Top

Published in:

Open Access 01-12-2022 | Parkinson's Disease | Research article

Lycium barbarum polysaccharide improves dopamine metabolism and symptoms in an MPTP-induced model of Parkinson’s disease

Authors: Jiangbo Song, Lian Liu, Zhiquan Li, Ting Mao, Jianfei Zhang, Lei Zhou, Xin Chen, Yunzhu Shang, Tao Sun, Yuxin Luo, Yu Jiang, Duan Tan, Xiaoling Tong, Fangyin Dai

Published in: BMC Medicine | Issue 1/2022

Abstract

Background

Parkinson’s disease (PD) is the second most common neurodegenerative disease in middle-aged and elderly populations, whereas there is no cure for PD so far. Novel animal models and medications await development to elucidate the aetiology of PD and attenuate the symptoms, respectively.

Methods

A neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was used in the current study to establish a PD pathologic model in silkworms. The time required to complete specific behaviours was recorded. Dopamine content was detected by ultra-performance liquid chromatography (UPLC). The activity of insect tyrosine hydroxylase (TH) was determined using a double-antibody sandwich method. Oxidative stress was assessed by changes in antioxidant enzyme activity and the content of oxidative products.

Results

MPTP-treated silkworms were characterized by impaired motor ability, reduced dopamine content, and elevated oxidative stress level. The expression of TH, a dopamine biosynthetic enzyme within dopaminergic neurons in the brain, was significantly reduced, indicating that dopaminergic neurons were damaged. Moreover, MPTP-induced motility impairment and reduced dopamine level in the silkworm PD model could be rescued after feeding a combination of levodopa (L-dopa [LD]) and carbidopa (CD). MPTP-induced oxidative damage was also alleviated, in ways consistent with other PD animal models. Interestingly, administration of Lycium barbarum polysaccharide (LBP) improved the motor ability, dopamine level, and TH activity, and the oxidative damage was concomitantly reduced in the silkworm PD model.

Conclusions

This study provides a promising animal model for elucidating the pathogenesis of PD, as well as a relevant preliminary drug screening (e.g., LBP) and evaluation.

Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosur Ps. 2008;79:368–76. https://doi.org/10.1136/jnnp.2007.131045.CrossRef

Ali K, Morris HR. Parkinson’s disease: chameleons and mimics. Pract Neurol. 2015;15(1):14–25. https://doi.org/10.1136/practneurol-2014-000849.CrossRefPubMed

Gilberto L. The relationship of Parkinson disease with aging. Arch Neurol. 2007;64(9):1242–6. https://doi.org/10.1001/archneur.64.9.1242.CrossRef

Dorsey ER, Sherer T, Okun M, Bloem BR. The emerging evidence of the Parkinson pandemic. J Parkinsons Dis. 2018;8(s1):S3–8. https://doi.org/10.3233/JPD-181474.CrossRefPubMedPubMedCentral

Dorsey ER, Bloem BR. The Parkinson pandemic-A call to action. JAMA Neurol. 2018;5(1):9–10. https://doi.org/10.1001/jamaneurol.2017.3299.CrossRef

Miller DB, O’Callaghan JP. Biomarkers of Parkinson’s disease: present and future. Metabolism. 2015;301:S40–60. https://doi.org/10.1016/j.metabol.2014.10.030.CrossRef

Olguín HJ, Guzmán DC, García EH, Mejía GB. The role of dopamine and its dysfunction as a consequence of oxidative stress. Oxid Med Cell Longev. 2015;2016:9730467. https://doi.org/10.1155/2016/9730467.CrossRef

Carr J, de la Fuente-Fernandez R, Schulzer M, Mak E, Calne SM, Calne DB. Familial and sporadic Parkinson’s disease usually display the same clinical features. Parkinsonism Relat Disord. 2003;9(4):201–4. https://doi.org/10.1016/s1353-8020(02)00048-2.CrossRefPubMed

Lewthwaite AJ, Nicholl DJ. Genetics of parkinsonism. Curr Neurol Neurosci Rep. 2005;5(5):397–404. https://doi.org/10.1007/s11910-005-0064-6.CrossRefPubMed

10.

Kim S, Wong YC, Gao F, Krainc D. Dysregulation of mitochondria-lysosome contacts by GBA1 dysfunction in dopaminergic neuronal models of Parkinson's disease. Nat Commun. 2021;12(1):1807. https://doi.org/10.1038/s41467-021-22113-3.CrossRefPubMedPubMedCentral

11.

