اثر شش هفته فعالیت شنای اختیاری بر محتوای پروتئین‌های GSK3β، mTOR،caspase-3 موش‌های صحرایی مبتلا به بیماری مولتیپل اسکلروزیس (MS) القاشده با کوپریزون

نوع مقاله : مقاله پژوهشی

نویسندگان

گروه فیزیولوژی ورزشی، دانشکدة علوم ورزشی، دانشگاه شهید چمران اهواز، اهواز، ایران

چکیده

زمینه و هدف: مالتیپل اسکلروزیس (MS) یک بیماری مزمن، التهابی و خودایمنی با جنبه‌های چندعاملی است که به شکل چشمگیری کیفیت زندگی بیماران را تحت تأثیر قرار می‌دهد و محدود می‌سازد. یافته‌ها نشان می‌دهد فعالیت بدنی می‌تواند با ایجاد آثار ضدالتهابی و نقش محافظتی بر آکسون‌ها در این بیماران مفید باشد. در هیپوکامپ، پیام‌رسانی GSK3β، mTOR،caspase-3 در تنظیم چندین فرایند مهم سلولی از جمله آپوپتوز، بقا، تکثیر و سوخت‌وساز نقش دارد، بر همین اساس، هدف این پژوهش بررسی تأثیر فعالیت ورزشی (شنای اختیاری) بر سطح پروتئین‌های کلیدی و برجسته‌ای GSK3β mTOR،caspase-3 در بافت هیپوکمپ موش‌های صحرایی مبتلا به MS القاشده با کوپر‌یزون است.
مواد و روش­ها: در این پژوهش 21 سر موش صحرایی نر نژاد ویستار با میانگین سن 12 هفته و وزن 16±225 گرم خریداری و در سه گروه شامل کنترل سالم، کنترل بیمار و بیمار تمرین جایگزین شدند. الگوی بیماری MS با استفاده از رژیم غذایی حاوی 5/0 درصد کوپریزون به مدت ۱۲ هفته القا شد. پس از تأیید القای بیماری با آزمون روتارود، تمرین شنا طی شش هفته اعمال شد. در هفتة اول، فعالیت شنا به مدت ۱۰ دقیقه بدون بار اضافی انجام گرفت و به‌منظور اعمال اضافه بار مدت شنا در هر هفته پنج دقیقه افزایش پیدا کرد. به‌منظور ارزیابی سازگاری، مدت زمان شنا در هفته‌های پنجم و ششم به مدت زمان ۳۰ دقیقه ثابت نگه داشته شد. پس از پایان تمرین و آزمون‌ روتارود و برای بررسی تعادل و حافظه انجام گرفت. سپس بافت هیپوکمپ استخراج و مقادیر پروتئین‌های GSK3β، mTOR و caspase-3 با روش وسترن بلات سنجش شد. داده‌ها با آزمون آماری آنووا یکطرفه و آزمون تعقیبی توکی در سطح معناداری کمتر از 05/0 تحلیل شدند.
نتایج:. یافته‌ها نشان داد که محتوای پروتئینی GSK3β و caspase-3 در گروه بیمار نسبت به گروه سالم بیشتر شد (001/0P=)؛ اما پس از شش هفته تمرین شنا، محتوای پروتئین‌های یادشده در گروه تمرینی نسبت به گروه بیمار کمتر شده (P<0/001). همچنین در محتوای پروتئین mTOR کاهش در گروه بیمار نسبت به گروه سالم دیده شد (001/0P=)؛ اما پس از شش هفته تمرین شنا، محتوای پروتئین یادشده در گروه تمرینی نسبت به گروه بیمار به افزایش یافت (001/0P=).
نتیجه‌گیری: یافته‌های این پژوهش نشان می‌دهد که ممکن است فعالیت ورزشی شنای اختیاری با القای سازگاری‌های مولکولی، بتواند تأثیرات ضدالتهابی و محافظت‌کنندة عصبی و همچنین اثر تعدیلی بر تغییر پروتئین‌های مؤثر در فرایند آپوپتوز سلول‌های هیپوکامپ در موش‌های دارای ام‌اس داشته باشد و موجب بقای سلول‌های هیپوکامپ شود.

