Does exercise have a neuroprotective function in multiple sclerosis? A brief overview of the physical training potential effects on cytokines and brain-derived neurotrophic factor

David Barbado Murillo, Ramón Gómez-Illán, Pedro Moreno, Nuria Mendoza, Raul Reina Vaillo, Angel P. Sempere


Although the advance in disease-modifying drugs has helped to stabilize the multiple sclerosis (MS) course increasing life-expectancy, physical deterioration still supervenes over time in most MS patients. In this context, physical exercise programs are considered a safe and well-tolerated tool to preserve functional independence in this population, which not only provides similar fitness improvements as usually observed in healthy general population, but it may also ameliorate some of the symptoms that this pathology entails (as fatigue, balance deficits, muscle weakness, etc.). Nowadays, the question is if exercise only aids to reverse physical deconditioning associated to the disease or it has the potential to have an impact on MS progression. In the present overview, the role of exercise as complementary therapy for modulating various physiopathological pathways related to MS disease such as inflammation and the neurotrophic support for neuronal survival was revised. Specifically, the exercise ability to modulate the immune system behaviour regulating the pro- and anti-inflammatory cytokine balance, as well as, to promote neuroprotective and neurorestorative mechanisms through the brain-derived neurotrophic factor stimulation was analysed.

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Aidar, F. J., Carneiro, A. L., Costa Moreira, O., Patrocinio de Oliveira, C. E., Garrido, N. D., Machado Reis, V., . . . & Gama de Matos, D. (2018). Effects of resistance training on the physical condition of people with multiple sclerosis. The Journal of Sports Medicine and Physical Fitness, 58(7-8), 1127-1134. doi: 10.23736/S0022-4707.17.07621-6.

Alexander, W. S. (2002). Suppressors of cytokine signalling (SOCS) in the immune system. Nature Reviews. Immunology, 2(6), 410-416. doi: 10.1038/nri818.

Alsina, B., Vu, T., & Cohen-Cory, S. (2001). Visualizing synapse formation in arborizing optic axons in vivo: dynamics and modulation by BDNF. Nature Neuroscience, 4(11), 1093-1101. doi: 10.1038/nn735.

Azoulay, D., Urshansky, N., & Karni, A. (2008). Low and dysregulated BDNF secretion from immune cells of MS patients is related to reduced neuroprotection. Journal of Neuroimmunology, 195(1-2), 186-193. doi: 10.1016/j.jneuroim.2008.01.010.

Azoulay, D., Vachapova, V., Shihman, B., Miler, A., & Karni, A. (2005). Lower brain-derived neurotrophic factor in serum of relapsing remitting MS: reversal by glatiramer acetate. Journal of Neuroimmunology, 167(1-2), 215-218. doi: 10.1016/j.jneuroim.2005.07.001.

Baecher-Allan, C., Kaskow, B. J., & Weiner, H. L. (2018). Multiple Sclerosis: Mechanisms and Immunotherapy. Neuron, 97(4), 742-768. doi: 10.1016/j.neuron.2018.01.021.

Barde, Y. A. (1994). Neurotrophins: a family of proteins supporting the survival of neurons. Progress in Clinical and Biological Research, 390, 45-56.

Begni, V., Riva, M. A., & Cattaneo, A. (2017). Cellular and molecular mechanisms of the brain-derived neurotrophic factor in physiological and pathological conditions. Clinical Science, 131(2), 123-138. doi: 10.1042/CS20160009.

Bergmann, M., Gornikiewicz, A., Sautner, T., Waldmann, E., Weber, T., Mittlbock, M., . . . & Fugger, R. (1999). Attenuation of catecholamine-induced immunosuppression in whole blood from patients with sepsis. Shock, 12(6), 421-427.

Bevan, R. J., Evans, R., Griffiths, L., Watkins, L. M., Rees, M. I., Magliozzi, R., . . . & Howell, O. W. (2018). Meningeal Inflammation and Cortical Demyelination in Acute Multiple Sclerosis. Annals of Neurology. doi: 10.1002/ana.25365.

Bilski, J., Mazur-Bialy, A., Brzozowski, B., Magierowski, M., Zahradnik-Bilska, J., Wojcik, D., . . . & Brzozowski, T. (2016). Can exercise affect the course of inflammatory bowel disease? Experimental and clinical evidence. Pharmacological Reports, 68(4), 827-836. doi: 10.1016/j.pharep.2016.04.009.

Brandt, C., & Pedersen, B. K. (2010). The role of exercise-induced myokines in muscle homeostasis and the defense against chronic diseases. Journal of Biomedicine & Biotechnology, 2010, 520258. doi: 10.1155/2010/520258.

Calabrese, M., Atzori, M., Bernardi, V., Morra, A., Romualdi, C., Rinaldi, L., . . . & Gallo, P. (2007). Cortical atrophy is relevant in multiple sclerosis at clinical onset. Journal of Neurology, 254(9), 1212-1220. doi: 10.1007/s00415-006-0503-6.

Caspersen, C. J., Powell, K. E., & Christenson, G. M. (1985). Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research. Public Health Reports, 100(2), 126-131.

Ceni, C., Unsain, N., Zeinieh, M. P., & Barker, P. A. (2014). Neurotrophins in the regulation of cellular survival and death. Handbook of Experimental Pharmacology, 220, 193-221. doi: 10.1007/978-3-642-45106-5_8.

