Long-term Levodopa Treatment Accelerates the Circadian Rhythm Dysfunction in a 6-hydroxydopamine Rat Model of Parkinson＇s Disease

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, Bmall 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 ofBmall, Rorα 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.