Objective: We aimed to study the effect of levodopa on circadian rhythms in 6-OHDA lesioned rats, and to clarify whether the disturbance of the circadian system in Parkinson’s disease (PD) patients was associated with the progression of the disease progression itself, or the long-term levodopa replacement therapy.

Background: PD patients with long-term levodopa therapy were suffering from circadian rhythm abnormalities, including impaired sleep-wake cycles, disrupted fluctuations of temperature, blood pressure, heart rate, hormonal levels and many other biological processes.

Methods: PD model was constructed by a bilateral stereotaxic injection of 6-OHDA into the striatum. 21days later, the rats received intraperitoneal administration of saline or 25mg/kg levodopa once daily for another 21 consecutive days. Behavioral tests were carried out to evaluate the motor functions. Next, we collected SCN, striatum, cortex, liver, plasma at ZT4, ZT10, ZT16, ZT22. Quantitative PCR was used to analyze the mRNA levels of Clock, Bmal1, Per2, Rorα; ELISA detected the levels of melatonin and cortisol; HPLC analyzed the amount of DA, DOPAC, 5-HIAA in striatum and cortex; Western blotting examined the expression of D1R, D2R in striatum and cortex.

Results: Daily injection of levodopa alleviated the motor deficits induced by 6-OHDA lesions. After levodopa treatment, the rhythm of Clock was abolished and phase of Per2 was reversed from a nocturnal to a diurnal pattern in SCN compared with 6-OHDA group. In striatum, the expression of Bmal1, Rorα was lower than that in the 6-OHDA group at ZT10, but the amplitude of Clock was elevated in cortex at four time points in levodopa group. In liver, levodopa did not affect the rhythmicity and expression of the four clock genes; In addition, the cortisol secretion was increased and melatonin was further inhibited after levodopa treatment at ZT22. Furthermore, the expression of D2R was decreased in the striatum in of 6-OHDA lesions lesioned rats but D1R remained unlatered in cortex.

Conclusions: Our research suggested that severe performance in circadian system of advanced PD patients owing to not only the progressive degeneration of the disease, but also the continuous L-DOPA treatment.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/chronic-levodopa-treatment-accelerates-the-disorders-of-circadian-rhythm-in-6-ohda-induced-parkinsons-disease-model/