Ciccarelli, O., Barkhof, F., Bodini, B., De Stefano, N., Golay, X., Nicolay, K., . . . & Miller, D. H. (2014). Pathogenesis of multiple sclerosis: insights from molecular and metabolic imaging. Lancet Neurology, 13(8), 807-822. doi: 10.1016/S1474-4422(14)70101-2.

Colcombe, S. J., Erickson, K. I., Raz, N., Webb, A. G., Cohen, N. J., McAuley, E., & Kramer, A. F. (2003). Aerobic fitness reduces brain tissue loss in aging humans. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 58(2), 176-180.

Colcombe, S. J., Erickson, K. I., Scalf, P. E., Kim, J. S., Prakash, R., McAuley, E., . . . & Kramer, A. F. (2006). Aerobic exercise training increases brain volume in aging humans. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 61(11), 1166-1170.

Compston, A., & Coles, A. (2008). Multiple sclerosis. Lancet, 372(9648), 1502-1517. doi: 10.1016/S0140-6736(08)61620-7.

Craig, J., Young, C. A., Ennis, M., Baker, G., & Boggild, M. (2003). A randomised controlled trial comparing rehabilitation against standard therapy in multiple sclerosis patients receiving intravenous steroid treatment. Journal of Neurology, Neurosurgery, and Psychiatry, 74(9), 1225-1230.

Cruickshank, T. M., Reyes, A. R., & Ziman, M. R. (2015). A systematic review and meta-analysis of strength training in individuals with multiple sclerosis or Parkinson disease. Medicine, 94(4), e411. doi: 10.1097/MD.0000000000000411.

Chaddock-Heyman, L., Erickson, K. I., Holtrop, J. L., Voss, M. W., Pontifex, M. B., Raine, L. B., . . . & Kramer, A. F. (2014). Aerobic fitness is associated with greater white matter integrity in children. Frontiers in Human Neuroscience, 8, 584. doi: 10.3389/fnhum.2014.00584.

Dalgas, U. (2011). Rehabilitation and multiple sclerosis: hot topics in the preservation of physical functioning. Journal of the Neurological Sciences, 311 Suppl 1, S43-47. doi: 10.1016/S0022-510X(11)70008-9.

Dalgas, U., & Stenager, E. (2012). Exercise and disease progression in multiple sclerosis: can exercise slow down the progression of multiple sclerosis? Therapeutic Advances in Neurological Disorders, 5(2), 81-95. doi: 10.1177/1756285611430719.

Dalgas, U., Stenager, E., & Ingemann-Hansen, T. (2008). Multiple sclerosis and physical exercise: recommendations for the application of resistance-, endurance- and combined training. Multiple Sclerosis, 14(1), 35-53. doi: 10.1177/1352458507079445.

De Stefano, N., Airas, L., Grigoriadis, N., Mattle, H. P., O'Riordan, J., Oreja-Guevara, C., . . . & Kieseier, B. C. (2014). Clinical relevance of brain volume measures in multiple sclerosis. CNS Drugs, 28(2), 147-156. doi: 10.1007/s40263-014-0140-z.

De Stefano, N., Giorgio, A., Battaglini, M., Rovaris, M., Sormani, M. P., Barkhof, F., . . . & Filippi, M. (2010). Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology, 74(23), 1868-1876. doi: 10.1212/WNL.0b013e3181e24136.

de Vries, J. E. (1995). Immunosuppressive and anti-inflammatory properties of interleukin 10. Annals of Medicine, 27(5), 537-541. doi: 10.3109/07853899509002465.

Deckx, N., Wens, I., Nuyts, A. H., Hens, N., De Winter, B. Y., Koppen, G., . . . & Cools, N. (2016). 12 Weeks of Combined Endurance and Resistance Training Reduces Innate Markers of Inflammation in a Randomized Controlled Clinical Trial in Patients with Multiple Sclerosis. Mediators of Inflammation, 2016, 6789276. doi: 10.1155/2016/6789276.

Dinoff, A., Herrmann, N., Swardfager, W., Liu, C. S., Sherman, C., Chan, S., & Lanctot, K. L. (2016). The Effect of Exercise Training on Resting Concentrations of Peripheral Brain-Derived Neurotrophic Factor (BDNF): A Meta-Analysis. PloS One, 11(9), e0163037. doi: 10.1371/journal.pone.0163037.

Driscoll, I., Martin, B., An, Y., Maudsley, S., Ferrucci, L., Mattson, M. P., & Resnick, S. M. (2012). Plasma BDNF is associated with age-related white matter atrophy but not with cognitive function in older, non-demented adults. PloS One, 7(4), e35217. doi: 10.1371/journal.pone.0035217.

Ebadi, M., Bashir, R. M., Heidrick, M. L., Hamada, F. M., Refaey, H. E., Hamed, A., . . . & Lassi, N. K. (1997). Neurotrophins and their receptors in nerve injury and repair. Neurochemistry International, 30(4-5), 347-374.

Elenkov, I. J., & Chrousos, G. P. (1999). Stress Hormones, Th1/Th2 patterns, Pro/Anti-inflammatory Cytokines and Susceptibility to Disease. Trends in Endocrinology and Metabolism, 10(9), 359-368.

Erickson, K. I., Leckie, R. L., & Weinstein, A. M. (2014). Physical activity, fitness, and gray matter volume. Neurobiology of Aging, 35 Suppl 2, S20-28. doi: 10.1016/j.neurobiolaging.2014.03.034.