Grimm S, Hoehn A, Davies KJ, Grune T. Protein oxidative modifications in the ageing brain: consequence for the onset of neurodegenerative disease. Free Radic Res. 2011;45(1):73–88. https://doi.org/10.3109/10715762.2010.512040.CrossRefPubMed

12.

Luo F, Ye M, Lv T, Hu B, Chen J, Yan J, et al. Efficacy of cognitive behavioral therapy on mood disorders, sleep, fatigue, and quality of life in Parkinson’s disease: a systematic review and meta-analysis. Front Psych. 2021;12:793804. https://doi.org/10.3389/fpsyt.2021.793804.CrossRef

13.

Walter BL, Vitek JL. Surgical treatment for Parkinson’s disease. Lancet Neurol. 2004;3(12):719–28. https://doi.org/10.1016/S1474-4422(04)00934-2.CrossRefPubMed

14.

Freeman TB. From transplants to gene therapy for Parkinson’s disease. Exp Neurol. 1997;144(1):47–50. https://doi.org/10.1006/exnr.1996.6387.CrossRefPubMed

15.

Parmar M, Grealish S, Henchcliffe C. The future of stem cell therapies for Parkinson disease. Nat Rev Neurosci. 2020;21(2):103–15. https://doi.org/10.1038/s41583-019-0257-7.CrossRefPubMed

16.

Zhang CL, Han QW, Chen NH, Yuan YH. Research on developing drugs for Parkinson’s disease. Brain Res Bull. 2021;168:100–9. https://doi.org/10.1016/j.brainresbull.2020.12.017.CrossRefPubMed

17.

Kim SR, Kim JY, Kim HY, So HY, Chung SJ. Factors associated with medication beliefs in patients with Parkinson’s disease: a cross-sectional study. J Mov Disord. 2021;14(2):133–43. https://doi.org/10.14802/jmd.20147.CrossRefPubMedPubMedCentral

18.

LeWitt PA. Levodopa therapy for Parkinson’s disease: pharmacokinetics and pharmacodynamics. Mov Disord. 2015;30(1):64–72. https://doi.org/10.1002/mds.26082.CrossRefPubMed

19.

Borovac JA. Side effects of a dopamine agonist therapy for Parkinson’s disease: a mini-review of clinical pharmacology. Yale J Biol Med. 2016;89(1):37–47.PubMedPubMedCentral

20.

Brocks DR. Anticholinergic drugs used in Parkinson’s disease: an overlooked class of drugs from a pharmacokinetic perspective. J Pharm Pharm Sci. 1999;2(2):39–46.PubMed

21.

Hubsher G, Haider M, Okun MS. Amantadine: the journey from fighting flu to treating Parkinson disease. Neurology. 2012;78(14):1096–9. https://doi.org/10.1212/WNL.0b013e31824e8f0d.CrossRefPubMed

22.

Dezsi L, Vecsei L. Monoamine oxidase B inhibitors in Parkinson’s disease. CNS Neurol Disord Drug Targets. 2017;16(4):425–39. https://doi.org/10.2174/1871527316666170124165222.CrossRefPubMed

23.

Finberg JPM. Inhibitors of MAO-B and COMT: their effects on brain dopamine levels and uses in Parkinson’s disease. J Neural Transm (Vienna). 2019;126(4):433–48. https://doi.org/10.1007/s00702-018-1952-7.CrossRef

24.

Ogura H, Nakagawa R, Ishido M, Yoshinaga Y, Watanabe J, Kurihara K, et al. Evaluation of motor complications in Parkinson’s disease: understanding the perception gap between patients and physicians. Parkinsons Dis. 2021;2021:1599477. https://doi.org/10.1155/2021/1599477.CrossRefPubMedPubMedCentral

25.

Wang CC, Wu TL, Lin FJ, Tai CH, Lin CH, Wu RM. Amantadine treatment and delayed onset of levodopa-induced dyskinesia in patients with early Parkinson’s disease. Eur J Neurol. 2022;29(4):1044–55. https://doi.org/10.1111/ene.15234.CrossRefPubMed

26.

Gray R, Patel S, Ives N, Rick C, Woolley R, Muzerengi S, et al. Long-term effectiveness of adjuvant treatment with catechol-O-methyltransferase or monoamine oxidase B inhibitors compared with dopamine agonists among patients with Parkinson disease uncontrolled by Levodopa therapy: The PD med randomized clinical trial. JAMA Neurol. 2022;79(2):131–40. https://doi.org/10.1001/jamaneurol.2021.4736.CrossRefPubMed

27.

