Abstract
Part I of this review addressed the possible modulatory role of exercise on neuronal growth factors to promote brain health in neurodegenerative diseases such as multiple sclerosis (MS), which is characterized by varied patterns of inflammation, demyelination and axonal loss. Part II presents evidence that supports the potential neuroprotective effect of exercise on the modulation of immune factors and stress hormones in MS. Many current therapies used to attenuate MS progression are mediated, at least in part, through alterations in the relative concentrations of pro- and anti-inflammatory cytokines. Exercise-induced alterations in local and systemic cytokine production may also benefit immune function in health and disease. Exercise immunomodulation appears to be mediated by a complex interaction of hormones, cytokines and neural factors that may favorably influence immune variables in MS. The promising interplay between exercise and brain health in MS deserves further investigation.
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References
Frohman EM. Multiple sclerosis. Med Clin North Am 2003; 87: 867–97, viii-x
White LJ, Castellano V. Exercise and brain health — implications for multiple sclerosis: part I — neuronal growth factors. Sports Med 2008; 38 (2): 91–100
Kempermann G, van Praag H, Gage FH. Activity—dependent regulation of neuronal plasticity and self repair. Prog Brain Res 2000; 127: 35–48
Edgerton VR, Roy RR. Paralysis recovery in humans and model systems. Curr Opin Neurobiol 2002; 12: 658–67
Edgerton VR, Tillakaratne NJ, Bigbee AJ, et al. Plasticity of the spinal neural circuitry after injury. Annu Rev Neurosci 2004; 27: 145–67
Febbraio MA, Pedersen BK. Muscle—derived interleukin−6: mechanisms for activation and possible biological roles. Faseb J 2002; 16: 1335–47
Pedersen BK, Steensberg A, Fischer C, et al. Searching for the exercise factor: is IL−6 a candidate? J Muscle Res Cell Motil 2003; 24: 113–9
Pedersen BK, Steensberg A, Schjerling P, et al. Exercise and interleukin−6. Curr Opin Hematol 2001; 8: 137–41
Kerschensteiner M, Stadelmann C, Dechant G, et al. Neurotrophic cross—talk between the nervous and immune systems: implications for neurological diseases. Ann Neurol 2003; 53: 292–304
Oppenheim JJ. Cytokines: past, present, and future. Int J Hematol 2001; 74: 3–8
Ozenci V, Kouwenhoven M, Link H. Cytokines in multiple sclerosis: methodological aspects and pathogenic implications. Mult Scler 2002; 8: 396–404
Persidsky Y. Model systems for studies of leukocyte migration across the blood—brain barrier. J Neurovirol 1999; 5: 579–90
Elenkov IJ, Chrousos GP. Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity. Ann N Y Acad Sci 2002; 966: 290–303
van Boxel-Dezaire AH, Hoff SC, et al. Decreased interleukin−10 and increased interleukin−12p40 mRNA are associated with disease activity and characterize different disease stages in multiple sclerosis. Ann Neurol 1999; 45: 695–703
Brosnan CF, Raine CS. Mechanisms of immune injury in multiple sclerosis. Brain Pathol 1996; 6: 243–57
Moreau T, Coles A, Wing M, et al. Transient increase in symptoms associated with cytokine release in patients with multiple sclerosis. Brain 1996; 119 (Pt 1): 225–37
Raine CS. Multiple sclerosis: TNF revisited, with promise. Nat Med 1995; 1: 211–4
Selmaj K, Brosnan CF, Raine CS. Expression of heat shock protein−65 by oligodendrocytes in vivo and in vitro: implications for multiple sclerosis. Neurology 1992; 42: 795–800
Steinman L. Escape from “horror autotoxicus”: pathogenesis and treatment of autoimmune disease. Cell 1995; 80: 7–10
Martiney JA, Cuff C, Litwak M, et al. Cytokine—induced inflammation in the central nervous system revisited. Neurochem Res 1998; 23: 349–59
Hartung HP, Reiners K, Archelos JJ, et al. Circulating adhesion molecules and tumor necrosis factor receptor in multiple sclerosis: correlation with magnetic resonance imaging. Ann Neurol 1995; 38: 186–93
