Long-term Levodopa Treatment Accelerates the Circadian Rhythm Dysfunction in a 6-hydroxydopamine Rat Model of Parkinson's Disease.
- Author:
Si-Yue LI
1
;
Ya-Li WANG
2
;
Wen-Wen LIU
2
;
Dong-Jun LYU
3
;
Fen WANG
2
;
Cheng-Jie MAO
1
;
Ya-Ping YANG
1
;
Li-Fang HU
2
;
Chun-Feng LIU
3
;
Author Information
- Publication Type:Journal Article
- MeSH: Animals; Blotting, Western; Body Weight; drug effects; Circadian Rhythm; drug effects; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Levodopa; therapeutic use; Male; Oxidopamine; toxicity; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction
- From: Chinese Medical Journal 2017;130(9):1085-1092
- CountryChina
- Language:English
-
Abstract:
BACKGROUNDParkinson'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.
METHODSThe 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.
RESULTSL-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).
CONCLUSIONSIn 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.