کلیدواژه‌ها

موضوعات


عنوان مقاله [English]

The effect of six weeks of voluntary swimming on the content of GSK3β, mTOR, and caspase-3 proteins in rats with cuprizone-induced multiple sclerosis

نویسندگان [English]

  • Mohammad Kahvazi zadeh
  • Abdolhamid Habibi
  • Mohammad Rami
Department of Sport Physiology, Faculty of Sport Sciences, Shahid Chamran University of Ahvaz, Ahvaz, Iran
چکیده [English]

Background and Purpose: Multiple sclerosis (MS) is a chronic, inflammatory, and autoimmune disease with multifactorial origins that significantly reduces patients' quality of life by impairing physical and cognitive functions. Physical activity has been shown to exert anti-inflammatory effects and neuroprotective actions, which may benefit MS patients by mitigating neural degeneration, particularly axonal damage. In the hippocampus, signaling pathways involving glycogen synthase kinase-3 beta (GSK3β), mechanistic target of rapamycin (mTOR), and caspase-3 play key roles in regulating cellular survival, apoptosis, proliferation, and metabolic homeostasis. Given the importance of these pathways, the current study aimed to investigate the effects of voluntary swimming exercise on the expression levels of GSK3β, mTOR, and caspase-3 proteins in the hippocampal tissue of male rats with cuprizone-induced MS.
Materials and Methods : Twenty-one male Wistar rats (average age 12 weeks; weight, 225 ± 16 g) were randomly assigned to three groups: healthy control, MS control, and MS plus exercise. MS was induced by feeding a diet containing 0.5% cuprizone for 12 weeks. Disease induction was confirmed using the rotarod performance test. Following MS confirmation, the exercise group underwent a six-week voluntary swimming training protocol. In the first week, rats swam for 10 minutes without added weight, and the swimming duration was increased by 5 minutes weekly, for the first 4 weeks. During weeks five and six, the duration was maintained at 30 minutes to ensure adaptation and avoid overtraining. After completion of the protocol, behavioral assessments were repeated, hippocampal tissues were extracted, and protein levels of GSK3β, mTOR, and caspase-3 were analyzed by using Western blotting. Statistical analysis was performed using one-way ANOVA followed by Tukey’s post-hoc test.
Results: A significant increase in GSK3β and caspase-3 protein levels was observed in the MS control group compared to the healthy group (p=0.001), indicating enhanced apoptotic signaling. Conversely, mTOR expression was significantly reduced in MS rats (p=0.001). Importantly, after six weeks of swimming, levels of GSK3β and caspase-3 were significantly decreased (p<0.001), while mTOR expression increased significantly in the exercise group compared to MS controls (p<0.001).
Conclusion: The results of this study suggest that swimming exercise leads to beneficial molecular adaptations in the hippocampus of MS-affected rats. These include the suppression of apoptosis-related proteins and enhancement of pro-survival signaling, which may contribute to hippocampal cell preservation. Therefore, voluntary swimming could serve as a promising non-pharmacological intervention to support neuronal health in MS.

کلیدواژه‌ها [English]