Erickson, K. I., Prakash, R. S., Voss, M. W., Chaddock, L., Heo, S., McLaren, M., . . . & Kramer, A. F. (2010). Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience, 30(15), 5368-5375. doi: 10.1523/JNEUROSCI.6251-09.2010.

Erickson, K. I., Prakash, R. S., Voss, M. W., Chaddock, L., Hu, L., Morris, K. S., . . . & Kramer, A. F. (2009). Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus, 19(10), 1030-1039. doi: 10.1002/hipo.20547.

Erickson, K. I., Raji, C. A., Lopez, O. L., Becker, J. T., Rosano, C., Newman, A. B., . . . & Kuller, L. H. (2010). Physical activity predicts gray matter volume in late adulthood: the Cardiovascular Health Study. Neurology, 75(16), 1415-1422. doi: 10.1212/WNL.0b013e3181f88359.

Erickson, K. I., Voss, M. W., Prakash, R. S., Basak, C., Szabo, A., Chaddock, L., . . . & Kramer, A. F. (2011). Exercise training increases size of hippocampus and improves memory. Proceedings of the National Academy of Sciences of the United States of America, 108(7), 3017-3022. doi: 10.1073/pnas.1015950108.

Fang, Z. H., Lee, C. H., Seo, M. K., Cho, H., Lee, J. G., Lee, B. J., . . . & Kim, Y. H. (2013). Effect of treadmill exercise on the BDNF-mediated pathway in the hippocampus of stressed rats. Neuroscience Research, 76(4), 187-194. doi: 10.1016/j.neures.2013.04.005.

Fernandez, O., Fernandez, V., Guerrero, M., Leon, A., Lopez-Madrona, J. C., Alonso, A., . . . & de Ramon, E. (2012). Multiple sclerosis prevalence in Malaga, Southern Spain estimated by the capture-recapture method. Multiple Sclerosis, 18(3), 372-376. doi: 10.1177/1352458511421917.

Ferrer, I., Goutan, E., Marin, C., Rey, M. J., & Ribalta, T. (2000). Brain-derived neurotrophic factor in Huntington disease. Brain Research, 866(1-2), 257-261.

Ferris, L. T., Williams, J. S., & Shen, C. L. (2007). The effect of acute exercise on serum brain-derived neurotrophic factor levels and cognitive function. Medicine and Science in Sports and Exercise, 39(4), 728-734. doi: 10.1249/mss.0b013e31802f04c7.

Feys, P., Moumdjian, L., Van Halewyck, F., Wens, I., Eijnde, B. O., Van Wijmeersch, B., . . . & Van Asch, P. (2017). Effects of an individual 12-week community-located "start-to-run" program on physical capacity, walking, fatigue, cognitive function, brain volumes, and structures in persons with multiple sclerosis. Multiple Sclerosis, 1352458517740211. doi: 10.1177/1352458517740211.

Filippini, G., Del Giovane, C., Vacchi, L., D'Amico, R., Di Pietrantonj, C., Beecher, D., & Salanti, G. (2013). Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis. The Cochrane Database of Systematic Reviews(6), CD008933. doi: 10.1002/14651858.CD008933.pub2.

Fisniku, L. K., Chard, D. T., Jackson, J. S., Anderson, V. M., Altmann, D. R., Miszkiel, K. A., . . . & Miller, D. H. (2008). Gray matter atrophy is related to long-term disability in multiple sclerosis. Annals of Neurology, 64(3), 247-254. doi: 10.1002/ana.21423.

Floel, A., Ruscheweyh, R., Kruger, K., Willemer, C., Winter, B., Volker, K., . . . & Knecht, S. (2010). Physical activity and memory functions: are neurotrophins and cerebral gray matter volume the missing link? NeuroImage, 49(3), 2756-2763. doi: 10.1016/j.neuroimage.2009.10.043.

Frota, E. R., Rodrigues, D. H., Donadi, E. A., Brum, D. G., Maciel, D. R., & Teixeira, A. L. (2009). Increased plasma levels of brain derived neurotrophic factor (BDNF) after multiple sclerosis relapse. Neuroscience Letters, 460(2), 130-132. doi: 10.1016/j.neulet.2009.05.057.

Gandhi, R., Laroni, A., & Weiner, H. L. (2010). Role of the innate immune system in the pathogenesis of multiple sclerosis. Journal of Neuroimmunology, 221(1-2), 7-14. doi: 10.1016/j.jneuroim.2009.10.015.

Garg, N., & Smith, T. W. (2015). An update on immunopathogenesis, diagnosis, and treatment of multiple sclerosis. Brain and Behavior, 5(9), e00362. doi: 10.1002/brb3.362.

Giesser, B. S. (2015). Exercise in the management of persons with multiple sclerosis. Therapeutic Advances in Neurological Disorders, 8(3), 123-130. doi: 10.1177/1756285615576663.

Gleeson, M. (2007). Immune function in sport and exercise. Journal of Applied Physiology, 103(2), 693-699. doi: 10.1152/japplphysiol.00008.2007.

Gleeson, M., Bishop, N. C., Stensel, D. J., Lindley, M. R., Mastana, S. S., & Nimmo, M. A. (2011). The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nature Reviews. Immunology, 11(9), 607-615. doi: 10.1038/nri3041.

Gokhale, R., Chandrashekara, S., & Vasanthakumar, K. C. (2007). Cytokine response to strenuous exercise in athletes and non-athletes--an adaptive response. Cytokine, 40(2), 123-127. doi: 10.1016/j.cyto.2007.08.006.

