细胞增生和过度肿瘤坏死因子-α，同时恢复了抗炎细胞因子白细胞介素-10 的生理水平。两种化合物均抑制了基底神经节核的左旋多巴诱导的血管生成，并且将背外侧纹状体中的左旋多巴诱导的 GLUR1 过表达恢复到正常水平。
结论
这些数据表明，降低肿瘤坏死因子-α水平可能有助于减少运动障碍的出现，沙利度胺及其更有效的衍生物可能为运动障碍提供有效的治疗方法。 © 2019 国际帕金森病和运动障碍学会。
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