  • GSK3β
  • mTOR
  • caspase-3
  • multiple sclerosis
  • physical activity
  1. Gentile A, Musella A, De Vito F, Rizzo FR, Fresegna D, Bullitta S, et al. Immunomodulatory Effects of Exercise in Experimental Multiple Sclerosis. Front Immunol. 2019;10:2197 https://doi.org/10.3389/fimmu.2019.02197
  2. Maciak K, Dziedzic A, Saluk J. Remyelination in multiple sclerosis from the miRNA perspective. Front Mol Neurosci. 2023;16:1199313. https://doi.org/10.3389/fnmol.2023.1199313
  3. Voskuhl RR, MacKenzie-Graham A. Chronic experimental autoimmune encephalomyelitis is an excellent model to study neuroaxonal degeneration in multiple sclerosis. Front Mol Neurosci. 2022;15:1024058. https://doi.org/10.3389/fnmol.2022.1024058
  4. Klaren RE, Stasula U, Steelman AJ, Hernandez J, Pence BD, Woods JA, et al. Effects of exercise in a relapsing‐remitting model of experimental autoimmune encephalomyelitis. J Neurosci Res. 2016;94(10):907–14. https://doi.org/10.1002/jnr.23783
  5. Rumrill Jr PD. Multiple sclerosis: Medical and psychosocial aspects, etiology, incidence, and prevalence. J Vocat Rehabil. 2009;31(2):75–82. https://doi.org/10.3233/JVR-2009-476
  6. Noseworthy JH. Progress in determining the causes and treatment of multiple sclerosis. Nature. 1999;399(SUPPL.):A40–7. https://doi.org/10.1038/399a040
  7. Miller DH, Barkhof F, Frank JA, Parker GJM, Thompson AJ. Measurement of atrophy in multiple sclerosis: Pathological basis, methodological aspects and clinical relevance. Brain. 2002;125(8):1676–95. https://doi.org/10.1093/brain/awf177
  8. Llorens-Martín M, Jurado J, Hernández F, Ávila J. GSK-3β, a pivotal kinase in Alzheimer disease. Front Mol Neurosci. 2014;7(MAY):46. https://doi.org/10.3389/fnmol.2014.00046
  9. Takeuchi C, Yamagata K, Takemiya T. Variation in experimental autoimmune encephalomyelitis scores in a mouse model of multiple sclerosis. World J Neurol. 2013;3(3):56. http://dx.doi.org/10.5316/wjn.v3.i3.56
  10. Ghaffari S, Nemati HH, Dehghan G. Protective effect of short-term administration of ethanolic saffron extract on improvement of cognitive deficits and decrement of lipid peroxidation induced by ethidium bromide in experimental models of MS. Physiol Pharmacol. 2013;17(3):315–27. [In Persian]. http://ppj.phypha.ir/article-1-930-en.html
  11. Joseph OA, Afeez OJ, Michael A, Omotuyi OI. Molecular docking based screening analysis of GSK3B. Bioinformation. 2019;15(3):201–8. https://doi.org/10.6026/97320630015201
  12. Muyllaert D, Kremer A, Jaworski T, Borghgraef P, Devijver H, Croes S, et al. Glycogen synthase kinase-3β, or a link between amyloid and tau pathology? Genes, Brain Behav. 2008;7(SUPPL. 1):57–66. https://doi.org/10.1111/j.1601-183X.2007.00376.x
  13. Cohen P, Goedert M. GSK3 inhibitors: Development and therapeutic potential. Nat Rev Drug Discov. 2004;3(6):479–87. https://doi.org/10.1038/nrd1415
  14. Coyle-Rink J, Del Valle L, Sweet T, Khalili K, Amini S. Developmental expression of Wnt signaling factors in mouse brain. Cancer Biol Ther. 2002;1(6):640–5. https://doi.org/10.4161/cbt.313
  15. Ye P, Hu Q, Liu H, Yan Y, D’Ercole AJ. β-catenin mediates insulin-like growth factor-I actions to promote cyclin D1 mRNA expression, cell proliferation and survival in oligodendroglial cultures. Glia. 2010;58(9):1031–41. https://doi.org/10.1002/glia.20984
  16. Salcedo-Tello P, Ortiz-Matamoros A, Arias C. GSK3 function in the brain during development, neuronal plasticity, and neurodegeneration. Int J Alzheimers Dis. 2011;2011(1):189728. https://doi.org/10.4061/2011/189728
