Document Type : Research Paper I Open Access I Released under CC BY-NC 4.0 license
Authors
1 Department of Exercise Physiology, Faculty of Sport Sciences and Health, University of Tehran, Tehran, Iran.
2 Corresponding Author, Department of Exercise Physiology, Faculty of Sport Sciences and Health, University of Tehran, Tehran, Iran.
Abstract
Introduction: Oxidative stress and the production of Reactive Nitrogen (RNS) and Oxygen (ROS) Species play an important role in the pathogenesis and the progression of MS. This study aimed to investigate the effect of exercise on disease severity, NRF2 protein levels, and xanthine oxidase enzyme in the spinal cord during the chronic period of the disease.
Methods: Thirty female C57Bl/6 mice (6-8 weeks) were divided into three Voluntary Exercise, Experimental Autoimmune Encephalomyelitis (EAE), and Healthy Control groups. After induction of EAE by Myelin Oligodendrocyte Glycoprotein (MOG35-55) and after the mice showed a clinical score of one for two consecutive days, they performed one hour of voluntary exercise for four weeks and five days a week. Forty-eight hours after the last training session, the mice were anesthetized with Ketamine and Xylazine, and the spinal cord tissue was removed. The location of NRF2 proteins in the gray and white matter of the spinal cord was investigated by Immunohistochemistry, and xanthine oxidase was measured by xanthine oxidase assay kit according to the kit manufacturer's instructions and by ELISA method.
Results: Voluntary exercise increased NRF2 protein levels in the white matter (P=0.0001) and gray matter (P=0.0001) of the spinal cord and decreased xanthine oxidase levels in the spinal cord (P=0.001), and attenuated disease severity during the chronic period (P=0.01).
Conclusion: Voluntary exercise reduces oxidative stress and disease severity during the chronic period of the disease and would be a good strategy for controlling and treatment of MS disease.
Keywords
Main Subjects
- Moser T, Akgün K, Proschmann U, Sellner J, Ziemssen T. The role of TH17 cells in multiple sclerosis: Therapeutic implications. Autoimmunity Reviews. 2020;19(10):102647.
- Ghasemi N, Razavi S, Nikzad E. Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy. Cell J. 2017;19(1):1-10.
- Solleiro-Villavicencio H, Rivas-Arancibia S. Effect of chronic oxidative stress on neuroinflammatory response mediated by CD4+ T cells in neurodegenerative diseases. Frontiers in cellular neuroscience. 2018;12:114.
- van Horssen J, Schreibelt G, Drexhage J, Hazes T, Dijkstra CD, van der Valk P, et al. Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free radical biology & medicine. 2008;45(12):1729-37.
- Mani S. Production of reactive oxygen species and its implication in human diseases. Free radicals in human health and disease: Springer; 2015. p. 3-15.
- Dasuri K, Zhang L, Keller JN. Oxidative stress, neurodegeneration, and the balance of protein degradation and protein synthesis. Free radical biology & medicine. 2013;62:170-85.
- Kim GH, Kim JE, Rhie SJ, Yoon S. The Role of Oxidative Stress in Neurodegenerative Diseases. Exp Neurobiol. 2015;24(4):325-40.
- Honorat JA, Kinoshita M, Okuno T, Takata K, Koda T, Tada S, et al. Xanthine Oxidase Mediates Axonal and Myelin Loss in a Murine Model of Multiple Sclerosis. PLOS ONE. 2013;8(8):e71329.
- Michaličková D, Hrnčíř T, Canová NK, Slanař O. Targeting Keap1/Nrf2/ARE signaling pathway in multiple sclerosis. European journal of pharmacology. 2020;873:172973.
- Johnson DA, Amirahmadi S, Ward C, Fabry Z, Johnson JA. The absence of the pro-antioxidant transcription factor Nrf2 exacerbates experimental autoimmune encephalomyelitis. Toxicological sciences : an official journal of the Society of Toxicology. 2010;114(2):237-46.
- Nellessen A, Nyamoya S, Zendedel A, Slowik A, Wruck C, Beyer C, et al. Nrf2 deficiency increases oligodendrocyte loss, demyelination, neuroinflammation and axonal damage in an MS animal model. Metabolic Brain Disease. 2020;35(2):353-62.
- Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011;134(Pt 3):678-92.
- Li B, Cui W, Liu J, Li R, Liu Q, Xie XH, et al. Sulforaphane ameliorates the development of experimental autoimmune encephalomyelitis by antagonizing oxidative stress and Th17-related inflammation in mice. Exp Neurol. 2013;250:239-49.
- Motl RW, Gosney J. Effect of exercise training on quality of life in multiple sclerosis: a meta-analysis. Multiple Sclerosis Journal. 2008;14(1):129-35.
- Pilutti L, Dlugonski D, Sandroff B, Klaren R, Motl RW. Randomized controlled trial of a behavioral intervention targeting symptoms and physical activity in multiple sclerosis. Multiple Sclerosis Journal. 2014;20(5):594-601.
