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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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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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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).

[1] Bose A, Beal MF (2016). Mitochondrial dysfunction in Parkinson’s disease. J Neurochem, 139 Suppl 1: 216-231
[2] Camara AK, Lesnefsky EJ, Stowe DF (2010). Potential therapeutic benefits of strategies directed to mitochondria. Antioxid Redox Signal, 13: 279-347
[3] Abeliovich A (2010). Parkinson’s disease: Mitochondrial damage control. Nature, 463: 744-745
[4] Pacelli C, Giguere N, Bourque MJ, Levesque M, Slack RS, Trudeau LE (2015). Elevated Mitochondrial Bioenergetics and Axonal Arborization Size Are Key Contributors to the Vulnerability of Dopamine Neurons. Curr Biol, 25: 2349-2360
[5] Requejo-Aguilar R, Bolanos JP (2016). Mitochondrial control of cell bioenergetics in Parkinson’s disease. Free Radic Biol Med, 100: 123-137
[6] Langston JW, Ballard P, Tetrud JW, Irwin I (1983). Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science, 219: 979-980
[7] Doudet D, Gross C, Lebrun-Grandie P, Bioulac B (1985). MPTP primate model of Parkinson’s disease: a mechanographic and electromyographic study. Brain Res, 335: 194-199
[8] Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000). Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci, 3: 1301-1306
[9] Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD (1989). Mitochondrial complex I deficiency in Parkinson’s disease. Lancet, 1: 1269
[10] Ferreira M, Massano J (2017). An updated review of Parkinson’s disease genetics and clinicopathological correlations. Acta Neurol Scand, 135: 273-284
[11] Kalinderi K, Bostantjopoulou S, Fidani L (2016). The genetic background of Parkinson’s disease: current progress and future prospects. Acta Neurol Scand, 134: 314-326
[12] Narendra D, Walker JE, Youle R (2012). Mitochondrial quality control mediated by PINK1 and Parkin: links to parkinsonism. Cold Spring Harb Perspect Biol, 4: a011338
[13] Schapira AH, Olanow CW, Greenamyre JT, Bezard E (2014). Slowing of neurodegeneration in Parkinson’s disease and Huntington’s disease: future therapeutic perspectives. Lancet, 384: 545-555
[14] Croci DO, Cumashi A, Ushakova NA, Preobrazhenskaya ME, Piccoli A, Totani L, et al. (2011). Fucans, but Not Fucomannoglucuronans, Determine the Biological Activities of Sulfated Polysaccharides from Laminaria saccharina Brown Seaweed. Plos One, 6: e17283
[15] Cui YQ, Jia YJ, Zhang T, Zhang QB, Wang XM (2012). Fucoidan protects against lipopolysaccharide-induced rat neuronal damage and inhibits the production of proinflammatory mediators in primary microglia. CNS Neurosci Ther, 18: 827-833
[16] Luo D, Zhang Q, Wang H, Cui Y, Sun Z, Yang J, et al. (2009). Fucoidan protects against dopaminergic neuron death in vivo and in vitro. Eur J Pharmacol, 617: 33-40
[17] Zhang FL, He Y, Zheng Y, Zhang WJ, Wang Q, Jia YJ, et al. (2014). Therapeutic Effects of Fucoidan in 6-Hydroxydopamine-Lesioned Rat Model of Parkinson’s disease: Role of NADPH oxidase-1. CNS Neurosci Ther, 20: 1036-1044
[18] Zhang Q, Li Z, Xu Z, Niu X, Zhang H (2003). Effects of fucoidan on chronic renal failure in rats. Planta Med, 69: 537-541
[19] El-Horany HE, El-Latif RN, ElBatsh MM, Emam MN (2016). Ameliorative Effect of Quercetin on Neurochemical and Behavioral Deficits in Rotenone Rat Model of Parkinson’s Disease: Modulating Autophagy (Quercetin on Experimental Parkinson’s Disease). J Biochem Mol Toxicol, 30: 360-369
[20] Hawong HY, Patterson JR, Winner BM, Goudreau JL, Lookingland KJ (2015). Comparison of the structure, function and autophagic maintenance of mitochondria in nigrostriatal and tuberoinfundibular dopamine neurons. Brain Res, 1622: 240-251