  17. Busceti CL, Biagioni F, Aronica E, Riozzi B, Storto M, Battaglia G, et al. Induction of the Wnt inhibitor, Dickkopf-1, is associated with neurodegeneration related to temporal lobe epilepsy. Epilepsia. 2007;48(4):694–705. https://doi.org/10.1111/j.1528-1167.2007.01055.x
  18. Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. Elsevier; 2017;168(6):960–76. https://doi.org/10.1016/j.cell.2017.02.004
  19. Zhang Y, Huang B, Wang H-Y, Chang A, Zheng XFS. Emerging role of microRNAs in mTOR signaling. Cell Mol Life Sci. Springer; 2017;74(14):2613–25. https://doi.org/10.1007/s00018-017-2485-1
  20. Chong ZZ, Maiese K. Mammalian target of rapamycin signaling in diabetic cardiovascular disease. Cardiovasc Diabetol. Springer; 2012;11(1):1–8. https://doi.org/10.1074/jbc.M113.521062
  21. McKenzie BA, Fernandes JP, Doan MAL, Schmitt LM, Branton WG, Power C. Activation of the executioner caspases-3 and-7 promotes microglial pyroptosis in models of multiple sclerosis. J Neuroinflammation. 2020;17(1):1–25. https://doi.org/10.1186/s12974-020-01902-5
  22. Zhang, J., Chen, Y., Yin, D., Feng, F., An, Q., Liu, Z., ... & Hu, X. (2021). Caspase-3/NLRP3 signaling in the mesenchymal stromal niche regulates myeloid-biased hematopoiesis. Stem Cell Research & Therapy, 12, 1-16. https://doi.org/10.1186/s13287-021-02640-y
  23. Rezaee, N., Rahmani-Nia, F., Delfan, M., & Ghahremani, R. (2022). The effect of aerobic training and probiotic supplementation on blood glucose levels and caspase-3 gene expression in skeletal muscle of streptozotocin-induced diabetic rats. Journal of Practical Studies of Biosciences in Sport, 10(23), 8-18. [In Persian]. https://doi.org/10.22077/jpsbs.2021.4589.1662
  24. Hajivand M, Fathi M, Karaji ZG, Rezaei R. the effect of swimming training on the expression of caspase 1 and AIM2 protein in Hippocampus male wistar rats. J Arak Univ Med Sci. 2024;26(6):0. [In Persian]. http://dx.doi.org/10.61186/jams.26.6.61
  25. Ma Z, Qi J, Meng S, Wen B, Zhang J. Swimming exercise training-induced left ventricular hypertrophy involves microRNAs and synergistic regulation of the PI3K/AKT/mTOR signaling pathway. Eur J Appl Physiol. 2023;113:2473–86. https://doi.org/10.1007/s00421-013-2685-9
  26. Greer JM, Trifilieff E, Pender MP. Correlation Between Anti-Myelin Proteolipid Protein (PLP) Antibodies and Disease Severity in Multiple Sclerosis Patients With PLP Response-Permissive HLA Types. Front Immunol. 2020;11:1891. https://doi.org/10.3389/fimmu.2020.01891
  27. Guo LY, Lozinski B, Yong VW. Exercise in multiple sclerosis and its models: Focus on the central nervous system outcomes. J Neurosci Res. 2020;98(3):509–23. https://doi.org/10.1002/jnr.24524
  28. Campbell E, Coulter EH, Paul L. High intensity interval training for people with multiple sclerosis: A systematic review. Mult Scler Relat Disord. 2018;24:55–63. https://doi.org/10.1016/j.msard.2018.06.005
  29. Bernardes D, Oliveira-Lima OC, da Silva TV, Faraco CCF, 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. https://doi.org/10.1016/j.jneuroim.2013.08.014
  30. Jadidi, D., Seifi, F., Bolboli, L., Pourrahim, A. (2021). The Effect of High-Intensity Interval Training on Gene Expression of Heat Shock Protein 70 and Caspase-3 in Cardiomyocytes of Male Rats Model of Myocardial Infarction. Journal of Applied Health Studies in Exercise Physiology, 2022; 9(2): 1-11. doi: 10.22049/jahssp.2021.27521.1407. [In Persian]. https://doi.org/10.22049/jahssp.2021.27521.1407
  31. Bazyar F, Shabani R, Elmiyeh A. The Effects of Endurance Training and Saffron Extract on the Expression of Bax, Bcl-2, and Caspase-3 Genes in the Hippocampal Tissue of Alzheimer's Male Rats. J Jiroft Univ Med Sci 2023; 9 (4) :1151-1159. URL: http://journal.jmu.ac.ir/article-1-680-fa.html. [In Persian]. https://dor.isc.ac/dor/20.1001.1.25382810.1401.9.4.7.9