Golzari, Z., Shabkhiz, F., Soudi, S., Kordi, M. R., & Hashemi, S. M. (2010). Combined exercise training reduces IFN-gamma and IL-17 levels in the plasma and the supernatant of peripheral blood mononuclear cells in women with multiple sclerosis. International Immunopharmacology, 10(11), 1415-1419. doi: 10.1016/j.intimp.2010.08.008.

Gustafsson, G., Lira, C. M., Johansson, J., Wisen, A., Wohlfart, B., Ekman, R., & Westrin, A. (2009). The acute response of plasma brain-derived neurotrophic factor as a result of exercise in major depressive disorder. Psychiatry Research, 169(3), 244-248. doi: 10.1016/j.psychres.2008.06.030.

Gustafsson, S., Liang, W., & Hilke, S. (2011). Effects of voluntary running in the female mice lateral septum on BDNF and corticotropin-releasing factor receptor 2. International Journal of Peptides, 2011, 932361. doi: 10.1155/2011/932361.

Halabchi, F., Alizadeh, Z., Sahraian, M. A., & Abolhasani, M. (2017). Exercise prescription for patients with multiple sclerosis; potential benefits and practical recommendations. BMC Neurology, 17(1), 185. doi: 10.1186/s12883-017-0960-9.

Hardmeier, M., Wagenpfeil, S., Freitag, P., Fisher, E., Rudick, R. A., Kooijmans, M., . . . & European, I. F. N. a. i. R. M. S. D. C. T. S. G. (2005). Rate of brain atrophy in relapsing MS decreases during treatment with IFNbeta-1a. Neurology, 64(2), 236-240. doi: 10.1212/01.WNL.0000149516.30155.B8.

Heine, M., van de Port, I., Rietberg, M. B., van Wegen, E. E., & Kwakkel, G. (2015). Exercise therapy for fatigue in multiple sclerosis. The Cochrane Database of Systematic Reviews(9), CD009956. doi: 10.1002/14651858.CD009956.pub2.

Hirsch, M. A., van Wegen, E. E. H., Newman, M. A., & Heyn, P. C. (2018). Exercise-induced increase in brain-derived neurotrophic factor in human Parkinson's disease: a systematic review and meta-analysis. Translational Neurodegeneration, 7, 7. doi: 10.1186/s40035-018-0112-1.

Hohlfeld, R. (1997). Biotechnological agents for the immunotherapy of multiple sclerosis. Principles, problems and perspectives. Brain, 120.5, 865-916.

Howells, D. W., Porritt, M. J., Wong, J. Y., Batchelor, P. E., Kalnins, R., Hughes, A. J., & Donnan, G. A. (2000). Reduced BDNF mRNA expression in the Parkinson's disease substantia nigra. Experimental Neurology, 166(1), 127-135. doi: 10.1006/exnr.2000.7483.

Huang, E. J., & Reichardt, L. F. (2001). Neurotrophins: roles in neuronal development and function. Annual Review of Neuroscience, 24, 677-736. doi: 10.1146/annurev.neuro.24.1.677.

Kebir, H., Kreymborg, K., Ifergan, I., Dodelet-Devillers, A., Cayrol, R., Bernard, M., . . . & Prat, A. (2007). Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nature Medicine, 13(10), 1173-1175. doi: 10.1038/nm1651.

Kelamangalath, L., & Smith, G. M. (2013). Neurotrophin treatment to promote regeneration after traumatic CNS injury. Frontiers in Biology, 8(5), 486-495. doi: 10.1007/s11515-013-1269-8.

Keller, C., Steensberg, A., Pilegaard, H., Osada, T., Saltin, B., Pedersen, B. K., & Neufer, P. D. (2001). Transcriptional activation of the IL-6 gene in human contracting skeletal muscle: influence of muscle glycogen content. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology, 15(14), 2748-2750. doi: 10.1096/fj.01-0507fje.

Kerschensteiner, M., Gallmeier, E., Behrens, L., Leal, V. V., Misgeld, T., Klinkert, W. E., . . . & Hohlfeld, R. (1999). Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? The Journal of Experimental Medicine, 189(5), 865-870.

Kierkegaard, M., Lundberg, I. E., Olsson, T., Johansson, S., Ygberg, S., Opava, C., . . . & Piehl, F. (2016). High-intensity resistance training in multiple sclerosis - An exploratory study of effects on immune markers in blood and cerebrospinal fluid, and on mood, fatigue, health-related quality of life, muscle strength, walking and cognition. Journal of the Neurological Sciences, 362, 251-257. doi: 10.1016/j.jns.2016.01.063.

Kjolhede, T., Siemonsen, S., Wenzel, D., Stellmann, J. P., Ringgaard, S., Pedersen, B. G., . . . & Dalgas, U. (2018). Can resistance training impact MRI outcomes in relapsing-remitting multiple sclerosis? Multiple Sclerosis, 24(10), 1356-1365. doi: 10.1177/1352458517722645.

Klaren, R. E., Hubbard, E. A., Motl, R. W., Pilutti, L. A., Wetter, N. C., & Sutton, B. P. (2015). Objectively Measured Physical Activity Is Associated with Brain Volumetric Measurements in Multiple Sclerosis. Behavioural Neurology, 2015, 482536. doi: 10.1155/2015/482536.

