EFFECTS OF ETHYL PYRUVATE IN LIPOPOLYSACCHARIDE MODEL OF PARKINSON’S DISEASE

Main Article Content

Rabia Syed
Najeeb Ullah
Muhammad Ikram
Saima Mumtaz Khattak
Sarwat Jahan
Mahnoor

Keywords

Parkinson’s disease, Lipopolysaccharide, Ethyl pyruvate, eurodegeneration, glial cells, inflammation, Substantia Nigra, motor disorder

Abstract

Objective: This study aims to evaluate the therapeutic effects of Ethyl Pyruvate (EP) in lipopolysaccharide (LPS)-induced mouse model of Parkinson’s disease (PD).


 Methods: Total 24 male Balb-c mice were used for the study. 4 day repeat injection model of LPS (1mg/kg/day) was chosen. EP was administered half hour before the LPS in co-treatment group (40mg/kg/day). ELISA test was performed for serum analysis of TNF-alpha levels. Immunohistochemistry was done to analyze the Tyrosine Hydroxylase (TH) positive cell count in Substantia Nigra (SN) of mice brain. Pole behavioral test was done by recording Ttotal in seconds.


 Results: Our study showed that TH+ cell count was significantly reduced in LPS treated group as compared to control group. This count was improved after the administration of EP in co-treatment group. These effects of EP were supported by the results of ELISA, which showed significant reduction in TNF-alpha levels of co-treatment group (LPS + EP) in contrast to LPS treated group. Motor deficits were also improved as assessed by pole behavior test showing a reduction in Ttotal of (LPS + EP) group as compared to Ttotal of LPS treated group.


Conclusion: In this study we found significant improvement in dopaminergic neuron count, and motor deficits of PD model. Level of Inflammatory marker was also reduced significantly confirming the ant-inflammatory potential of EP. Together these data supports that progressive neurodegeneration of PD is slowed down after the use of EP.

