Long-term Levodopa Treatment Accelerates the Circadian Rhythm Dysfunction in a 6-hydroxydopamine Rat Model of Parkinson's Disease.
Long-term Levodopa Treatment Accelerates the Circadian Rhythm Dysfunction in a 6-hydroxydopamine Rat Model of Parkinson's Disease.
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长期左旋多巴治疗会加速 6-羟基多巴胺帕金森病大鼠模型的昼夜节律紊乱
DOI：
10.4103/0366-6999.204920
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发表时间：
2017-05-05
影响因子：
6.1
通讯作者：
Liu CF
中科院分区：
文献类型：
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作者：
Li SY;Wang YL;Liu WW;Lyu DJ;Wang F;Mao CJ;Yang YP;Hu LF;Liu CF
背景：长期左旋多巴（L-DOPA）治疗的帕金森病（PD）患者存在严重的昼夜节律紊乱。然而，很难区分患者的昼夜节律紊乱是由于疾病进展本身，还是受左旋多巴替代治疗的影响。本研究旨在探讨左旋多巴（L-DOPA）对帕金森病（PD）大鼠昼夜节律紊乱的影响。研究方法：采用双侧纹状体注射6-羟基多巴胺（6-OHDA），然后连续21天给予生理盐水或25 mg/kg L-DOPA的方法建立PD大鼠模型。采用转棒试验、足印试验和旷场试验评价运动功能。在6：00、12：00、18：00和24：00采集纹状体、视交叉上核（SCN）、肝脏和血浆。实时定量聚合酶链反应检测时钟基因的表达。酶联免疫吸附法测定皮质醇和褪黑素的分泌水平。采用高效液相色谱法测定神经递质。数据分析采用方差分析。结果：左旋多巴能明显改善6-OHDA所致大鼠足印试验和旷场试验中的运动障碍（P < 0.01，P < 0.001）。左旋多巴治疗后，SCN组12：00和24：00时Bmal 1较6-OHDA组降低（P <0.01）。纹状体内Bmal 1、Ror的表达在18：00时低于6-OHDA组（P < 0.05），L-DOPA使Per 2的表达高峰延迟至24：00。在肝脏中，左旋多巴不影响这些时钟基因的节律性和表达（P > 0.05）。6：00时给予左旋多巴后，皮质醇分泌增加（P > 0.05），褪黑素分泌进一步受到抑制（P < 0.01）。结论：在晚期PD大鼠模型的昼夜节律系统中，昼夜节律功能障碍不仅是由疾病本身的退化造成的，而且长期的L-DOPA治疗可能会进一步加重它。
Background: Parkinson's disease (PD) patients with long-term levodopa (L-DOPA) treatment are suffering from severe circadian dysfunction. However, it is hard to distinguish that the circadian disturbance in patients is due to the disease progression itself, or is affected by L-DOPA replacement therapy. This study was to investigate the role of L-DOPA on the circadian dysfunction in a rat model of PD. Methods: The rat model of PD was constructed by a bilateral striatal injection with 6-hydroxydopamine (6-OHDA), followed by administration of saline or 25 mg/kg L-DOPA for 21 consecutive days. Rotarod test, footprint test, and open-field test were carried out to evaluate the motor function. Striatum, suprachiasmatic nucleus (SCN), liver, and plasma were collected at 6:00, 12:00, 18:00, and 24:00. Quantitative real-time polymerase chain reaction was used to examine the expression of clock genes. Enzyme-linked immunosorbent assay was used to determine the secretion level of cortisol and melatonin. High-performance liquid chromatography was used to measure the neurotransmitters. Analysis of variance was used for data analysis. Results: L-DOPA alleviated the motor deficits induced by 6-OHDA lesions in the footprint and open-field test (P < 0.01, P < 0.001, respectively). After L-DOPA treatment, Bmal1 decreased in the SCN compared with 6-OHDA group at 12:00 (P < 0.01) and 24:00 (P < 0.001). In the striatum, the expression of Bmal1, Ror&agr; was lower than that in the 6-OHDA group at 18:00 (P < 0.05) and L-DOPA seemed to delay the peak of Per2 to 24:00. In liver, L-DOPA did not affect the rhythmicity and expression of these clock genes (P > 0.05). In addition, the cortisol secretion was increased (P > 0.05), but melatonin was further inhibited after L-DOPA treatment at 6:00 (P < 0.01). Conclusions: In the circadian system of advanced PD rat models, circadian dysfunction is not only contributed by the degeneration of the disease itself but also long-term L-DOPA therapy may further aggravate it.