Knaepen, K., Goekint, M., Heyman, E. M., & Meeusen, R. (2010). Neuroplasticity - exercise-induced response of peripheral brain-derived neurotrophic factor: a systematic review of experimental studies in human subjects. Sports Medicine, 40(9), 765-801. doi: 10.2165/11534530-000000000-00000.

Koch-Henriksen, N., & Sorensen, P. S. (2010). The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol, 9(5), 520-532. doi: 10.1016/S1474-4422(10)70064-8.

Koo, J. H., Kwon, I. S., Kang, E. B., Lee, C. K., Lee, N. H., Kwon, M. G., . . . & Cho, J. Y. (2013). Neuroprotective effects of treadmill exercise on BDNF and PI3-K/Akt signaling pathway in the cortex of transgenic mice model of Alzheimer's disease. Journal of Exercise Nutrition & Biochemistry, 17(4), 151-160. doi: 10.5717/jenb.2013.17.4.151.

Kraszula, L., Jasinska, A., Eusebio, M., Kuna, P., Glabinski, A., & Pietruczuk, M. (2012). Evaluation of the relationship between leptin, resistin, adiponectin and natural regulatory T cells in relapsing-remitting multiple sclerosis. Neurologia i Neurochirurgia Polska , 46(1), 22-28.

Ksiazek-Winiarek, D. J., Szpakowski, P., & Glabinski, A. (2015). Neural Plasticity in Multiple Sclerosis: The Functional and Molecular Background. Neural Plasticity, 2015, 307175. doi: 10.1155/2015/307175.

Kutzelnigg, A., Lucchinetti, C. F., Stadelmann, C., Bruck, W., Rauschka, H., Bergmann, M., . . . & Lassmann, H. (2005). Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain, 128(Pt 11), 2705-2712. doi: 10.1093/brain/awh641.

Lancaster, G. I., Halson, S. L., Khan, Q., Drysdale, P., Wallace, F., Jeukendrup, A. E., . . . & Gleeson, M. (2004). Effects of acute exhaustive exercise and chronic exercise training on type 1 and type 2 T lymphocytes. Exercise Immunology Review, 10, 91-106.

Latimer-Cheung, A. E., Pilutti, L. A., Hicks, A. L., Martin Ginis, K. A., Fenuta, A. M., MacKibbon, K. A., & Motl, R. W. (2013). Effects of exercise training on fitness, mobility, fatigue, and health-related quality of life among adults with multiple sclerosis: a systematic review to inform guideline development. Archives of Physical Medicine and Rehabilitation, 94(9), 1800-1828. doi: 10.1016/j.apmr.2013.04.020.

Leal, L. G., Lopes, M. A., & Batista, M. L., Jr. (2018). Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases. Frontiers in Physiology, 9, 1307. doi: 10.3389/fphys.2018.01307.

Leavitt, V. M., Cirnigliaro, C., Cohen, A., Farag, A., Brooks, M., Wecht, J. M., . . . & Sumowski, J. F. (2014). Aerobic exercise increases hippocampal volume and improves memory in multiple sclerosis: preliminary findings. Neurocase, 20(6), 695-697. doi: 10.1080/13554794.2013.841951.

Lemus, H. N., Warrington, A. E., & Rodriguez, M. (2018). Multiple Sclerosis: Mechanisms of Disease and Strategies for Myelin and Axonal Repair. Neurologic Clinics, 36(1), 1-11. doi: 10.1016/j.ncl.2017.08.002.

Linker, R., Gold, R., & Luhder, F. (2009). Function of neurotrophic factors beyond the nervous system: inflammation and autoimmune demyelination. Critical Reviews in Immunology, 29(1), 43-68.

Liu, Y. F., Chen, H. I., Wu, C. L., Kuo, Y. M., Yu, L., Huang, A. M., . . . & Jen, C. J. (2009). Differential effects of treadmill running and wheel running on spatial or aversive learning and memory: roles of amygdalar brain-derived neurotrophic factor and synaptotagmin I. The Journal of Physiology, 587(Pt 13), 3221-3231. doi: 10.1113/jphysiol.2009.173088.

Loma, I., & Heyman, R. (2011). Multiple sclerosis: pathogenesis and treatment. Current Neuropharmacology, 9(3), 409-416. doi: 10.2174/157015911796557911.

Lucchinetti, C. F., Popescu, B. F., Bunyan, R. F., Moll, N. M., Roemer, S. F., Lassmann, H., . . . & Ransohoff, R. M. (2011). Inflammatory cortical demyelination in early multiple sclerosis. The New England Journal of Medicine, 365(23), 2188-2197. doi: 10.1056/NEJMoa1100648.

Luhder, F., Gold, R., Flugel, A., & Linker, R. A. (2013). Brain-derived neurotrophic factor in neuroimmunology: lessons learned from multiple sclerosis patients and experimental autoimmune encephalomyelitis models. Archivum Immunologiae et Therapiae Experimentalis, 61(2), 95-105. doi: 10.1007/s00005-012-0211-0.

Manna, A., Piras, F., Caltagirone, C., Bossu, P., Sensi, S. L., & Spalletta, G. (2015). Left hippocampus-amygdala complex macro- and microstructural variation is associated with BDNF plasma levels in healthy elderly individuals. Brain and Behavior, 5(7), e00334. doi: 10.1002/brb3.334.

Marais, L., Stein, D. J., & Daniels, W. M. (2009). Exercise increases BDNF levels in the striatum and decreases depressive-like behavior in chronically stressed rats. Metabolic Brain Disease, 24(4), 587-597. doi: 10.1007/s11011-009-9157-2.