Selmaj KW, Raine CS. Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann Neurol 1988; 23: 339–46
Feuerstein GZ, Liu T, Barone FC. Cytokines, inflammation, and brain injury: role of tumor necrosis factor—alpha. Cerebrovasc Brain Metab Rev 1994; 6: 341–60
Zimmerman GA, Weingarten K, Lavyne MH. Symptomatic lumbar epidural varices: report of two cases. J Neurosurg 1994; 80: 914–8
Ozenci V, Kouwenhoven M, Huang YM, et al. Multiple sclerosis is associated with an imbalance between tumour necrosis factor—alpha (TNF—alpha)— and IL−10−secreting blood cells that is corrected by interferon—beta (IFN—beta) treatment. Clin Exp Immunol 2000; 120: 147–53
Schwid SR, Thornton CA, Pandya S, et al. Quantitative assessment of motor fatigue and strength in MS. Neurology 1999; 53: 743–50
Spector NH. Neuroimmunomodulation: a brief review. Can conditioning of natural killer cell activity reverse cancer and/or aging? Regul Toxicol Pharmacol 1996; 24: S32–8
Stuve O, Cree BC, von Budingen HC, et al. Approved and future pharmacotherapy for multiple sclerosis. Neurologist 2002; 8: 290–301
Beebe AM, Cua DJ, de Waal Malefyt R. The role of interleukin−10 in autoimmune disease: systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Cytokine Growth Factor Rev 2002; 13: 403–12
Kennedy MK, Torrance DS, Picha KS, et al. Analysis of cytokine mRNA expression in the central nervous system of mice with experimental autoimmune encephalomyelitis reveals that IL−10 mRNA expression correlates with recovery. J Immunol 1992; 149: 2496–505
Balashov KE, Comabella M, Ohashi T, et al. Defective regulation of IFNgamma and IL−12 by endogenous IL−10 in progressive MS. Neurology 2000; 55: 192–8
Navikas V, Link H. Review: cytokines and the pathogenesis of multiple sclerosis. J Neurosci Res 1996; 45: 322–33
Ellison MD, Merchant RE. Appearance of cytokine—associated central nervous system myelin damage coincides temporally with serum tumor necrosis factor induction after recombinant interleukin−2 infusion in rats. J Neuroimmunol 1991; 33: 245–51
Heesen C, Gold SM, Hartmann S, et al. Endocrine and cytokine responses to standardized physical stress in multiple sclerosis. Brain Behav Immun 2003; 17: 473–81
Nieman DC. Current perspective on exercise immunology. Curr Sports Med Rep 2003; 2: 239–42
Shepard RJ, Shek PN. Impact of physical activity and sport on the immune system. Rev Environ Health 1996; 11: 133–47
Moldoveanu AI, Shephard RJ, Shek PN. The cytokine response to physical activity and training. Sports Med 2001; 31 (2): 115–44
Smith JK, Dykes R, Douglas JE, et al. Long—term exercise and atherogenic activity of blood mononuclear cells in persons at risk of developing ischemic heart disease. JAMA 1999; 281: 1722–7
Castaneda C, Gordon PL, Parker RC, et al. Resistance training to reduce the malnutrition—inflammation complex syndrome of chronic kidney disease. Am J Kidney Dis 2004; 43: 607–16
Goldhammer E, Tanchilevitch A, Maor I, et al. Exercise training modulates cytokines activity in coronary heart disease patients. Int J Cardiol 2005; 100: 93–9
Petitto JM, Streit WJ, Huang Z, et al. Interleukin−2 gene deletion produces a robust reduction in susceptibility to experimental autoimmune encephalomyelitis in C57BL/6 mice. Neurosci Lett 2000; 285: 66–70
Sprenger H, Jacobs C, Nain M, et al. Enhanced release of cytokines, interleukin−2 receptors, and neopterin after long distance running. Clin Immunol Immunopathol 1992; 63: 188–95
White L, Castellano V, Mc Coy S. Cytokine changes after a resistance training program in multiple sclerosis patients. J Sport Sci 2006; 24: 1–4
Le Page C, Ferry A, Rieu M. Effect of muscular exercise on chronic relapsing experimental autoimmune encephalomyelitis. J Appl Physiol 1994; 77: 2341–7
