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

Abstract

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, Bmal1 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 of Bmal1, 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.

Circadian Rhythm Abnormalities in Parkinson’s Disease from Humans to Flies and Back

“…6-OHDA treatments in rodents have been found to deregulate circadian behavioral and physiological outputs, as well as the expression of clock genes in different brain regions [38,39,40,41]. Furthermore, a recent study reported that levodopa administration further modified hormone secretion levels and the expression profiles of some clock genes in specific brain regions in 6-OHDA treated-rats, corroborating the notion that the pro-drug may contribute to circadian alterations seen in PD patients [42]. Contrasting data relating to the effects of MPTP treatment on mouse circadian phenotypes were obtained [33,34,35] (Table 1).…”

Differential effects of vagus nerve stimulation paradigms guide clinical development for Parkinson’s disease

“…In this lesion model we also saw higher intrasomal asynuclein, demonstrating a pathological expression pattern similar to PD [37,38] that may contribute to greater neuroinflammation [39], whereas non-pathological a-synuclein is localized to neuronal processes and is thought to assist in neurotransmitter release [40]. While current pharmacological therapies for PD help manage symptoms [41,42], these therapies cannot delay symptom progression [43,44]. Because of these issues, a large portion of PD research has been devoted to development of disease-modifying therapies.…”

Moving to the Rhythm with Clock (Circadian) Genes, Autophagy, mTOR, and SIRT1 in Degenerative Disease and Cancer

“…In patients with Alzheimer's disease, rhythmic methylation of BMAL1 has been found to be changed in the brains of patients with Alzheimer's disease, suggesting that alterations in the DNA methylation of clock genes may contribute to cognitive loss and behavior changes in individuals with Alzheimer's disease (9). Animal models of Parkinson's disease with 6-hydroxydopamine (6-OHDA) also show decreased BMAL1 and RORα that persisted with levodopa treatment, indication that long-term levodopa treatment may impair circadian rhythm function (10). …”