  32. Yang L, Zhang Y, Li C, Wei C. Effects of aerobic exercise on the expression of Notch1 and Caspase-3 in the hippocampus of Alzheimer’s disease mice. Chinese Journal of Tissue Engineering Research. 2024 Sep 18;28(26):4113.
  33. Hamidi, F., Sadeghipour, H. R., Zar, Abdolsaleh, R., Ranjbar, R. (2021). Gene Pathway Changes of TSC2(RAGs)/mTOR/4E-BPs in Male Rats Following a Period of Resistance Training and Spirulina Plantesis Supplementation. Sport Physiology, 2024; 16(61): 31-46. doi: 10.22089/spj.2024.16068.2291. [In Persian]. https://doi.org/10.22089/spj.2024.16068.2291
  34. Izadimanesh, F., Haghighi, A.H., Hosseini Kakhk, S. A., Asadi Shekari, M., Marefati, H. (2021). The Effect of Moderate Intensity TED Omi Training on the Expression of C/EBPβ and mTOR Genes Associated with Autophagy in the Prefrontal Cortex of METH-Dependent Rats. Journal of Applied Studies in Sport Sciences in Sport, 2024; 12(31): 8-19. doi: 10.22077/jpsbs.2024.6397.1795. [In Persian]. https://doi.org/10.22077/jpsbs.2024.6397.1795
  35. Hu M, Han M, Zhang H, Li Z, Xu K, Kang H, Zong J, Zhao F, Liu Y, Liu W. Curcumin (CUMINUP60®) mitigates exercise fatigue through regulating PI3K/Akt/AMPK/mTOR pathway in mice. Aging (Albany NY). 2023 Mar 28;15(6):2308. https://doi.org/10.18632/aging.204614
  36. Alinezhad H, Abbasi A, Farzanegi P, Abdi A. Effect of Hyaluronic Acid Injection and Aerobic Exercise on the Expression of β-catenin and GSK-3β Genes in Heart Tissue of Rats in the Experimental Model of Knee Osteoarthritis. Paramedical Sciences and Military Health 2021; 16 (2) :1-10. URL: http://jps.ajaums.ac.ir/article-1-282-fa.html. [In Persian].
  37. Turkistani, A., Al-Kuraishy, H. M., Al-Gareeb, A. I., Albuhadily, A. K., Alexiou, A., Papadakis, M., ... & Batiha, G. E. S. (2024). Therapeutic potential effect of glycogen synthase kinase 3 beta (GSK-3β) inhibitors in Parkinson disease: exploring an overlooked avenue. Molecular Neurobiology, 61(9), 7092-7108. https://doi.org/10.1007/s12035-024-04003-z
  38. Vakrakou, A. G., Alexaki, A., Brinia, M. E., Anagnostouli, M., Stefanis, L., & Stathopoulos, P. (2022). The mTOR signaling pathway in multiple sclerosis; from animal models to human data. International journal of molecular sciences, 23(15), 8077. https://doi.org/10.3390/ijms23158077
  39. Pupyshev AB, Belichenko VM, Tenditnik MV, Bashirzade AA, Dubrovina NI, Ovsyukova MV, Akopyan AA, Fedoseeva LA, Korolenko TA, Amstislavskaya TG, Tikhonova MA. Combined induction of mTOR-dependent and mTOR-independent pathways of autophagy activation as an experimental therapy for Alzheimer's disease-like pathology in a mouse model. Pharmacology Biochemistry and Behavior. 2022 Jun 1;217:173406. https://doi.org/10.1016/j.pbb.2022.173406
  40. Mammana, S., Bramanti, P., Mazzon, E., Cavalli, E., Basile, M. S., Fagone, P., ... & Mangano, K. (2018). Preclinical evaluation of the PI3K/Akt/mTOR pathway in animal models of multiple sclerosis. Oncotarget, 9(9), 8263. https://doi.org/10.18632/oncotarget.23862
  41. Ke H, Wang X, Zhou Z, Ai W, Wu Z, Zhang Y. Effect of weimaining on apoptosis and Caspase-3 expression in a breast cancer mouse model. Journal of Ethnopharmacology. 2021 Jan 10;264:113363. https://doi.org/10.1016/j.jep.2020.113363
  42. Dou, H., Yu, P. Y., Liu, Y. Q., Zhu, Y., Li, F. C., Wang, Y. Y., ... & Xiao, M. (2024). Recent advances in caspase-3, breast cancer, and traditional Chinese medicine: a review. Journal of Chemotherapy, 36(5), 370-388. https://doi.org/10.1080/1120009X.2023.2278014