Santos-Lobato BL, Bortolanza M, Pinheiro LC, Batalhao ME, Pimental AV, Capellari-Carnio, et al. Levodopa-induced dyskinesias in Parkinson’s disease increase cerebrospinal fluid nitric oxide metabolites’levels. J Neural Transm (Vienna). 2022;129(1):55–63. https://doi.org/10.1007/s00702-021-02447-4.CrossRef

28.

Kalia LV, Lang AE. Parkinson’s disease. Lancet. 2015;386(9996):896–912. https://doi.org/10.1016/S0140-6736(14)61393-3.CrossRefPubMed

29.

Oczkowska A, Kozubski W, Lianeri M, Dorszewska J. Mutations in PRKN and SNCA genes important for the progress of Parkinson’s disease. Curr Genomics. 2013;14(8):502–17. https://doi.org/10.2174/1389202914666131210205839.CrossRefPubMedPubMedCentral

30.

Bastias-Candia S, Zolezzi JM, Inestrosa NC. Revisiting the paraquat-induced sporadic Parkinson’s disease-like model. Mol Neurobiol. 2019;56(2):1044–55. https://doi.org/10.1007/s12035-018-1148-z.CrossRefPubMed

31.

Leal PC, Bispo JMM, Engelberth R, KDDA S, Meurer YR, Ribeiro AM, et al. Serotonergic dysfunction in a model of parkinsonism induced by reserpine. J Chem Neuroanat. 2019;96:73–8. https://doi.org/10.1016/j.jchemneu.2018.12.011.CrossRefPubMed

32.

Simola N, Morelli M, Carta AR. The 6-hydroxydopamine model of Parkinson’s disease. Neurotox Res. 2007;11(3-4):151–67. https://doi.org/10.1007/BF03033565.CrossRefPubMed

33.

Sherer TB, Betarbet R, Testa CM, Seo BB, Richardson JR, Kim JH, et al. Mechanism of toxicity in rotenone models of Parkinson’s disease. J Neurosci. 2003;23(34):10756–64. https://doi.org/10.1523/JNEUROSCI.23-34-10756.2003.CrossRefPubMedPubMedCentral

34.

Blum D, Torch S, Lambeng N, Nissou M, Benabid AL, Sadoul R, et al. Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol. 2001;65(2):135–72. https://doi.org/10.1016/s0301-0082(01)00003-x.CrossRefPubMed

35.

Santana M, Palmer T, Simplicio H, Fuentes R, Petersson P. Characterization of long-term motor deficits in the 6-OHDA model of Parkinson’s disease in the common marmoset. Behav Brain Res. 2015;290:90–101. https://doi.org/10.1016/j.bbr.2015.04.037.CrossRefPubMed

36.

Xiong N, Long X, Xiong J, Jia M, Chen C, Huang J, et al. Mitochondrial complex I inhibitor rotenone-induced toxicity and its potential mechanisms in Parkinson’s disease models. Crit Rev Toxicol. 2012;42(7):613–32. https://doi.org/10.3109/10408444.2012.680431.CrossRefPubMed

37.

Leao AH, Sarmento-Silva AJ, Santos JR, Ribeiro AM, Silva RH. Molecular, neurochemical, and behavioral hallmarks of reserpine as a model for Parkinson’s disease: new perspectives to a long-standing model. Brain Pathol. 2015;25(4):377–90. https://doi.org/10.1111/bpa.12253.CrossRefPubMedPubMedCentral

38.

Schildknecht S, Di Monte DA, Pape R, Tieu K, Leist M. Tipping points and endogenous determinants of nigrostriatal degeneration by MPTP. Trends Pharmacol Sci. 2017;38(6):541–55. https://doi.org/10.1016/j.tips.2017.03.010.CrossRefPubMed

39.

Narmashiri A, Abbaszadeh M, Ghazizadeh A. The effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the cognitive and motor functions in rodents: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2022;140:104792. https://doi.org/10.1016/j.neubiorev.2022.104792.CrossRefPubMed

40.

AlShimemeri S, Di Luca DG, Fox SH. MPTP parkinsonism and implications for understanding Parkinson’s disease. Mov Disord Clin Pract. 2021;9(1):42–7. https://doi.org/10.1002/mdc3.13344.CrossRefPubMedPubMedCentral

41.

Graham DG, Tiffany SM, Bell WR, Gutknecht WF. Autoxidation versus covalent binding of quinones as the mechanism of toxicity of dopamine, 6-hydroxydopamine, and related compounds toward C1300 neuroblastoma cells in vitro. Mol Pharmacol. 1978;14(4):644–53.PubMed

42.

Argyropoulou A, Aligiannis N, Trougakos IP, Skaltsounis AL. Natural compounds with anti-ageing activity. Nat Prod Rep. 2013;30(11):1412–37. https://doi.org/10.1039/c3np70031c.CrossRefPubMed

43.

