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

Background: Parkinson Disease(PD) patients with long-term L-DOPA treatment are 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 were received intraperitoneal administration of saline or 25mg/kg of L-DOPA once daily for another 21 consecutive days.

Rotarod test, footprint test and open field test were carried out to evaluate the motor function. Next, we collected SCN, striatum, cortex, liver and plasma at ZT4(Zeitgber Time), ZT10, ZT16, ZT22. Quantitative PCR was used to analyze the mRNA levels of Clock, Bmal1, Per2, Rora; ELISA detected the levels of melatonin and cortisol; HPLC analyzed the expressions of D1R, D2R in striatum and cortex.

Results: Daily injection of L-DOPA alleviated the motor deficits induced by 6-OHDA lesions. And then, we observed the expression of different clock genes in different tissues.

After L-DOPA treatment ，compared with 6-OHDA group. 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,Rora 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 L-DOPA group. In liver, L-DOPA unaltered did not affect the rhythmicity and levels expression of the four clock genes; in addition, secretion of the cortisol secretion was increased and melatonin was further inhibited after L-DOPA treatment at ZT22.

Furthermore, the expression of D2R was decreased in the striatum in of 6-OHDA lesions lesioned rats but D1R remained unchanged unaltered in cortex.

Conclusions: Our research indicated 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-DPOA treatment.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/long-term-levodopa-therapy-accelerates-the-circadian-rhythm-dysfunction-in-6-ohda-rat-model/