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References

1. Zhang X, Zhang Y, Li R, Zhu L, Fu B, Yan T. Salidroside ameliorates Parkinson's disease by inhibiting NLRP3-dependent pyroptosis. Aging. 2020 May 19;12(10):9405-26. PubMed PMID: 32432571. Pubmed Central PMCID: PMC7288953. Epub 2020/05/21. eng.
2. Tysnes OB, Storstein A. Epidemiology of Parkinson's disease. Journal of neural transmission (Vienna, Austria : 1996). 2017 Aug;124(8):901-5. PubMed PMID: 28150045. Epub 2017/02/06. eng.
3. Jo MG, Ikram M, Jo MH, Yoo L, Chung KC, Nah SY, et al. Gintonin Mitigates MPTP-Induced Loss of Nigrostriatal Dopaminergic Neurons and Accumulation of α-Synuclein via the Nrf2/HO-1 Pathway. Molecular neurobiology. 2019 Jan;56(1):39-55. PubMed PMID: 29675576. Epub 2018/04/21. eng.
4. Shen XL, Song N, Du XX, Li Y, Xie JX, Jiang H. Nesfatin-1 protects dopaminergic neurons against MPP(+)/MPTP-induced neurotoxicity through the C-Raf-ERK1/2-dependent anti-apoptotic pathway. Scientific reports. 2017 Jan 20;7:40961. PubMed PMID: 28106099. Pubmed Central PMCID: PMC5247731. Epub 2017/01/21. eng.
6. Dorsey Ea, Constantinescu R, Thompson J, Biglan K, Holloway R, Kieburtz K, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 2007;68(5):384-6.
7. Tufail M. Clinical features and risk factors of Parkinson’s disease in a population of Khyber Pakhtunkhwa, Pakistan: a case-control study. Neurodegenerative Diseases. 2019;19(5-6):211-7.
8. Beier EE, Neal M, Alam G, Edler M, Wu LJ, Richardson JR. Alternative microglial activation is associated with cessation of progressive dopamine neuron loss in mice systemically administered lipopolysaccharide. Neurobiology of disease. 2017 Dec;108:115-27. PubMed PMID: 28823928. Pubmed Central PMCID: PMC5734673. Epub 2017/08/22. eng.
9. Kelly LP, Carvey PM, Keshavarzian A, Shannon KM, Shaikh M, Bakay RA, et al. Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society. 2014 Jul;29(8):999-1009. PubMed PMID: 24898698. Pubmed Central PMCID: PMC4050039. Epub 2014/06/06. eng.
10. Suda Y, Kuzumaki N, Narita M, Hamada Y, Shibasaki M, Tanaka K, et al. Effect of ghrelin on the motor deficit caused by the ablation of nigrostriatal dopaminergic cells or the inhibition of striatal dopamine receptors. Biochemical and biophysical research communications. 2018;496(4):1102-8.
11. Kordower JH, Olanow CW, Dodiya HB, Chu Y, Beach TG, Adler CH, et al. Disease duration and the integrity of the nigrostriatal system in Parkinson's disease. Brain : a journal of neurology. 2013 Aug;136(Pt 8):2419-31. PubMed PMID: 23884810. Pubmed Central PMCID: PMC3722357. Epub 2013/07/26. eng.
12. Jellinger KA. Neuropathology of sporadic Parkinson's disease: evaluation and changes of concepts. Movement disorders : official journal of the Movement Disorder Society. 2012 Jan;27(1):8-30. PubMed PMID: 22081500. Epub 2011/11/15. eng.
13. Kozina EA, Khakimova GR, Khaindrava VG, Kucheryanu VG, Vorobyeva NE, Krasnov AN, et al. Tyrosine hydroxylase expression and activity in nigrostriatal dopaminergic neurons of MPTP-treated mice at the presymptomatic and symptomatic stages of parkinsonism. Journal of the neurological sciences. 2014 May 15;340(1-2):198-207. PubMed PMID: 24768159. Epub 2014/04/29. eng.
14. Hunter R, Ojha U, Bhurtel S, Bing G, Choi DY. Lipopolysaccharide-induced functional and structural injury of the mitochondria in the nigrostriatal pathway. Neurosci Res. 2017 Jan;114:62-9. PubMed PMID: 27667002. Epub 2016/09/27. eng.
15. Gu C, Wang F, Zhang YT, Wei SZ, Liu JY, Sun HY, et al. Microglial MT1 activation inhibits LPS‐induced neuroinflammation via regulation of metabolic reprogramming. Aging Cell. 2021;20(6):e13375.
16. Sharma N, Nehru B. Apocyanin, a Microglial NADPH Oxidase Inhibitor Prevents Dopaminergic Neuronal Degeneration in Lipopolysaccharide-Induced Parkinson's Disease Model. Molecular neurobiology. 2016 Jul;53(5):3326-37. PubMed PMID: 26081143. Epub 2015/06/18. eng.
17. Zhang FX, Xu RS. Juglanin ameliorates LPS-induced neuroinflammation in animal models of Parkinson's disease and cell culture via inactivating TLR4/NF-κB pathway. Biomed Pharmacother. 2018 Jan;97:1011-9. PubMed PMID: 29136779. Epub 2017/11/16. eng.
18. Wang Y, Yin P, Huang S, Wang J, Sun R. Ethyl pyruvate protects against lipopolysaccharide-induced white matter injury in the developing rat brain. Int J Dev Neurosci. 2013 May;31(3):181-8. PubMed PMID: 23280059. Epub 2013/01/03. eng.
19. Qiu X, Cheng X, Zhang J, Yuan C, Zhao M, Yang X. Ethyl pyruvate confers protection against endotoxemia and sepsis by inhibiting caspase-11-dependent cell pyroptosis. International immunopharmacology. 2020 Jan;78:106016. PubMed PMID: 31796383. Epub 2019/12/05. eng.
20. Shen H, Hu X, Liu C, Wang S, Zhang W, Gao H, et al. Ethyl pyruvate protects against hypoxic-ischemic brain injury via anti-cell death and anti-inflammatory mechanisms. Neurobiology of disease. 2010;37(3):711-22.
21. Chavali VD, Agarwal M, Vyas VK, Saxena B. Neuroprotective effects of ethyl pyruvate against aluminum chloride-induced Alzheimer’s disease in rats via inhibiting toll-like receptor 4. Journal of Molecular Neuroscience. 2020;70:836-50.
22. Deng I, Bobrovskaya L. Lipopolysaccharide mouse models for Parkinson's disease research: a critical appraisal. Neural regeneration research. 2022 Nov;17(11):2413-7. PubMed PMID: 35535880. Pubmed Central PMCID: PMC9120679. Epub 2022/05/11. eng.
23. Song S, Jiang L, Oyarzabal EA, Wilson B, Li Z, Shih Y-YI, et al. Loss of brain norepinephrine elicits neuroinflammation-mediated oxidative injury and selective caudo-rostral neurodegeneration. Molecular neurobiology. 2019;56:2653-69.
24. Khan MS, Ali T, Kim MW, Jo MH, Chung JI, Kim MO. Anthocyanins improve hippocampus-dependent memory function and prevent neurodegeneration via JNK/Akt/GSK3β signaling in LPS-treated adult mice. Molecular neurobiology. 2019;56:671-87.
25. Badshah H, Ali T, Shafiq-ur R, Faiz-ul A, Ullah F, Kim TH, et al. Protective Effect of Lupeol Against Lipopolysaccharide-Induced Neuroinflammation via the p38/c-Jun N-Terminal Kinase Pathway in the Adult Mouse Brain. J Neuroimmune Pharmacol. 2016 Mar;11(1):48-60. PubMed PMID: 26139594. Epub 2015/07/04. eng.
26. Jiang MJ, Chen YH, Li L, Xu L, Liu H, Qu XL, et al. Protective effects of DL‑3‑n‑butylphthalide in the lipopolysaccharide‑induced mouse model of Parkinson's disease. Molecular Medicine Reports. 2017;16(5):6184-9.
27. Satpute R, Lomash V, Kaushal M, Bhattacharya R. Neuroprotective effects of alpha-ketoglutarate and ethyl pyruvate against motor dysfunction and oxidative changes caused by repeated 1-methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine exposure in mice. Human & experimental toxicology. 2013;32(7):747-58.

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