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CNS & Neurological Disorders - Drug Targets

Author(s): Xin Jiang, Pei-Chen Tang, Qin Chen, Xin Zhang, Yi-Yun Fan, Bo-Cheng Yu, Xin-Xia Gu, Ying Sun, Xiao-Qun Ge* and Xiao-Ling Zhang*

DOI: 10.2174/1871527318666190905152138

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Cordycepin Exerts Neuroprotective Effects via an Anti-Apoptotic Mechanism based on the Mitochondrial Pathway in a Rotenone-Induced Parkinsonism Rat Model

Page: [609 - 620] Pages: 12

  • * (Excluding Mailing and Handling)

Abstract

Background: Cordycepin (Cor), one of the major bioactive components of the traditional Chinese medicine Cordyceps militaris, has been used in clinical practice for several years. However, its neuroprotective effect remains unknown.

Aims: The purpose of the study was to evaluate the neuroprotective effects of Cor using a rotenoneinduced Parkinson’s Disease (PD) rat model and to delineate the possible associated molecular mechanisms.

Methods: In vivo, behavioural tests were performed based on the 10-point scale and grid tests. Levels of dopamine and its metabolites in the striatum and the numbers of TH-positive neurons in the Substantia Nigra pars compacta (SNpc) were investigated by high-performance liquid chromatography with electrochemical detection and immunohistochemical staining, respectively. In vitro, cell apoptosis rates and Mitochondrial Membrane Potential (MMP) were analysed by flow cytometry and the mRNA and protein levels of Bax, Bcl-2, Bcl-xL, Cytochrome c (Cyt-c), and caspase-3 were determined by quantitative real-time PCR and western blotting.

Results: Showed that Cor significantly improved dyskinesia, increased the numbers of TH-positive neurons in the SNpc, and maintained levels of dopamine and its metabolites in the striatum in rotenone- induced PD rats. We also found that apoptosis was suppressed and the loss of MMP was reversed with Cor treatment. Furthermore, Cor markedly down-regulated the expression of Bax, upregulated Bcl-2 and Bcl-xL, inhibited the activation of caspase-3, and decreased the release of Cyt-c from the mitochondria to the cytoplasm, as compared to those in the rotenone-treated group.

Conclusion: Therefore, Cor protected dopamine neurons against rotenone-induced apoptosis by improving mitochondrial dysfunction in a PD model, demonstrating its therapeutic potential for this disease.

Keywords: Parkinson's disease, cordycepin, rotenone, apoptosis, mitochondria, Cordyceps militaris.

