Abstract
Objective: Patients with Parkinson's disease (PD) frequently experience disruptions in the 24-h daily profile of both behavioral and biological markers. However, whether L-3,4-dihydroxyphenylalanine (L-dopa) influences these markers associated with circadian rhythm or not is still an open question. This study aims to explore the L-dopa effects on the rhythmic expression of core clock proteins [brain and muscle Arnt-like protein-1 (BMAL1) and circadian locomotor cycle kaput (CLOCK)], in the striatum of the rat model of PD and its underlying molecular mechanisms.Methods: Unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat models were used in this study. L-dopa administrations were adopted to investigate the changes of circadian rhythm in PD. The behavioral tests and the measurements of the blood pressure (BP) and temperature were evaluated. The striatum was collected at intervals of 4 h. Western blot was used to examine the expressions of clock protein and the molecular protein of the D1R-ERK1/2-mTOR pathway. The rhythmic expressions of symptom parameters and circadian proteins were analyzed using the Cosinor model and/or the coefficient of variability (CV) that was used to describe the variability of the 24-h rhythm.Results: The circadian rhythms of BP and temperature were disrupted in 6-OHDA-lesioned PD rats compared with the sham group, while this process was reversed mildly by L-dopa treatment. The expressions of BMAL1 and CLOCK protein were rhythmic fluctuated without significant phase alterations when 6-OHDA or L-dopa was applied. Furthermore, the expressions of striatal BMAL1 protein in the 6-OHDA-lesioned group were significantly lower than those in the sham group at 04:00, 08:00, and 12:00, and the CLOCK protein was decreased at 04:00, 08:00, 12:00, 16:00, and 20:00 (all p < 0.05). The CV of the expressions of both BMAL1 and CLOCK was decreased in the 6-OHDA group; this process was reversed by L-dopa. Moreover, the CV of BMAL1 and CLOCK was elevated in the L-dopa rats. The phosphorylation levels of ERK1/2, S6K1, and 4E-BP1 in 6-OHDA-lesioned striatum were increased by L-dopa or D1 receptor agonist SKF38393 (p < 0.05, respectively), not by the combination of L-dopa and D1 receptor antagonist SCH23390, which was similar to the expressions of BMAL1 and CLOCK.Conclusion: L-dopa recovers the circadian rhythm disturbances in PD rats by regulating the D1R-ERK1/2-mTOR pathway.
Highlights
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders characterized by the progressive death of dopaminergic neuron projection from the substantia nigra to the striatum and the formation of Lewy bodies (Poewe et al, 2017)
We explored the effect of L-dopa treatment on the rhythmic expression of core clock proteins (i.e., BMAL1 and CLOCK) in the striatum of the rat models with PD through the regulation of the D1 receptor (D1R)-extracellular signal-regulated kinases 1/2 (ERK1/2)-mammalian target of rapamycin (mTOR) pathway
The rats of the 6-OHDA-lesioned+L-dopa group were further evaluated with the Abnormal Involuntary Movement (AIM) scores
Summary
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders characterized by the progressive death of dopaminergic neuron projection from the substantia nigra to the striatum and the formation of Lewy bodies (Poewe et al, 2017). The expression of circadian clock molecules is altered in different brain regions (Leng et al, 2019). The circadian rhythm, which is an endogenously generated rhythm that roughly repeats every 24 h, is modulated by external cues (Hood and Amir, 2017) and regulated by clock genes/proteins expressed in all brain tissues (Kondratov et al, 2006). The characteristics of mammalian circadian rhythm are based on the changes in the expressions of certain clock genes and their proteins, forming a transcriptional–translational feedback loop (TTFL) to keep a period of 24 h. The core TTFL consists of two activators (i.e., CLOCK and BMAL1) and two repressors (i.e., cryptochrome and period), as well as other kinases and phosphatases. The alteration of expression patterns of clock molecules has been observed in PD (Wang et al, 2018)
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