Shen CY, Jiang JG, Yang L, Wang DW, Zhu W. Anti-ageing active ingredients from herbs and nutraceuticals used in traditional Chinese medicine: pharmacological mechanisms and implications for drug discovery. Br J Pharmacol. 2017;174(11):1395–425. https://doi.org/10.1111/bph.13631.CrossRefPubMed

44.

Wang HB, Li YX, Hao YJ, Wang TF, Lei Z, Wu Y, et al. Neuroprotective effects of LBP on brain ischemic reperfusion neurodegeneration. Eur Rev Med Pharmacol Sci. 2013;17(20):2760–5.PubMed

45.

Wang X, Pang L, Zhang Y, Xu J, Ding D, Yang T, et al. Lycium barbarum Polysaccharide promotes nigrostriatal dopamine function by modulating PTEN/AKT/mTOR pathway in a Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson’s disease. Neurochem Res. 2018;43(4):938–47. https://doi.org/10.1007/s11064-018-2499-6.CrossRefPubMed

46.

Cao S, Du J, Hei Q. Lycium barbarum polysaccharide protects against neurotoxicity via the Nrf2-HO-1 pathway. Exp Ther Med. 2017;14(5):4919–27. https://doi.org/10.3892/etm.2017.5127.CrossRefPubMedPubMedCentral

47.

Lakshmanan Y, Wong FSY, Zuo B, So KF, Bui BV, Chan HH. Posttreatment intervention with Lycium barbarum polysaccharides is neuroprotective in a Rat model of chronic ocular hypertension. Invest Ophthalmol Vis Sci. 2019;60(14):4606–18. https://doi.org/10.1167/iovs.19-27886.CrossRefPubMed

48.

Schapira AH, Jenner P. Etiology and pathogenesis of Parkinson’s disease. Mov Disord. 2011;26(6):1049–55. https://doi.org/10.1002/mds.23732.CrossRefPubMed

49.

Wang GH, Xia QY, Cheng DJ, Duan J, Zhao P, Chen J, et al. Reference genes identified in the silkworm Bombyx mori during metamorphism based on oligonucleotide microarray and confirmed by Qrt-PCR. Insect Sci. 2008;15(005):405–13. https://doi.org/10.1111/j.1744-7917.2008.00227.x.CrossRef

50.

Li W, Fu Y, Halliday GM, Sue CM. PARK genes link mitochondrial dysfunction and alpha-synuclein pathology in sporadic Parkinson’s disease. Front Cell Dev Biol. 2021;9:612476. https://doi.org/10.3389/fcell.2021.612476.CrossRefPubMedPubMedCentral

51.

Trist BG, Hare DJ, Double KL. Oxidative stress in the aging substantia nigra and the etiology of Parkinson’s disease. Aging Cell. 2019;18(6):e13031. https://doi.org/10.1111/acel.13031.CrossRefPubMedPubMedCentral

52.

Xing X, Liu F, Xiao J, So KF. Neuro-protective mechanisms of Lycium barbarum. Neuromolecular Med. 2016;18(3):253–63. https://doi.org/10.1007/s12017-016-8393-y.CrossRefPubMed

53.

Im AR, Kim YH, Uddin MR, Chae S, Lee HW, Kim YS, et al. Neuroprotective effects of Lycium chinense miller against rotenone-induced neurotoxicity in PC12 cells. Am J Chin Med. 2013;41(6):1343–59. https://doi.org/10.1142/S0192415X13500900.CrossRefPubMed

54.

Gao K, Liu M, Cao J, Yao M, Lu Y, Li J, et al. Protective effects of Lycium barbarum polysaccharide on 6-OHDA-induced apoptosis in PC12 cells through the ROS-NO pathway. Molecules. 2014;20(1):293–308. https://doi.org/10.3390/molecules20010293.CrossRefPubMedPubMedCentral

55.

Zhang Z, Teng X, Chen M, Li F. Orthologs of human disease associated genes and RNAi analysis of silencing insulin receptor gene in Bombyx mori. Int J Mol Sci. 2014;15(10):18102–16. https://doi.org/10.3390/ijms151018102.CrossRefPubMedPubMedCentral

56.

Jiang G, Song J, Hu H, Tong X, Dai F. Evaluation of the silkworm lemon mutant as an invertebrate animal model for human sepiapterin reductase deficiency. R Soc Open Sci. 2020;7(3):191888. https://doi.org/10.1098/rsos.191888.CrossRefPubMedPubMedCentral

57.