Graphical Abstract

[1]
Darvas M, Henschen CW, Palmiter RD. Contributions of signaling by dopamine neurons in dorsal striatum to cognitive behaviors corresponding to those observed in Parkinson’s disease. Neurobiol Dis 2014; 65: 112-23.
[http://dx.doi.org/10.1016/j.nbd.2014.01.017] [PMID: 24491966]
[2]
Olanow CWM, Stern MB, Sethi K. The scientific and clinical basis for the treatment of Parkinson disease. Neurology 2009; 72(21): S1-S136.
[http://dx.doi.org/10.1212/WNL.0b013e3181a1d44c] [PMID: 19470958]
[3]
Verhagen ML. Recognition and treatment of response fluctuations in Parkinson’s disease: Review article. Amino Acids 2002; 23(1-3): 141-5.
[http://dx.doi.org/10.1007/s00726-001-0119-1] [PMID: 12373528]
[4]
Samarghandian S, Farkhondeh T, Samini F. A Review on possible therapeutic effect of Nigella sativa and thymoquinone in neurodegenerative diseases. CNS Neurol Disord Drug Targets 2018; 17(6): 412-20.
[http://dx.doi.org/10.2174/1871527317666180702101455] [PMID: 29962349]
[5]
Huang Y, Ma S, Wang Y, et al. The role of traditional Chinese herbal medicines and bioactive ingredients on ion channels: A brief review and prospect. CNS Neurol Disord Drug Targets 2018; 17: 1-9.
[6]
Kingsbury AE, Mardsen CD, Foster OJF. DNA fragmentation in human substantia nigra, apoptosis or perimortem effect? Mov Disord 1998; 13(6): 877-84.
[http://dx.doi.org/10.1002/mds.870130604] [PMID: 9827610]
[7]
Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem 1990; 54(3): 823-7.
[http://dx.doi.org/10.1111/j.1471-4159.1990.tb02325.x] [PMID: 2154550]
[8]
Zhang S, Ye J, Dong G. Neuroprotective effect of baicalein on hydrogen peroxide-mediated oxidative stress and mitochondrial dysfunction in PC12 cells. J Mol Neurosci 2010; 40(3): 311-20.
[http://dx.doi.org/10.1007/s12031-009-9285-5] [PMID: 19731100]
[9]
Cikankova T, Sigitova E, Zverova M, Fisar Z, Raboch J, Hroudova J. Mitochondrial dysfunctions in bipolar disorder: Effect of the disease and pharmacotherapy. CNS Neurol Disord Drug Targets 2017; 16(2): 176-86.
[http://dx.doi.org/10.2174/1871527315666161213110518] [PMID: 27978794]
[10]
Abdelkader NF, Safar MM, Salem HA. Ursodeoxycholic acid ameliorates apoptotic cascade in the rotenone model of Parkinson’s disease: Modulation of mitochondrial perturbations. Mol Neurobiol 2016; 53(2): 810-7.
[http://dx.doi.org/10.1007/s12035-014-9043-8] [PMID: 25502462]
[11]
Nakamura K, Shinozuka K, Yoshikawa N. Anticancer and antimetastatic effects of cordycepin, an active component of Cordyceps sinensis. J Pharmacol Sci 2015; 127(1): 53-6.
[http://dx.doi.org/10.1016/j.jphs.2014.09.001] [PMID: 25704018]
[12]
Tuli HS, Sharma AK, Sandhu SS, Kashyap D. Cordycepin: A bioactive metabolite with therapeutic potential. Life Sci 2013; 93(23): 863-9.
[http://dx.doi.org/10.1016/j.lfs.2013.09.030] [PMID: 24121015]
[13]
Ramesh T, Yoo SK, Kim SW, et al. Cordycepin (3′-deoxyadenosine) attenuates age-related oxidative stress and ameliorates antioxidant capacity in rats. Exp Gerontol 2012; 47(12): 979-87.
[http://dx.doi.org/10.1016/j.exger.2012.09.003] [PMID: 23000874]
[14]
Cheng Z, He W, Zhou X, et al. Cordycepin protects against cerebral ischemia/reperfusion injury in vivo and in vitro. Eur J Pharmacol 2011; 664(1-3): 20-8.
[http://dx.doi.org/10.1016/j.ejphar.2011.04.052] [PMID: 21554870]
[15]
Hwang IK, Lim SS, Yoo KY, et al. A phytochemically characterized extract of Cordyceps militaris and cordycepin protect hippocampal neurons from ischemic injury in gerbils. Planta Med 2008; 74(2): 114-9.
[http://dx.doi.org/10.1055/s-2008-1034277] [PMID: 18214814]
[16]
Cai ZL, Wang CY, Jiang ZJ, et al. Effects of cordycepin on Y-maze learning task in mice. Eur J Pharmacol 2013; 714(1-3): 249-53.
[http://dx.doi.org/10.1016/j.ejphar.2013.05.049] [PMID: 23819912]
[17]
Jin ML, Park SY, Kim YH, Oh JI, Lee SJ, Park G. The neuroprotective effects of cordycepin inhibit glutamate-induced oxidative and ER stress-associated apoptosis in hippocampal HT22 cells. Neurotoxicology 2014; 41: 102-11.