Schulz KH, Gold SM, Witte J, et al. Impact of aerobic training on immune—endocrine parameters, neurotrophic factors, quality of life and coordinative function in multiple sclerosis. J Neurol Sci 2004; 225: 11–8
Elfont R. Emerging therapies. In: Burks J, editor. Multiple sclerosis. New York: Demos Medical Publishing, 2000: 193
Noronha A, Toscas A, Jensen MA. Interferon beta decreases T cell activation and interferon gamma production in multiple sclerosis. J Neuroimmunol 1993; 46: 145–53
Pedersen BK, Febbraio M. Muscle—derived interleukin−6: a possible link between skeletal muscle, adipose tissue, liver, and brain. Brain Behav Immun 2005; 19: 371–6
Pedersen BK, Steensberg A, Fischer C, et al. The metabolic role of IL−6 produced during exercise: is IL−6 an exercise factor? Proc Nutr Soc 2004; 63: 263–7
Pedersen BK, Akerström TC, Nielsen AR, et al. Role of myokines in exercise and metabolism. J Appl Physiol 2007; 103 (3): 1093–8
Sheppard RJ. Exercise and cytokines. In: Mackinnon LT, editor. Advances in exercise immunology. Champaign (IL): Human Kinetics, 1999: 364
Plomgaard P, Penkowa M, Pedersen BK. Fiber type specific expression of TNF—alpha, IL−6 and IL−18 in human skeletal muscles. Exerc Immunol Rev 2005; 11: 53–63
Cannon JG, Meydani SN, Fielding RA, et al. Acute phase response in exercise: II. Associations between vitamin E, cytokines, and muscle proteolysis. Am J Physiol 1991; 260: R1235–40
Dufaux B, Order U. Complement activation after prolonged exercise. Clin Chim Acta 1989; 179: 45–9
Drenth JP, Van Uum SH, Van Deuren M, et al. Endurance run increases circulating IL−6 and IL−1ra but downregulates ex vivo TNF—alpha and IL−1 beta production. J Appl Physiol 1995; 79: 1497–503
Smith JA, Telford RD, Baker MS, et al. Cytokine immunoreactivity in plasma does not change after moderate endurance exercise. J Appl Physiol 1992; 73: 1396–401
Mellor AL, Munn D, Chandler P, et al. Tryptophan catabolism and T cell responses. Adv Exp Med Biol 2003; 527: 27–35
Pahan K, Smith BT, Singh AK, et al. Cytochrome P−450 2E1 in rat liver peroxisomes: downregulation by ischemia/reperfusion—induced oxidative stress. Free Radic Biol Med 1997; 23: 963–71
Stanislaus R, Pahan K, Singh AK, et al. Amelioration of experimental allergic encephalomyelitis in Lewis rats by lovastatin. Neurosci Lett 1999; 269: 71–4
Okazaki H, Nagashima T, Minota S. Immunomodulatory activities of statins [in Japanese]. Nihon Rinsho Meneki Gakkai Kaishi 2004; 27: 357–60
Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing—remitting multiple sclerosis. Lancet 2004; 363: 1607–8
Desvergne B, Wahli W. Peroxisome proliferator—activated receptors: nuclear control of metabolism. Endocr Rev 1999; 20: 649–88
Constantinescu CS, Grossman RI, Finelli PF, et al. Clinical and subclinical neurological involvement in children of conjugal multiple sclerosis patients. Mult Scler 1995; 1: 170–2
Lovett-Racke AE, Hussain RZ, Northrop S, et al. Peroxisome proliferator—activated receptor alpha agonists as therapy for autoimmune disease. J Immunol 2004; 172: 5790–8
Ehrhard PB, Erb P, Graumann U, et al. Expression of nerve growth factor and nerve growth factor receptor tyrosine kinase Trk in activated CD4−positive T—cell clones. Proc Natl Acad Sci U S A 1993; 90: 10984–8
Leon A, Buriani A, Dal Toso R, et al. Mast cells synthesize, store, and release nerve growth factor. Proc Natl Acad Sci U S A 1994; 91: 3739–43
Santambrogio L, Benedetti M, Chao MV, et al. Nerve growth factor production by lymphocytes. J Immunol 1994; 153: 4488–95
Besser M, Wank R. Cutting edge: clonally restricted production of the neurotrophins brain—derived neurotrophic factor and neurotrophin−3 mRNA by human immune cells and Th1/Th2−polarized expression of their receptors. J Immunol 1999; 162: 6303–6
Braun A, Lommatzsch M, Lewin GR, et al. Neurotrophins: a link between airway inflammation and airway smooth muscle contractility in asthma? Int Arch Allergy Immunol 1999; 118: 163–5