[21] Makrecka-Kuka M, Krumschnabel G, Gnaiger E (2015). High-Resolution Respirometry for Simultaneous Measurement of Oxygen and Hydrogen Peroxide Fluxes in Permeabilized Cells, Tissue Homogenate and Isolated Mitochondria. Biomolecules, 5: 1319-1338
[22] Cacabelos R (2017). Parkinson’s Disease: From Pathogenesis to Pharmacogenomics. Int J Mol Sci, 18: E551
[23] Gnaiger E (2003). Oxygen conformance of cellular respiration. A perspective of mitochondrial physiology. Adv Exp Med Biol, 543: 39-55
[24] Gnaiger E (2009). Capacity of oxidative phosphorylation in human skeletal muscle: new perspectives of mitochondrial physiology. Int J Biochem Cell Biol, 41: 1837-1845
[25] Baradaran R, Berrisford JM, Minhas GS, Sazanov LA (2013). Crystal structure of the entire respiratory complex I. Nature, 494: 443-448
[26] Schapira AH (2008). Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol, 7: 97-109
[27] Teh JT, Zhu WL, Ilkayeva OR, Li Y, Gooding J, Casey PJ, et al. (2015). Isoprenylcysteine carboxylmethyltransferase regulates mitochondrial respiration and cancer cell metabolism. Oncogene, 34: 3296-3304
[28] Wu M, Gu J, Guo R, Huang Y, Yang M (2016). Structure of Mammalian Respiratory Supercomplex I1III2IV1. Cell, 167: 1598-1609 e1510
[29] Alam ZI, Jenner A, Daniel SE, Lees AJ, Cairns N, Marsden CD, et al. (1997). Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J Neurochem, 69: 1196-1203
[30] Dexter DT, Holley AE, Flitter WD, Slater TF, Wells FR, Daniel SE, et al. (1994). Increased levels of lipid hydroperoxides in the parkinsonian substantia nigra: an HPLC and ESR study. Mov Disord, 9: 92-97
[31] Floor E, Wetzel MG (1998). Increased protein oxidation in human substantia nigra pars compacta in comparison with basal ganglia and prefrontal cortex measured with an improved dinitrophenylhydrazine assay. J Neurochem, 70: 268-275
[32] Meenakshi S, Umayaparvathi S, Saravanan R, Manivasagam T, Balasubramanian T (2016). Neuroprotective effect of fucoidan from Turbinaria decurrens in MPTP intoxicated Parkinsonic mice. Int J Biol Macromol, 86: 425-433
[33] Austin S, St-Pierre J (2012). PGC1alpha and mitochondrial metabolism--emerging concepts and relevance in ageing and neurodegenerative disorders. J Cell Sci, 125: 4963-4971
[34] Handschin C, Spiegelman BM (2006). Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev, 27: 728-735
[35] Uguccioni G, Hood DA (2011). The importance of PGC-1alpha in contractile activity-induced mitochondrial adaptations. Am J Physiol Endocrinol Metab, 300: E361-371
[36] Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML, et al. (2010). PGC-1alpha, a potential therapeutic target for early intervention in Parkinson’s disease. Sci Transl Med, 2: 52ra73
[37] Jiang H, Kang SU, Zhang S, Karuppagounder S, Xu J, Lee YK, et al. (2016). Adult Conditional Knockout of PGC-1alpha Leads to Loss of Dopamine Neurons. eNeuro, 3: e0183
[38] Mudo G, Makela J, Di Liberto V, Tselykh TV, Olivieri M, Piepponen P, et al. (2012). Transgenic expression and activation of PGC-1alpha protect dopaminergic neurons in the MPTP mouse model of Parkinson’s disease. Cell Mol Life Sci, 69: 1153-1165
[39] Dinkova-Kostova AT, Abramov AY (2015). The emerging role of Nrf2 in mitochondrial function. Free Radic Biol Med, 88: 179-188
[40] Handschin C, Kobayashi YM, Chin S, Seale P, Campbell KP, Spiegelman BM (2007). PGC-1alpha regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy. Genes Dev, 21: 770-783
[41] Ventura-Clapier R, Garnier A, Veksler V (2008). Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. Cardiovasc Res, 79: 208-217
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