[http://dx.doi.org/10.1016/j.neuro.2014.01.005] [PMID: 24486958]
[18]
Olatunji OJ, Feng Y, Olatunji OO, Tang J, Ouyang Z, Su Z. Cordycepin protects PC12 cells against 6-hydroxydopamine induced neurotoxicity via its antioxidant properties. Biomed Pharmacother 2016; 81: 7-14.
[http://dx.doi.org/10.1016/j.biopha.2016.03.009] [PMID: 27261571]
[19]
Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 2000; 3(12): 1301-6.
[http://dx.doi.org/10.1038/81834] [PMID: 11100151]
[20]
Zhang XL, Yuan YH, Shao QH, et al. DJ-1 regulating PI3K-Nrf2 signaling plays a significant role in bibenzyl compound 20C-mediated neuroprotection against rotenone-induced oxidative insult. Toxicol Lett 2017; 271: 74-83.
[21]
Cannon JR, Tapias V, Na HM, Honick AS, Drolet RE, Greenamyre JT. A highly reproducible rotenone model of Parkinson’s disease. Neurobiol Dis 2009; 34(2): 279-90.
[http://dx.doi.org/10.1016/j.nbd.2009.01.016] [PMID: 19385059]
[22]
Tong Q, Wu L, Jiang T, Ou Z, Zhang Y, Zhu D. Inhibition of endoplasmic reticulum stress-activated IRE1α-TRAF2-caspase-12 apoptotic pathway is involved in the neuroprotective effects of telmisartan in the rotenone rat model of Parkinson’s disease. Eur J Pharmacol 2016; 776: 106-15.
[http://dx.doi.org/10.1016/j.ejphar.2016.02.042] [PMID: 26879867]
[23]
Ojha S, Javed H, Azimullah S, Abul Khair SB, Haque ME. Glycyrrhizic acid attenuates neuroinflammation and oxidative stress in rotenone model of Parkinson’s disease. Neurotox Res 2016; 29(2): 275-87.
[http://dx.doi.org/10.1007/s12640-015-9579-z] [PMID: 26607911]
[24]
Serviddio G, Romano AD, Cassano T, Bellanti F, Altomare E, Vendemiale G. Principles and therapeutic relevance for targeting mitochondria in aging and neurodegenerative diseases. Curr Pharm Des 2011; 17(20): 2036-55.
[http://dx.doi.org/10.2174/138161211796904740] [PMID: 21718251]
[25]
Sharma N, Jamwal S, Kumar P. Beneficial effect of antidepressants against rotenone induced Parkinsonism like symptoms in rats. Pathophysiology 2016; 23(2): 123-34.
[http://dx.doi.org/10.1016/j.pathophys.2016.03.002] [PMID: 26996500]
[26]
von Wrangel C, Schwabe K, John N, Krauss JK, Alam M. The rotenone-induced rat model of Parkinson’s disease is behavioral and electrophysiological findings. Behav Brain Res 2015; 279: 52-61.
[http://dx.doi.org/10.1016/j.bbr.2014.11.002] [PMID: 25446762]
[27]
Pan P, Qiao L, Wen XN. Safranal prevents rotenone-induced oxidative stress and apoptosis in an in vitro model of Parkinson’s disease through regulating Keap1/Nrf2 signaling pathway. Cell Mol Biol 2016; 62(14): 11-7.
[28]
Nataraj J, Manivasagam T, Justin Thenmozhi A, Essa MM. Neuroprotective effect of asiatic acid on rotenone-induced mitochondrial dysfunction and oxidative stress-mediated apoptosis in differentiated SH-SYS5Y cells. Nutr Neurosci 2017; 20(6): 351-9.
[http://dx.doi.org/10.1080/1028415X.2015.1135559] [PMID: 26856988]
[29]
Dhanalakshmi C, Janakiraman U, Manivasagam T, et al. Vanillin attenuated behavioural impairments, neurochemical deficts, oxidative stress and apoptosis against rotenone induced rat model of Parkinson’s Disease. Neurochem Res 2016; 41(8): 1899-910.
[http://dx.doi.org/10.1007/s11064-016-1901-5] [PMID: 27038927]
[30]
Fatima A, Jyoti S, Siddique YH. Models of Parkinson’s disease with special emphasis on Drosophila melanogaster. CNS Neurol Disord Drug Targets 2018; 17(10): 757-66.
[http://dx.doi.org/10.2174/1871527317666180820164250] [PMID: 30129420]
[31]
Li H, Park G, Bae N, Kim J, Oh MS, Yang HO. Anti-apoptotic effect of modified Chunsimyeolda-tang, a traditional Korean herbal formula, on MPTP-induced neuronal cell death in a Parkinson’s disease mouse model. J Ethnopharmacol 2015; 176: 336-44.
[http://dx.doi.org/10.1016/j.jep.2015.11.013] [PMID: 26593210]
[32]
Daubner SC, Le T, Wang S. Tyrosine hydroxylase and regulation of dopamine synthesis. Arch Biochem Biophys 2011; 508(1): 1-12.
[http://dx.doi.org/10.1016/j.abb.2010.12.017] [PMID: 21176768]
[33]
