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Aging and disease    2018, Vol. 9 Issue (4) : 590-604     DOI: 10.14336/AD.2017.0831
Orginal Article |
Fucoidan Protects Dopaminergic Neurons by Enhancing the Mitochondrial Function in a Rotenone-induced Rat Model of Parkinson’s Disease
Zhang Li1,3, Hao Junwei1,3, Zheng Yan2,3, Su Ruijun1,3, Liao Yajin4, Gong Xiaoli2,3, Liu Limin2,3,*, Wang Xiaomin1,3,5,*
1Department of Neurobiology,
2Department of Physiology,
3Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing 100069, China.
4The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing 100039, China.
5 Beijing Institute for Brain Disorders, Beijing 100069, China
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Abstract  

The mitochondrion is susceptible to neurodegenerative disorders such as Parkinson’s disease (PD). Mitochondrial dysfunction has been considered to play an important role in the dopaminergic degeneration in PD. However, there are no effective drugs to protect mitochondria from dysfunction during the disease development. In the present study, fucoidan, a sulfated polysaccharide derived from Laminaria japonica, was investigated and characterized for its protective effect on the dopamine system and mitochondrial function of dopaminergic neurons in a rotenone-induced rat model of PD. We found that chronic treatment with fucoidan significantly reversed the loss of nigral dopaminergic neurons and striatal dopaminergic fibers and the reduction of striatal dopamine levels in PD rats. Fucoidan also alleviated rotenone-induced behavioral deficits. Moreover, the mitochondrial respiratory function as detected by the mitochondrial oxygen consumption and the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and nuclear transcription factor 2 (NRF2) were reduced in the substantia nigra of PD rats, which were markedly reversed by fucoidan. Oxidative products induced by rotenone were significantly reduced by fucoidan. Taken together, these results demonstrate that fucoidan possesses the ability to protect the dopamine system in PD rats. The neuroprotective effect of fucoidan may be mediated via reserving mitochondrial function involving the PGC-1α/NRF2 pathway. This study provides new evidence that fucoidan can be explored in PD therapy.

Keywords fucoidan      Parkinson’s disease      mitochondria      rotenone      PGC-1α      NRF2     
Corresponding Authors: Liu Limin,Wang Xiaomin   
About author:

These authors contributed equally to this work.

Issue Date: 01 August 2018
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Zhang Li
Hao Junwei
Zheng Yan
Su Ruijun
Liao Yajin
Gong Xiaoli
Liu Limin
Wang Xiaomin
Cite this article:   
Zhang Li,Hao Junwei,Zheng Yan, et al. Fucoidan Protects Dopaminergic Neurons by Enhancing the Mitochondrial Function in a Rotenone-induced Rat Model of Parkinson’s Disease[J]. Aging and disease, 2018, 9(4): 590-604.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.0831     OR     http://www.aginganddisease.org/EN/Y2018/V9/I4/590
Figure 1  A schematic diagram of experiment arrangements

Rats were pretreated with fucoidan for 10 days (once daily). Animals were then co-treated with fucoidan (once daily) and rotenone (5 times a week) for 4 weeks. Behavioral tests were conducted 1 day before fucoidan pretreatment, and 1 day before and 2 and 4 weeks after rotenone co-treatment with fucoidan or rasagiline. Other neurochemical assays, including immunohistochemistry, western blot, electron microscopy, HPLC-ECD analysis, mitochondrial respirometry and oxidative stress measurement were performed 1 day after a 4-week co-treatment period.

Figure 2  Effects of fucoidan on rotenone-induced catalepsy in rats

(A and B) Effects of fucoidan on rotenone-induced catalepsy as detected by a bar test (A) and a grid test (B). Data collected at the fourth week were quantified in the right panels. Note that fucoidan (Fu) dose-dependently reduced cataleptic responses to rotenone (Rot). Comparison between the 140 mg/kg/d fucoidan group and the 0.3 mg/kg rasagiline (Rasa) group yields P < 0.05 for the bar test. Data are shown as means ± SEM (n = 9-12 per group). *P < 0.05 and **P < 0.01 versus vehicle group at the same time point. #P < 0.05, ##P < 0.01, and ###P < 0.001 versus model group (rotenone only) at the same time point. &P < 0.05 versus rasagiline group at the fourth week.