- Alvarenga-Filho H, Sacramento PM, Ferreira TB, Hygino J, Abreu JEC, Carvalho SR, et al. Combined exercise training reduces fatigue and modulates the cytokine profile of T-cells from multiple sclerosis patients in response to neuromediators. J Neuroimmunol. 2016;293:91-9.
- Bernardes D, Brambilla R, Bracchi-Ricard V, Karmally S, Dellarole A, Carvalho-Tavares J, et al. Prior regular exercise improves clinical outcome and reduces demyelination and axonal injury in experimental autoimmune encephalomyelitis. J Neurochem. 2016;136 Suppl 1:63-73.
- Bernardes D, Oliveira-Lima OC, Silva TV, Faraco CC, Leite HR, Juliano MA, et al. Differential brain and spinal cord cytokine and BDNF levels in experimental autoimmune encephalomyelitis are modulated by prior and regular exercise. J Neuroimmunol. 2013;264(1-2):24-34.
- Souza PS, Gonçalves ED, Pedroso GS, Farias HR, Junqueira SC, Marcon R, et al. Physical Exercise Attenuates Experimental Autoimmune Encephalomyelitis by Inhibiting Peripheral Immune Response and Blood-Brain Barrier Disruption. Mol Neurobiol. 2017;54(6):4723-37.
- Xie Y, Li Z, Wang Y, Xue X, Ma W, Zhang Y, et al. Effects of moderate- versus high- intensity swimming training on inflammatory and CD4(+) T cell subset profiles in experimental autoimmune encephalomyelitis mice. J Neuroimmunol. 2019;328:60-7.
- Shahidi SH, Kordi MR, Rajabi H, Malm C, Shah F, Quchan ASK. Exercise modulates the levels of growth inhibitor genes before and after multiple sclerosis. Journal of Neuroimmunology. 2020;341:577172.
- Saffar Kohneh Quchan AH, Kordi MR, Namdari H, Shabkhiz F. Voluntary wheel running stimulates the expression of Nrf-2 and interleukin-10 but suppresses interleukin-17 in experimental autoimmune encephalomyelitis. Neuroscience Letters. 2020;738:135382.
- Higashi C, Kawaji A, Tsuda N, Hayashi M, Saito R, Yagishita Y, et al. The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice. Eur J Pharmacol. 2017;802:76-84.
- Schulze-Topphoff U, Varrin-Doyer M, Pekarek K, Spencer CM, Shetty A, Sagan SA, et al. Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2. Proceedings of the National Academy of Sciences of the United States of America. 2016;113(17):4777-82.
- Liu N, Kan Q-c, Zhang X-j, Xv Y-m, Zhang S, Zhang G-X, et al. Upregulation of immunomodulatory molecules by matrine treatment in experimental autoimmune encephalomyelitis. Experimental and molecular pathology. 2014;97(3):470-6.
- Morales-Pantoja IE, Hu C-l, Perrone-Bizzozero NI, Zheng J, Bizzozero OA. Nrf2-dysregulation correlates with reduced synthesis and low glutathione levels in experimental autoimmune encephalomyelitis. Journal of neurochemistry. 2016;139(4):640-50.
- Farahmand F, Nourshahi M, Soleimani M, Rajabi H, Power KE. The effect of 6 weeks of high intensity interval training on myelin biomarkers and demyelination in experimental autoimmune encephalomyelitis model. Journal of Neuroimmunology. 2020;346:577306.
- Done AJ, Traustadóttir T. Nrf2 mediates redox adaptations to exercise. Redox Biology. 2016;10:191-9.
- Muthusamy VR, Kannan S, Sadhaasivam K, Gounder SS, Davidson CJ, Boeheme C, et al. Acute exercise stress activates Nrf2/ARE signaling and promotes antioxidant mechanisms in the myocardium. Free radical biology & medicine. 2012;52(2):366-76.
- Gounder SS, Kannan S, Devadoss D, Miller CJ, Whitehead KJ, Odelberg SJ, et al. Impaired transcriptional activity of Nrf2 in age-related myocardial oxidative stress is reversible by moderate exercise training. PLoS One. 2012;7(9):e45697.
- Dimitrijevic M, Kotur-Stevuljevic J, Stojic-Vukanic Z, Vujnovic I, Pilipovic I, Nacka-Aleksic M, et al. Sex Difference in Oxidative Stress Parameters in Spinal Cord of Rats with Experimental Autoimmune Encephalomyelitis: Relation to Neurological Deficit. Neurochemical research. 2017;42(2):481-92.
- Honorat JA, Kinoshita M, Okuno T, Takata K, Koda T, Tada S, et al. Xanthine oxidase mediates axonal and myelin loss in a murine model of multiple sclerosis. PloS one. 2013;8(8):e71329.
)