Gastrodia elata Blume alleviates L-DOPA-induced dyskinesia by normalizing FosB and ERK activation in a 6-OHDA-lesioned Parkinson's disease mouse model

Abstract

Background: Gastrodia elata Blume (GEB), commonly used medicinal herb, has been reported as a promising candidate for neurodegenerative diseases such as Parkinson's disease. The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), is the gold-standard drug for Parkinson's disease, but long-term treatment results in the L-dopa-induced dyskinesia (LID). This study was undertaken to examine the beneficial effects of GEB on L-DOPA induced dyskinesia in 6-hydroxydopamine (6-OHDA)-induced experimental Parkinsonism.

Methods: We tested the effects of GEB on LID in 6-hydroxydopamine hydrochloride-hemiparkinsonian mice. To analyze the dyskinetic anomalies, we measured abnormal involuntary movement (AIM). Immunohistological analyses of pERK and FosB expressions in the striatum are performed to explore the mechanism of GEB on LID.

Results: The finding of this study demonstrated that GEB (200, 400 and 800 mg/kg) alleviated L-dopa induced AIMs in a dose-dependent manner. In each integrative AIM subtype analysis, we also found that the GEB (400 and 800 mg/kg) treatment decreased L-DOPA-induced axial, limb, orolingual, and locomotive AIMs compared to the LID group. In addition, GEB normalized the abnormal LID-induced increase of pERK1/2 and FosB, the immediate early genes of LID in the striatum.

Conclusions: In conclusion, our results provide a novel insight into the pharmacological actions of GEB that could have a benefit for PD patients through the reduction of LID.

Figure 1

Schematic representation of experimental design. Numerals within the time course arrow denote the number of days after the start of chronic treatment with L-DOPA, GEB (200, 400, and 800 mg/kg), AMTD (40 mg/kg), or vehicle. Contralateral turning behavior was tested 14 days later, after apomorphine injection. Three weeks after the introduction of 6-OHDA lesions, mice were administered with L-DOPA, GEB, or AMTD daily for 10 days. AIMs scores were assessed on days 2, 5, and 9 after initial treatment.

Figure 2

A representative chromatogram for standardization of the Gastrodia elata Blume (GEB) extract sample. The X-axis shows retention time; the Y-axis shows UV absorbance. Arrow indicates peak of gastrodin.

Figure 3

Effect of the GEB extract on L-DOPA-induced abnormal involuntary movements (AIMs) in a PD mouse model bearing 6-OHDA lesions. (A-C) Total AIMs were scored every 20 min over a 140 min period following L-DOPA injection. The integrated total AIMs scores on days 2 (A), 5 (B), and 9 (C) are shown. *P < 0.05, **P < 0.01, and ***P < 0.001 compared with the LID group. (D-F) The integrated temporal profiles of total AIMs scores on days 2 (D), 5 (E), and 9 (F) of the LID and LID + GEB800 treated group are shown. *P < 0.05 and **P < 0.01 compared with the LID group.

Figure 4

The effect of GEB extract treatment on each subtype of axial, limb, and orolingual abnormal involuntary movement (AIM) induced by L-DOPA in a PD mouse model bearing 6-OHDA lesions. (A) Axial AIM, (B) limb AIM, (C) orolingual AIM, and (D) locomotive AIM scores were measured on days 2, 5, and 9 after the initial L-DOPA injection. AIM scores were assessed every 20 min over 140 min following L-DOPA administration and were then integrated. *P < 0.05 and **P < 0.01 compared with the LID group.

Figure 5

Protein analysis of ERK1/2 phosphorylation and FosB expression in striatal tissue. Protein levels were evaluated by western blotting the striatal extracts from each group of mice. (A, B) Phospho-ERK1/2 (A) and FosB (B) signals were observed in the ipsilateral sides of striata. Representative bar graph showing optical densities from the blotting experiments. *P < 0.05 and **P < 0.01 compared with the 6-OHDA control (Cont) group. #P < 0.05 and ##P < 0.01 compared with the LID group.