Immunomodulatory Drugs Alleviate L-Dopa-Induced Dyskinesia in a Rat Model of Parkinson's Disease
Immunomodulatory Drugs Alleviate L-Dopa-Induced Dyskinesia in a Rat Model of Parkinson's Disease
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DOI：
10.1002/mds.27799
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发表时间：
2019-12-01
影响因子：
8.6
通讯作者：
Carta, Anna R.
中科院分区：
文献类型：
--
作者：
Boi, Laura;Pisanu, Augusta;Carta, Anna R.
背景资料：沙利度胺和密切相关的类似物在临床上用于通过抑制促炎细胞因子肿瘤坏死因子α介导的免疫调节和抗血管生成特性。神经炎症和血管生成有助于经典的神经元机制，支持左旋多巴诱导的运动障碍的病理生理学，与左旋多巴治疗帕金森病相关的运动并发症。在6-羟基多巴胺帕金森病模型中测试沙利度胺和更有效的衍生物3，6'-二硫沙利度胺对运动障碍的功效。6-羟基多巴胺输注3周后，大鼠接受10天的左旋多巴加苄丝肼治疗每天记录（各6 mg/kg）和沙利度胺（70 mg/kg）或3，6 '-二硫沙利度胺（56 mg/kg）以及运动障碍和对侧翻身。在最后一次注射左旋多巴后1小时对大鼠实施安乐死，并在其纹状体和黑质网状物中测量肿瘤坏死因子-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的水平，以评估神经炎症和血管生成。纹状体水平的GLUR1被测量为L-多巴诱导的突触后变化，是肿瘤坏死因子-α control.Results：沙利度胺和3，6 '-二硫沙利度胺显着衰减的严重程度，L-多巴诱导的运动障碍，而不影响对侧转向。此外，这两种化合物都抑制了纹状体和黑质网状中L-多巴诱导的小胶质细胞增生和过量的肿瘤坏死因子-α，同时恢复了抗炎细胞因子白细胞介素-10的生理水平。左旋多巴诱导的血管生成在两个基底神经节核中均受到抑制，左旋多巴诱导的背外侧纹状体GLUR 1过表达恢复至正常水平。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，而沙利度胺和更有效的衍生物可能为运动障碍提供一种有效的治疗方法。(C)2019国际帕金森和运动障碍协会
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 alpha. 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-alpha, 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-alpha 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-alpha 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-alpha levels may be useful to reduce the appearance of dyskinesia, and thalidomide, and more potent derivatives may provide an effective therapeutic approach to dyskinesia. (C) 2019 International Parkinson and Movement Disorder Society