Figure 3  Effects of fucoidan on rotenone-induced reduction of locomotor activity in rats

(A-D) Effects of fucoidan on the rotenone-induced reduction in floor plane (FP) movements (A), moving time (B), moving distance (C), and mean velocity (D). Note that fucoidan reversed the reduction of all four types of locomotor activities. Data are shown as means ± SEM (n = 9-12 per group). **P < 0.01 and ***P < 0.001 versus vehicle group at the same time point. #P < 0.05, ##P < 0.01, and ###P < 0.001 versus model group (rotenone only) at the same time point.

Figure 4  Effects of fucoidan on the rotenone-induced loss of TH-positive neurons and fibers in the nigrostriatal system

(A) Representative immunohistochemical images depicting changes in TH immunoreactive neurons and fibers in the SNpc and striatum, respectively. (B and C) Quantifications of the number of nigral TH-positive neurons (B) and the mean density of striatal TH-positive fibers (C). Note that rotenone caused a loss of TH-positive neurons in the SNpc and TH-positive fibers in the striatum, and fucoidan was able to reverse these losses. Data are shown as means ± SEM (n = 3-5 per group). **P < 0.01 and ***P < 0.001 versus vehicle group. #P < 0.05, ##P < 0.01, and ###P < 0.001 versus model group (rotenone only).

Figure 5  Effects of fucoidan on contents of striatal DA and its metabolites

(A-C) Effects of fucoidan on striatal DA, DOPAC, and HVA levels. (D) Effects of fucoidan on the ratio of DOPAC + HVA to DA. The contents of DA, DOPAC, and HVA in the striatum were measured by HPLC. Note that fucoidan reversed a decrease in DA and DOPAC levels and an increase in the ratio of DOPAC + HVA to DA induced by rotenone. The difference of DA turnover rate between the 140 mg/kg fucoidan group and 0.3 mg/kg rasagiline group was significant. Data are shown as means ± SEM (n = 3-5 per group). *P < 0.05 versus vehicle group. #P < 0.05, ##P < 0.01, and ###P < 0.001 versus model group (rotenone only). && P < 0.01 versus rasagiline group.

Figure 6  Effects of fucoidan on rotenone-induced alterations of mitochondrial morphology and respiration function in the rat ventral midbrain

(A) Electron microscopic images illustrating morphological changes in the mitochondria in the rat SNpc. (B) Representative recordings of mitochondrial respiration. (C-F) Quantification of basal respiration (C), ATP production (D), maximal respiration (E), and residual oxygen consumption (F) in the ventral midbrain of rats. Data are shown as means ± SEM (n = 3-4 per group). **P < 0.01 and ***P < 0.001 versus vehicle group. #P < 0.05, ##P < 0.01, and ###P < 0.001 versus model group (rotenone only). &P < 0.05 and &&P < 0.01 versus rasagiline group. Scale bar = 1μm.

Figure 7  Effects of fucoidan on rotenone-induced reduction of mitochondrial complex activity in the rat ventral midbrain

(A) Profiles of OCRs in the digitonin-permeabilized ventral midbrain tissue subjected to rotenone (red line) or fucoidan with rotenone (green line). (B-D) Quantification of basal respiration (B), complex I activity (C), and complex II activity (D) in the ventral midbrain of rats. Data are shown as means ± SEM (n = 3-4 per group). *P < 0.05 and **P < 0.01 versus vehicle group. #P < 0.05 and ##P < 0.01 versus model group (rotenone only). Abbreviation: P + M = pyruvate + malate, G = glutamate, S = succinate.

Figure 8  Effects of fucoidan on oxidative stress responses to rotenone in the rat ventral midbrain

(A-C) Effects of fucoidan on the rotenone-induced increases in MDA (A), 3-NT (B), and 8-OHdG (C) levels in the ventral midbrain of rats. Data are shown as means ± SEM (n = 4-5 per group). **P < 0.01 and ***P < 0.001 versus vehicle group. #P < 0.05, ##P < 0.01 and ###P < 0.001 versus model group (rotenone only). &&& P < 0.001 versus rasagiline group.

Figure 9  Effects of fucoidan on PGC-1α and NRF2 expression in the rat ventral midbrain

(A) Representative immunoblots illustrating effects of fucoidan on PGC-1α and NRF2 expression in the ventral midbrain of rotenone-treated rats. (B and C) Quantification of PGC-1α (B) and NRF2 (C) expression in the ventral midbrain of rotenone-treated rats. Note that rotenone decreased PGC-1α and NRF2 expression in the ventral midbrain, which was reversed by fucoidan. Data are shown as means ± SEM (n = 3-4 per group). ***P < 0.001 versus vehicle group. ##P < 0.01 versus model group (rotenone only).

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