Fukuda T, Takahashi J, Tanaka J. Tyrosine hydroxylase-immunoreactive neurons are decreased in number in the cerebral cortex of Parkinson’s disease. Neuropathology 1999; 19(1): 10-3.
[34]
Nicholson SL, Brotchie JM. 5-hydroxytryptamine (5-HT, serotonin) and Parkinson’s disease - opportunities for novel therapeutics to reduce the problems of levodopa therapy. Eur J Neurol 2002; 9(S3): 1-6.
[http://dx.doi.org/10.1046/j.1468-1331.9.s3.1.x] [PMID: 12464115]
[35]
Huang JY, Yuan YH, Yan JQ, et al. 20C, a bibenzyl compound isolated from Gastrodia elata, protects PC12 cells against rotenone-induced apoptosis via activation of the Nrf2/ARE/HO-1 signaling pathway. Acta Pharmacol Sin 2016; 37(6): 731-40.
[http://dx.doi.org/10.1038/aps.2015.154] [PMID: 27180985]
[36]
Khalil WKB, Assaf N, ElShebiney SA, Salem NA. Neuroprotective effects of bee venom acupuncture therapy against rotenone-induced oxidative stress and apoptosis. Neurochem Int 2015; 80: 79-86.
[http://dx.doi.org/10.1016/j.neuint.2014.11.008] [PMID: 25481089]
[37]
Yuan J, Wang A, He Y, et al. Cordycepin attenuates traumatic brain injury-induced impairments of blood-brain barrier integrity in rats. Brain Res Bull 2016; 127: 171-6.
[http://dx.doi.org/10.1016/j.brainresbull.2016.09.010] [PMID: 27646481]
[38]
Leu SF, Poon SL, Pao HY, Huang BM. The in vivo and in vitro stimulatory effects of cordycepin on mouse leydig cell steroidogenesis. Biosci Biotechnol Biochem 2011; 75(4): 723-31.
[http://dx.doi.org/10.1271/bbb.100853] [PMID: 21512251]
[39]
Park ES, Kang DH, Yang MK, et al. Cordycepin, 3′-deoxyadenosine, prevents rat hearts from ischemia/reperfusion injury via activation of Akt/GSK-3β/p70s6k signaling pathway and HO-1 expression. Cardiovasc Toxicol 2014; 14(1): 1-9.
[http://dx.doi.org/10.1007/s12012-013-9232-0] [PMID: 24178833]
[40]
Sampson TR, Debelius JW, Thron T, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 2016; 167(6): 1469-1480.e12.
[http://dx.doi.org/10.1016/j.cell.2016.11.018] [PMID: 27912057]
[41]
Cenit MC, Sanz Y, Codoñer-Franch P. Influence of gut microbiota on neuropsychiatric disorders. World J Gastroenterol 2017; 23(30): 5486-98.
[http://dx.doi.org/10.3748/wjg.v23.i30.5486] [PMID: 28852308]
[42]
An Y, Li Y, Wang X, et al. Cordycepin reduces weight through regulating gut microbiota in high-fat diet-induced obese rats. Lipids Health Dis 2018; 17(1): 276.
[http://dx.doi.org/10.1186/s12944-018-0910-6] [PMID: 30522511]
[43]
Henchcliffe C, Beal MF. Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract Neurol 2008; 4(11): 600-9.
[http://dx.doi.org/10.1038/ncpneuro0924] [PMID: 18978800]
[44]
Gogvadze V, Orrenius S. Mitochondrial regulation of apoptotic cell death. Chem Biol Interact 2006; 163(1-2): 4-14.
[http://dx.doi.org/10.1016/j.cbi.2006.04.010] [PMID: 16730343]
[45]
Kumar A, Dhawan A, Kadam A, Shinde A. Autophagy and mitochondria: Targets in neurodegenerative disorders. CNS Neurol Disord Drug Targets 2018; 17(9): 696-705.
[http://dx.doi.org/10.2174/1871527317666180816100203] [PMID: 30113005]
[46]
Dawson TM, Dawson VL. Molecular pathways of neurodegeneration in Parkinson’s disease. Science 2003; 302(5646): 819-22.
[http://dx.doi.org/10.1126/science.1087753] [PMID: 14593166]
[47]
Kelekar A, Thompson CB. Bcl-2-family proteins: The role of the BH3 domain in apoptosis. Trends Cell Biol 1998; 8(8): 324-30.
[http://dx.doi.org/10.1016/S0962-8924(98)01321-X] [PMID: 9704409]
[48]
Circu ML, Aw TY. Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med 2010; 48(6): 749-62.
[http://dx.doi.org/10.1016/j.freeradbiomed.2009.12.022] [PMID: 20045723]
[49]
Porter AG, Jänicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ 1999; 6(2): 99-104.
[http://dx.doi.org/10.1038/sj.cdd.4400476] [PMID: 10200555]
[50]
Wang Z, Wang D, Li Y, Zhang X. Protective effects of verapamil against H2O2-induced apoptosis in human lens epithelial cells. Biomol Ther (Seoul) 2014; 22(6): 553-7.
[http://dx.doi.org/10.4062/biomolther.2014.033] [PMID: 25489424]