Matarese, G., Procaccini, C., & De Rosa, V. (2008). The intricate interface between immune and metabolic regulation: a role for leptin in the pathogenesis of multiple sclerosis? Journal of Leukocyte Biology, 84(4), 893-899. doi: 10.1189/jlb.0108022.

Minagar, A., & Alexander, J. S. (2003). Blood-brain barrier disruption in multiple sclerosis. Multiple sclerosis, 9(6), 540-549. doi: 10.1191/1352458503ms965oa.

Minty, A., Chalon, P., Derocq, J. M., Dumont, X., Guillemot, J. C., Kaghad, M., . . . & Caput, D. (1993). Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature, 362(6417), 248-250. doi: 10.1038/362248a0.

Mokhtarzade, M., Motl, R., Negaresh, R., Zimmer, P., Khodadoost, M., Baker, J. S., . . . & Ranjbar, R. (2018). Exercise-induced changes in neurotrophic factors and markers of blood-brain barrier permeability are moderated by weight status in multiple sclerosis. Neuropeptides, 70, 93-100. doi: 10.1016/j.npep.2018.05.010.

Mokhtarzade, M., Ranjbar, R., Majdinasab, N., Patel, D., & Molanouri Shamsi, M. (2017). Effect of aerobic interval training on serum IL-10, TNFalpha, and adipokines levels in women with multiple sclerosis: possible relations with fatigue and quality of life. Endocrine, 57(2), 262-271. doi: 10.1007/s12020-017-1337-y.

Motl, R. W., McAuley, E., & Snook, E. M. (2005). Physical activity and multiple sclerosis: a meta-analysis. Multiple Sclerosis, 11(4), 459-463. doi: 10.1191/1352458505ms1188oa.

Motl, R. W., & Pilutti, L. A. (2012). The benefits of exercise training in multiple sclerosis. Nature Reviews. Neurology, 8(9), 487-497. doi: 10.1038/nrneurol.2012.136.

Motl, R. W., & Sandroff, B. M. (2015). Benefits of exercise training in multiple sclerosis. Current Neurology and Neuroscience Reports, 15(9), 62. doi: 10.1007/s11910-015-0585-6.

Motl, R. W., Sandroff, B. M., Kwakkel, G., Dalgas, U., Feinstein, A., Heesen, C., . . . & Thompson, A. J. (2017). Exercise in patients with multiple sclerosis. Lancet Neurology, 16(10), 848-856. doi: 10.1016/S1474-4422(17)30281-8.

Narayana, P. A., Govindarajan, K. A., Goel, P., Datta, S., Lincoln, J. A., Cofield, S. S., . . . & The CombiRx Investigators, G. (2012). Regional cortical thickness in relapsing remitting multiple sclerosis: A multi-center study. NeuroImage. Clinical, 2, 120-131. doi: 10.1016/j.nicl.2012.11.009.

Nave, K. A., & Trapp, B. D. (2008). Axon-glial signaling and the glial support of axon function. Annual Review of Neuroscience, 31, 535-561. doi: 10.1146/annurev.neuro.30.051606.094309.

Neeper, S. A., Gomez-Pinilla, F., Choi, J., & Cotman, C. W. (1996). Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain. Brain Research, 726(1-2), 49-56.

Negaresh, R., Motl, R. W., Mokhtarzade, M., Dalgas, U., Patel, D., Shamsi, M. M., . . . & Baker, J. S. (2018). Effects of exercise training on cytokines and adipokines in multiple Sclerosis: A systematic review. Multiple Sclerosis and Related Disorders, 24, 91-100. doi: 10.1016/j.msard.2018.06.008.

Nortvedt, M. W., Riise, T., & Maeland, J. G. (2005). Multiple sclerosis and lifestyle factors: the Hordaland Health Study. Neurological Science, 26(5), 334-339. doi: 10.1007/s10072-005-0498-2.

O'Connor, K. C., Bar-Or, A., & Hafler, D. A. (2001). The neuroimmunology of multiple sclerosis: possible roles of T and B lymphocytes in immunopathogenesis. Journal of Clinical Immunology, 21(2), 81-92.

Olsson, T. (1995). Critical influences of the cytokine orchestration on the outcome of myelin antigen-specific T-cell autoimmunity in experimental autoimmune encephalomyelitis and multiple sclerosis. Immunological Reviews, 144, 245-268.

Opara, J. A., Brola, W., Wylegala, A. A., & Wylegala, E. (2016). Uhthoff`s phenomenon 125 years later - what do we know today? Journal of Medicine and Life, 9(1), 101-105.

Orton, S. M., Herrera, B. M., Yee, I. M., Valdar, W., Ramagopalan, S. V., Sadovnick, A. D., . . . & Canadian Collaborative Study, G. (2006). Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurology, 5(11), 932-936. doi: 10.1016/S1474-4422(06)70581-6.

Ozenci, V., Kouwenhoven, M., & Link, H. (2002). Cytokines in multiple sclerosis: methodological aspects and pathogenic implications. Multiple Sclerosis, 8(5), 396-404. doi: 10.1191/1352458502ms837rr.

Pan, W., Banks, W. A., Fasold, M. B., Bluth, J., & Kastin, A. J. (1998). Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology, 37(12), 1553-1561.

Pearson, M. J., Mungovan, S. F., & Smart, N. A. (2018). Effect of aerobic and resistance training on inflammatory markers in heart failure patients: systematic review and meta-analysis. Heart Failure Reviews, 23(2), 209-223. doi: 10.1007/s10741-018-9677-0.

