L-3,4-Dihydroxyphenylalanine Recovers Circadian Rhythm Disturbances in the Rat Models of Parkinson's Disease by Regulating the D1R-ERK1/2-mTOR Pathway

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.

The Effects of a Single Session of a Rhythmic Movement Program on Selected Biopsychological Parameters in PD Patients: A Methodological Approach

“…In general, patients with PD frequently experience disruptions in the 24 h daily profile of both behavioral and biological markers [ 29 ]. This lack of rhythmicity or disruption of inner-rhythm can negatively affect elements of health [ 30 , 31 ] and physical performance [ 32 ].…”

Importance of Bmal1 in Alzheimer's disease and associated aging‐related diseases: Mechanisms and interventions

“…Moreover, a lack of time-dependent variation in Bmal1 expression was observed (Breen et al, 2014). some timepoints (Yang et al, 2021). Further, in another rat model of PD induced by lipopolysaccharide combined with rotenone, the mRNA and protein expressions of Bmal1 also decreased (Li et al, 2019).…”

“…After melatonin treatment, the levels of Bmal1 were increased in PD patients (Delgado‐Lara et al, 2020 ), reinforcing a close link between Bmal1 and PD. In a rat model of PD, the expression of Bmal1 in the striatum was significantly lower than that in the sham group at some timepoints (Yang et al, 2021 ). Further, in another rat model of PD induced by lipopolysaccharide combined with rotenone, the mRNA and protein expressions of Bmal1 also decreased (Li et al, 2019 ).…”

Circadian disruption and sleep disorders in neurodegeneration

“… [ 280 ] Rat 6-OHDA Decreased amplitude of heart rate and heart rhythm [ 281 ] Rat 6-OHDA The circadian rhythms of blood pressure and temperature are disrupted. [ 282 ] Monkey MPTP Loss of circadian locomotor activity in the absence of light/dark cues [ 283 ] Drosophila pink1 and parkin mutants The fragmentation of sleep, the anticipation of dawn [ 12 ] Drosophila pink1 and parkin mutants Weakened circadian rhythms in locomotor activity [ 284 ] Drosophila TP-αS TP-αS expression in neurons interferes with the circadian rhythm of aging flies [ 285 ] Zebrafish MPP + Decreased activity, sleep disruptions, and impaired habituation to repetitive startles [ 286 ] ASO: alpha-synuclein overexpressing; TP-αS: three alanine replacements by prolines (at positions A30P, A56P and A76P) …”