  43. Kim JY, Yi ES, Lee H, Kim JS, Jee YS, Kim SE, et al. Swimming exercise ameliorates symptoms of MOG-induced experimental autoimmune encephalomyelitis by inhibiting inflammation and demyelination in rats. Int Neurourol J. 2020;24(Suppl 1):S39. https://doi.org/10.5213/inj.2040156.078
  44. Muller HB, Scholl G, Far J, De Pauw E, Eppe G. Sliding windows in ion mobility (SWIM): a new approach to increase the resolving power in trapped ion mobility-mass spectrometry hyphenated with chromatography. Analytical Chemistry. 2023 Nov 17;95(48):17586-94. https://doi.org/10.1021/acs.analchem.3c03039
  45. Hajivand M, Fathi M, Karaji ZG, Rezaei R. the effect of swimming training on the expression of caspase 1 and AIM2 protein in Hippocampus male wistar rats. Journal of Arak University of Medical Sciences. 2024 Feb 10;26(6):0-12. [In Persian]. http://dx.doi.org/10.61186/jams.26.6.61
  46. Önel, T., Arıcıoğlu, F., Yıldırım, E., Zortul, H., & Yaba, A. (2023). The effect of maternal separation stress-induced depression on ovarian reserve in Sprague Dawley Rats: The possible role of imipramine and agmatine through a mTOR signal pathway. Physiology & Behavior, 269, 114270. https://doi.org/10.1016/j.physbeh.2023.114270
  47. Zhan J, Mann T, Joost S, Behrangi N, Frank M, Kipp M. The cuprizone model: dos and do nots. Cells 9: 843. 2020. https://doi.org/10.3390/cells9040843
  48. Saxton, R. A., & Sabatini, D. M. (2017). mTOR signaling in growth, metabolism, and disease. Cell, 168(6), 960-976. https://doi.org/10.1016/j.cell.2017.02.004
  49. Jope, R. S., & Johnson, G. V. (2004). The glamour and gloom of glycogen synthase kinase-3. Trends in Biochemical Sciences, 29(2), 95–102. https://doi.org/10.1016/j.tibs.2003.12.004
  50. Li, X., Alafuzoff, I., Soininen, H., Winblad, B., & Pei, J. J. (2020). Levels of mTOR and its downstream targets 4E-BP1, eIF4E, and p70S6K in the Alzheimer’s disease brain. Journal of Alzheimer’s Disease, 77(1), 47–57. https://doi.org/10.3233/JAD-200203
  51. Leem, Y. H., Lee, Y. I., Son, H. J., & Kim, Y. K. (2019). Chronic exercise ameliorates the neuroinflammation in mice carrying human Alzheimer’s mutant APP/PS1 genes via the reduction of TNF-α and activation of Akt pathway. Experimental Gerontology, 116, 25–32. https://doi.org/10.1016/j.exger.2018.12.006
  52. Hou, Y., Dan, X., Babbar, M., Wei, Y., Hasselbalch, S. G., Croteau, D. L., & Bohr, V. A. (2019). Ageing as a risk factor for neurodegenerative disease. Nature Reviews Neurology, 15(10), 565–581. https://doi.org/10.1038/s41582-019-0244-7
  53. Ye JN, Chen XS, Su L, Liu YL, Cai QY,Zhan XL, et al. Progesterone alleviates neural behavioral deficits and demyelination with reduced degeneration of oligodendroglial cells in cuprizone-induced mice. PLoS One. 2013;8(1):e54590. https://doi.org/10.1371/journal.pone.0054590
  54. Lubrich C, Giesler P, Kipp M. Motor Behavioral Deficits in the Cuprizone Model: Validity of the Rotarod Test Paradigm. Int J Mol Sci. 2022;23(19). https://doi.org/10.3390/ijms231911342
  55. Ghotbeddin Z, Khazaeel K, Tabandeh M-R, Aliheydari M, Yaghobi H. Effects of Omega-3 Fatty acid supplementation during chronic maternal hypoxia on behavioral disorders in male rat offspring2022. https://doi.org/10.1007/s11011-022-01012-6
  56. Zimmermann J, Emrich M, Krauthausen M,Saxe S, Nitsch L, Heneka MT, et al. IL-17A promotes granulocyte infiltration, myelin loss, microglia activation, and behavioral deficits during cuprizone-induced demyelination. Molecular neurobiology.2018;55:946-57. https://doi.org/10.1007/s12035-016-0368-3

57. Dobson R, Giovannoni G. Multiple sclerosis–a review. European journal of neurology. 2019;26(1):27-40. https://doi.org/10.1111/ene.13819

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