Pedersen, B. K. (2017). Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease. European journal of clinical investigation, 47(8), 600-611. doi: 10.1111/eci.12781.

Pedersen, B. K., & Febbraio, M. (2005). Muscle-derived interleukin-6--a possible link between skeletal muscle, adipose tissue, liver, and brain. Brain, Behavior, and Immunity, 19(5), 371-376. doi: 10.1016/j.bbi.2005.04.008.

Pedersen, B. K., & Hoffman-Goetz, L. (2000). Exercise and the immune system: regulation, integration, and adaptation. Physiological Reviews, 80(3), 1055-1081. doi: 10.1152/physrev.2000.80.3.1055.

Petersen, A. M., & Pedersen, B. K. (2005). The anti-inflammatory effect of exercise. Journal of Applied Physiology, 98(4), 1154-1162. doi: 10.1152/japplphysiol.00164.2004.

Pilutti, L. A., Greenlee, T. A., Motl, R. W., Nickrent, M. S., & Petruzzello, S. J. (2013). Effects of exercise training on fatigue in multiple sclerosis: a meta-analysis. Psychosomatic Medicine, 75(6), 575-580. doi: 10.1097/PSY.0b013e31829b4525.

Pilutti, L. A., Platta, M. E., Motl, R. W., & Latimer-Cheung, A. E. (2014). The safety of exercise training in multiple sclerosis: a systematic review. Journal of the Neurological Science, 343(1-2), 3-7. doi: 10.1016/j.jns.2014.05.016.

Pilli, D., Zou, A., Tea, F., Dale, R. C., & Brilot, F. (2017). Expanding Role of T Cells in Human Autoimmune Diseases of the Central Nervous System. Frontiers in Immunology, 8, 652. doi: 10.3389/fimmu.2017.00652.

Platta, M. E., Ensari, I., Motl, R. W., & Pilutti, L. A. (2016). Effect of Exercise Training on Fitness in Multiple Sclerosis: A Meta-Analysis. Archives of Physical Medicine and Rehabilitation, 97(9), 1564-1572. doi: 10.1016/j.apmr.2016.01.023.

Prakash, R. S., Snook, E. M., Motl, R. W., & Kramer, A. F. (2010). Aerobic fitness is associated with gray matter volume and white matter integrity in multiple sclerosis. Brain Research, 1341, 41-51. doi: 10.1016/j.brainres.2009.06.063.

Rasmussen, P., Brassard, P., Adser, H., Pedersen, M. V., Leick, L., Hart, E., . . . & Pilegaard, H. (2009). Evidence for a release of brain-derived neurotrophic factor from the brain during exercise. Experimental Physiology, 94(10), 1062-1069. doi: 10.1113/expphysiol.2009.048512.

Rivera-Quinones, C., McGavern, D., Schmelzer, J. D., Hunter, S. F., Low, P. A., & Rodriguez, M. (1998). Absence of neurological deficits following extensive demyelination in a class I-deficient murine model of multiple sclerosis. Nature Medicine, 4(2), 187-193.

Rojas Vega, S., Struder, H. K., Vera Wahrmann, B., Schmidt, A., Bloch, W., & Hollmann, W. (2006). Acute BDNF and cortisol response to low intensity exercise and following ramp incremental exercise to exhaustion in humans. Brain Research, 1121(1), 59-65. doi: 10.1016/j.brainres.2006.08.105.

Rudick, R. A., Fisher, E., Lee, J. C., Simon, J., & Jacobs, L. (1999). Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology, 53(8), 1698-1704.

Ruscheweyh, R., Willemer, C., Kruger, K., Duning, T., Warnecke, T., Sommer, J., . . . & Floel, A. (2011). Physical activity and memory functions: an interventional study. Neurobiology of Aging, 32(7), 1304-1319. doi: 10.1016/j.neurobiolaging.2009.08.001.

Sacco, R., Bisecco, A., Corbo, D., Della Corte, M., d'Ambrosio, A., Docimo, R., . . . & Bonavita, S. (2015). Cognitive impairment and memory disorders in relapsing-remitting multiple sclerosis: the role of white matter, gray matter and hippocampus. Journal of Neurology, 262(7), 1691-1697. doi: 10.1007/s00415-015-7763-y.

Scalfari, A., Knappertz, V., Cutter, G., Goodin, D. S., Ashton, R., & Ebers, G. C. (2013). Mortality in patients with multiple sclerosis. Neurology, 81(2), 184-192. doi: 10.1212/WNL.0b013e31829a3388.

Schwartz, C. E., Dwyer, M. G., Benedict, R., Weinstock-Guttman, B., Bergsland, N. P., Li, J., . . . & Zivadinov, R. (2016). Reserve-related activities and MRI metrics in multiple sclerosis patients and healthy controls: an observational study. BMC Neurology, 16, 108. doi: 10.1186/s12883-016-0624-1.

Sexton, C. E., Betts, J. F., Demnitz, N., Dawes, H., Ebmeier, K. P., & Johansen-Berg, H. (2016). A systematic review of MRI studies examining the relationship between physical fitness and activity and the white matter of the ageing brain. NeuroImage, 131, 81-90. doi: 10.1016/j.neuroimage.2015.09.071.