Moalem G, Gdalyahu A, Shani Y, et al. Production of neurotrophins by activated T cells: implications for neuroprotective autoimmunity. J Autoimmun 2000; 15: 331–45
Villoslada P, Hauser SL, Bartke I, et al. Human nerve growth factor protects common marmosets against autoimmune encephalomyelitis by switching the balance of T helper cell type 1 and 2 cytokines within the central nervous system. J Exp Med 2000; 191: 1799–806
Micera A, Properzi F, Triaca V, et al. Nerve growth factor antibody exacerbates neuropathological signs of experimental allergic encephalomyelitis in adult Lewis rats. J Neuroimmunol 2000; 104: 116–23
Steinman L. Engineering better cytokines. Nat Biotechnol 2003; 21: 1293–4
Elenkov IJ, Chrousos GP, Wilder RL. Neuroendocrine regulation of IL−12 and TNF—alpha/IL−10 balance: clinical implications. Ann N Y Acad Sci 2000; 917: 94–105
Webster JI, Tonelli L, Sternberg EM. Neuroendocrine regulation of immunity. Annu Rev Immunol 2002; 20: 125–63
Goodin DS, Ebers GC, Johnson KP, et al. The relationship of MS to physical trauma and psychological stress: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 1999; 52: 1737–45
Martinelli V. Trauma, stress and multiple sclerosis. Neurol Sci 2000; 21: S849–52
Bukilica M, Djordjevic S, Maric I, et al. Stress—induced suppression of experimental allergic encephalomyelitis in the rat. Int J Neurosci 1991; 59: 167–75
Griffin AC, Lo WD, Wolny AC, et al. Suppression of experimental autoimmune encephalomyelitis by restraint stress: sex differences. J Neuroimmunol 1993; 44: 103–16
Levine S, Wenk EJ. Hyperacute allergic encephalomyelitis: lymphatic system as site of adjuvant effect of pertussis vaccine. Am J Pathol 1967; 50: 465–83
Levine S, Sowinski R. The role of the adrenal in relapses of experimental allergic encephalomyelitis. Proc Soc Exp Biol Med 1975; 149: 1032–5
Levine S, Saltzman A. Nonspecific stress prevents relapses of experimental allergic encephalomyelitis in rats. Brain Behav Immun 1987; 1: 336–41
Elenkov IJ. Systemic stress—induced Th2 shift and its clinical implications. Int Rev Neurobiol 2002; 52: 163–86
Schumann EM, Kumpfel T, Then Bergh F, et al. Activity of the hypothalamic—pituitary—adrenal axis in multiple sclerosis: correlations with gadolinium—enhancing lesions and ventricular volume. Ann Neurol 2002; 51: 763–7
Besedovsky HO, del Rey A. Immune—neuro—endocrine interactions: facts and hypotheses. Endocr Rev 1996; 17: 64–102
Luger A, Deuster PA, Kyle SB, et al. Acute hypothalamicpituitary—adrenal responses to the stress of treadmill exercise: physiologic adaptations to physical training. N Engl J Med 1987; 316: 1309–15
Hasko G, Szabo C, Nemeth ZH, et al. Stimulation of beta—adrenoceptors inhibits endotoxin—induced IL−12 production in normal and IL−10 deficient mice. J Neuroimmunol 1998; 88: 57–61
Panina-Bordignon P, Mazzeo D, Lucia PD, et al. Beta2−agonists prevent Th1 development by selective inhibition of interleukin 12. J Clin Invest 1997; 100: 1513–9
Oleshansky MA, Zoltick JM, Herman RH, et al. The influence of fitness on neuroendocrine responses to exhaustive treadmill exercise. Eur J Appl Physiol Occup Physiol 1990; 59: 405–10
Smith GD, Watson LP, Mathias CJ. Cardiovascular and catecholamine changes induced by supine exercise and upright posture in vasovagal syncope: comparisons with normal subjects and subjects with sympathetic denervation. Eur Heart J 1996; 17: 1882–90
Acknowledgements
The authors thank Rudy Dressendorfer, PhD and Sean C. McCoy for their editorial contributions. No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.
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White, L.J., Castellano, V. Exercise and Brain Health — Implications for Multiple Sclerosis. Sports Med 38, 179–186 (2008). https://doi.org/10.2165/00007256-200838030-00001
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DOI: https://doi.org/10.2165/00007256-200838030-00001