Matsumoto Y, Sumiya E, Sugita T, Sekimizu K. An invertebrate hyperglycemic model for the identification of anti-diabetic drugs. PLoS One. 2011;6(3):e18292. https://doi.org/10.1371/journal.pone.0018292.CrossRefPubMedPubMedCentral

58.

Matsumoto Y, Ishii M, Hayashi Y, Miyazaki S, Sugita T, Sumiya E, et al. Diabetic silkworms for evaluation of therapeutically effective drugs against type II diabetes. Sci Rep. 2015;5:10722. https://doi.org/10.1038/srep10722.CrossRefPubMedPubMedCentral

59.

Matsumoto Y, Sekimizu K. Evaluation of anti-diabetic drugs by using silkworm, Bombyx mori. Drug Discov Ther. 2016;10(1):19–23. https://doi.org/10.5582/ddt.2016.01017.CrossRefPubMed

60.

Zhang X, Xue R, Cao G, Pan Z, Zheng X, Gong C. Silkworms can be used as an animal model to screen and evaluate gouty therapeutic drugs. J Insect Sci. 2012;12:4. https://doi.org/10.1673/031.012.0401.CrossRefPubMedPubMedCentral

61.

Nie H, Cheng T, Huang X, Zhou M, Zhang Y, Dai F, et al. Functional loss of Bmsei causes thermosensitive epilepsy in contractile mutant silkworm, Bombyx mori. Sci Rep. 2015;5:12308. https://doi.org/10.1038/srep12308.CrossRefPubMedPubMedCentral

62.

Tabunoki H, Bono H, Ito K, Yokoyama T. Can the silkworm (Bombyx mori) be used as a human disease model? Drug Discov Ther. 2016;10(1):3–8. https://doi.org/10.5582/ddt.2016.01011.CrossRefPubMed

63.

Tabunoki H, Ono H, Ode H, Ishikawa K, Kawana N, Banno Y, et al. Identification of key uric acid synthesis pathway in a unique mutant silkworm Bombyx mori model of Parkinson’s disease. PLoS One. 2013;8(7):e69130. https://doi.org/10.1371/journal.pone.0069130.CrossRefPubMedPubMedCentral

64.

Zhu F, Chen H, Han J, Zhou W, Tang Q, Yu Q, et al. Proteomic and targeted metabolomic studies on a silkworm model of Parkinson’s disease. J Proteome Res. 2022;21(9):2114–23. https://doi.org/10.1021/acs.jproteome.2c00149.CrossRefPubMed

65.

Prediger RD, Aguiar AS Jr, Moreira EL, Matheus FC, Castro AA, Walz R, et al. The intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a new rodent model to test palliative and neuroprotective agents for Parkinson’s disease. Curr Pharm Des. 2011;17(5):489–507. https://doi.org/10.2174/138161211795164095.CrossRefPubMed

66.

Jenner P. Oxidative stress in Parkinson’s disease. Ann Neurol. 2003;53(S3):S26–36. https://doi.org/10.1002/ana.10483.CrossRefPubMed

67.

Shulman JM, De Jager PL, Feany MB. Parkinson’s disease: genetics and pathogenesis. Annu Rev Pathol. 2011;6:193–222. https://doi.org/10.1146/annurev-pathol-011110-130242.CrossRefPubMed

Title: Lycium barbarum polysaccharide improves dopamine metabolism and symptoms in an MPTP-induced model of Parkinson’s disease
Authors: Jiangbo Song
Lian Liu
Zhiquan Li
Ting Mao
Jianfei Zhang
Lei Zhou
Xin Chen
Yunzhu Shang
Tao Sun
Yuxin Luo
Yu Jiang
Duan Tan
Xiaoling Tong
Fangyin Dai
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Parkinson's Disease
Carbidopa
Levodopa
Published in: BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/s12916-022-02621-9

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Lycium barbarum polysaccharide improves dopamine metabolism and symptoms in an MPTP-induced model of Parkinson’s disease

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2022

Efficacy of metformin therapy in patients with cancer: a meta-analysis of 22 randomised controlled trials

Differences in risk factors for incident and recurrent preterm birth: a population-based linkage of 3.5 million births from the CIDACS birth cohort

Diabetic kidney disease and risk of incident stroke among adults with type 2 diabetes

Heart rate variability is associated with left ventricular systolic, diastolic function and incident heart failure in the general population

Inequalities in the impact of COVID-19-associated disruptions on tuberculosis diagnosis by age and sex in 45 high TB burden countries

A digital application and augmented physician rounds reduce postoperative pain and opioid consumption after primary total knee replacement (TKR): a randomized clinical trial