Sharif, K., Watad, A., Bragazzi, N. L., Lichtbroun, M., Amital, H., & Shoenfeld, Y. (2018). Physical activity and autoimmune diseases: Get moving and manage the disease. Autoimmunity Reviews, 17(1), 53-72. doi: 10.1016/j.autrev.2017.11.010.

Siffrin, V., Vogt, J., Radbruch, H., Nitsch, R., & Zipp, F. (2010). Multiple sclerosis - candidate mechanisms underlying CNS atrophy. Trends in Neurosciences, 33(4), 202-210. doi: 10.1016/j.tins.2010.01.002.

Simon, J. H. (2006). Brain atrophy in multiple sclerosis: what we know and would like to know. Multiple Sclerosis, 12(6), 679-687. doi: 10.1177/1352458506070823.

Stadelmann, C., Kerschensteiner, M., Misgeld, T., Bruck, W., Hohlfeld, R., & Lassmann, H. (2002). BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain, 125(Pt 1), 75-85.

Steensberg, A., Toft, A. D., Bruunsgaard, H., Sandmand, M., Halkjaer-Kristensen, J., & Pedersen, B. K. (2001). Strenuous exercise decreases the percentage of type 1 T cells in the circulation. Journal of Applied Physiology, 91(4), 1708-1712. doi: 10.1152/jappl.2001.91.4.1708.

Sutherland, G., & Andersen, M. B. (2001). Exercise and multiple sclerosis: physiological, psychological, and quality of life issues. The Journal of Sports Medicine and Physical Fitness, 41(4), 421-432.

Szuhany, K. L., Bugatti, M., & Otto, M. W. (2015). A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor. Journal of Psychiatric Research, 60, 56-64. doi: 10.1016/j.jpsychires.2014.10.003.

Thompson, A. J., Banwell, B. L., Barkhof, F., Carroll, W. M., Coetzee, T., Comi, G., . . . & Cohen, J. A. (2018). Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurology, 17(2), 162-173. doi: 10.1016/S1474-4422(17)30470-2.

Tongiorgi, E., Sartori, A., Baj, G., Bratina, A., Di Cola, F., Zorzon, M., & Pizzolato, G. (2012). Altered serum content of brain-derived neurotrophic factor isoforms in multiple sclerosis. Journal of the Neurolical Science, 320(1-2), 161-165. doi: 10.1016/j.jns.2012.07.016.

Trapp, B. D., & Nave, K. A. (2008). Multiple sclerosis: an immune or neurodegenerative disorder? Annual Review of Neuroscience, 31, 247-269. doi: 10.1146/annurev.neuro.30.051606.094313.

Vacaras, V., Major, Z. Z., & Buzoianu, A. D. (2017). Brain-derived neurotrophic factor levels under chronic natalizumab treatment in multiple sclerosis. A preliminary report. Neurologia i Neurochirurgia Polska, 51(3), 221-226. doi: 10.1016/j.pjnns.2017.03.002.

Verstynen, T. D., Lynch, B., Miller, D. L., Voss, M. W., Prakash, R. S., Chaddock, L., . . . & Erickson, K. I. (2012). Caudate Nucleus Volume Mediates the Link between Cardiorespiratory Fitness and Cognitive Flexibility in Older Adults. Journal of Aging Research, 2012, 939285. doi: 10.1155/2012/939285.

Vollmer, T., Signorovitch, J., Huynh, L., Galebach, P., Kelley, C., DiBernardo, A., & Sasane, R. (2015). The natural history of brain volume loss among patients with multiple sclerosis: a systematic literature review and meta-analysis. Journal of the Neurological Science, 357(1-2), 8-18. doi: 10.1016/j.jns.2015.07.014.

Weinstock-Guttman, B., Zivadinov, R., Tamano-Blanco, M., Abdelrahman, N., Badgett, D., Durfee, J., . . . & Ramanathan, M. (2007). Immune cell BDNF secretion is associated with white matter volume in multiple sclerosis. Journal of Neuroimmunology, 188(1-2), 167-174. doi: 10.1016/j.jneuroim.2007.06.003.

White, L. J., & Castellano, V. (2008). Exercise and brain health--implications for multiple sclerosis: Part 1--neuronal growth factors. Sports Medicine, 38(2), 91-100. doi: 10.2165/00007256-200838020-00001.

Wujek, J. R., Bjartmar, C., Richer, E., Ransohoff, R. M., Yu, M., Tuohy, V. K., & Trapp, B. D. (2002). Axon loss in the spinal cord determines permanent neurological disability in an animal model of multiple sclerosis. Journal of Neuropathology and Experimental Neurology, 61(1), 23-32.

Ye, X., Tai, W., & Zhang, D. (2012). The early events of Alzheimer's disease pathology: from mitochondrial dysfunction to BDNF axonal transport deficits. Neurobiology of Aging, 33(6), 1122 e1121-1110. doi: 10.1016/j.neurobiolaging.2011.11.004.

Zamvil, S. S., & Steinman, L. (2003). Diverse targets for intervention during inflammatory and neurodegenerative phases of multiple sclerosis. Neuron, 38(5), 685-688.

Zhu, J., & Paul, W. E. (2008). CD4 T cells: fates, functions, and faults. Blood, 112(5), 1557-1569. doi: 10.1182/blood-2008-05-078154.

Zuccato, C., & Cattaneo, E. (2007). Role of brain-derived neurotrophic factor in Huntington's disease. Progress in Neurobiology, 81(5-6), 294-330. doi: 10.1016/j.pneurobio.2007.01.003.


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