Exercise and Neuroinflammation in Health and Disease

Article information

Int Neurourol J. 2019;23(Suppl 2):S82-92
Publication date (electronic) : 2019 November 30
doi : https://doi.org/10.5213/inj.1938214.107
1National Research Laboratory for Mitochondrial Signaling, Department of Physiology, Cardiovascular and Metabolic Disease Center, Inje University College of Medicine, Busan, Korea
2Department of Kinesiology, Inha University, Incheon, Korea
Corresponding author: Hyo-Bum Kwak https://orcid.org/0000-0003-0451-4554 Department of Kinesiology, Inha University, 100 Inha-ro, Michuhol-gu, Incheon 22212, Korea E-mail: kwakhb@inha.ac.kr / Tel: +82-32-860-8183 / Fax: +82-32-860-8188
Received 2019 October 2; Accepted 2019 November 8.


Neuroinflammation is a central pathological feature of several acute and chronic brain diseases, including Alzheimer disease (AD), Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). It induces microglia activation, mitochondrial dysfunction, the production of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), pro-inflammatory cytokines, and reactive oxygen species. Exercise, which plays an important role in maintaining and improving brain health, might be a highly effective intervention for preventing neuroinflammation-related diseases. Thus, since exercise can improve the neuroimmune response, we hypothesized that exercise would attenuate neuroinflammation-related diseases. In this review, we will highlight (1) the biological mechanisms that underlie AD, PD, ALS, and MS, including the neuroinflammation pathways associated with microglia activation, NF-κB, pro-inflammatory cytokines, mitochondrial dysfunction, and reactive oxygen species, and (2) the role of exercise in neuroinflammation-related neurodegenerative diseases.


- Neuroinflammation is a central pathological feature of brain disease.

- Neuroinflammation induces microglia activation, mitochondrial dysfunction, the production of NF-κB, pro-inflammatory cytokines, and reactive oxygen species.

- Exercise plays an important role in preventing neuroinflammation.


Inflammation plays a pivotal role during the biological response to defend and support the body following noxious stimuli and conditions such as injury, trauma, and infection [1]. It removes invading pathogens and induces angiogenesis and wound healing [2] through phagocytosis and the activation of inflammasomes, which induce programmed cell death [3] to ultimately facilitate tissue regeneration [4]. However, even though inflammation is beneficial and protective, excessive inflammation can induce tissue damage and lead to the development of pathological diseases [4]. In the brain, the inflammatory response may be beneficial and vital in some circumstances, but can also be harmful by causing acute and chronic brain disorders [1]. Therefore, knowing when inflammation is protective or detrimental could be paramount in understanding brain-related diseases.

Neuroinflammation is an immune reaction that occurs in response to various signals, such as infection, traumatic brain injury [5], autoimmunity, or toxic metabolites [6] within the central nervous system (CNS), which is composed of macroglia, microglia, neurons, and astrocytes. Neuroinflammation is considered to be a pathological mediator in a variety of neurodegenerative diseases [7]. The blood-brain barrier (BBB), a highly specialized structure made of endothelium and astrocytes, was previously considered to separate the CNS from the peripheral immune cells [4,8]. However, after injury and the prolonged release of inflammatory factors such as chemokines, the BBB is not only permeable to peripheral inflammation-induced proinflammatory mediators, but also allows leukocytes to migrate into the brain, which can induce pathogenesis in the CNS [9,10]. Dysfunction of the BBB facilitates neuroinflammation, giving rise to synaptic disruption, neuronal death, and aggravation of various brain-related diseases [2,11,12], which in turn aggravates chronic degenerative diseases including Alzheimer disease (AD), Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) [13-16]. In addition, these neurodegenerative diseases can also occur as a result of the activation of microglia [17] and pathways involving nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [18], pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β) [4], mitochondrial dysfunction, and reactive oxygen species (ROS) [1,19].

Exercise has a beneficial impact on the whole body. It can improve cognitive function and brain health [20-23]. In response to exercise-related stimuli and mild injuries, the body activates the endogenous protective and recovery systems by altering gene expression and producing numerous factors involved in trophic effects, energy metabolism, antioxidation, and particularly, anti-inflammation [24-26]. These factors improve brain function and mitigate brain disorders by activating neuroplasticity, enhancing metabolic efficiency, and boosting antioxidative capacity [27,28]. Additionally, exercise maintains homeostasis of the brain and prevents brain pathology by modulating the activation of glia, pro-inflammatory cytokines, and neuroinflammation, thereby preventing neurodegenerative diseases such as AD, PD, ALS, and MS [24,29-31]. To determine the effects of exercise on neurodegenerative diseases, the type, intensity, frequency, and duration of exercise should be considered. Nonetheless, it is clear that exercise plays a protective role in neurodegenerative diseases by increasing levels of anti-inflammatory molecules and reducing those of pro-inflammatory molecules.

With this background, this review highlights the causes and consequences of neuroinflammation by focusing on (1) biological mechanisms that involve microglia, NF-κB, pro-inflammatory cytokines, and mitochondrial dysfunction in neurodegenerative diseases and (2) the effects of physical exercise on inflammation-related neurodegenerative diseases.


Neuroinflammation Pathways


Physiologically, microglia, which are the resident macrophages in the CNS, play a vital role in organism protection and tissue repair in the CNS [32]. Microglia scavenge plaques, unnecessary or disrupted synapses and neurons, and infectious agents in the CNS [33]. However, microglia that are activated by pathogens, abnormal stimulation, tissue damage, neurotoxins, injury, or infection are pivotal mediators in neuroinflammatory responses and neurodegenerative diseases [17]. More specifically, following the activation of microglia, they cause neuronal disruption and cell death by releasing proteins such as inducible nitric oxide synthase (iNOS), pro-inflammatory cytokines, including IL-1β, TNF-α, and cyclooxygenase-1 and 2 (COX-1, COX-2), ROS, and potential neurotoxic compounds, all of which induce neuroinflammation [34]. These proteins may attack healthy neurons, either by releasing pro-apoptotic factors or by phagocytosis [34].


NF-κB, located in almost all eukaryotic cells, is a protein complex that regulates DNA transcription, cytokine production, and cell survival [35]. NF-κB modulates multiple processes such as inflammation, immunity, apoptosis, cell survival, and the development of cancer; furthermore, it also controls the secretion of immune and inflammatory response genes [36]. NF-κB activation in glia plays a crucial role in the process of inflammation by causing neurodegeneration [37]. In particular, lipopolysaccharide (LPS), also known as endotoxin, causes systemic inflammatory response syndrome via toll-like receptor (TLR) signaling. LPS activates several signals, including phosphoinositide 3-kinase/protein kinase, mitogen-activated protein kinase, and mammalian target of rapamycin, which ultimately result in NF-κB activation [1]. Activated NF-κB then instigates the production of pro-neuroinflammatory mediators such as pro-inflammatory cytokines, inducible enzymes and chemokines, iNOS, and COX-2 [38].

Pro-inflammatory cytokines

Cytokines play a role in cell proliferation, survival, and death, and contribute to increased levels of leukocytes in the brain [39]. Even though physiological levels of cytokines, such as TNF-α and IL-1β, are important for synaptic plasticity during consolidation and memory formation, excessive cytokine levels are harmful [12,40]. As stated earlier, microglia induce TNF-α signaling, leading to inflammation and apoptosis [1]. For example, excessive apoptosis of hippocampal neurons is associated with high TNF-α level, suggesting that elevated concentrations of TNF-α can be an early indicator of apoptosis [4,41]. Similar to TNF-α, IL-1β has also been implicated in neuronal disruption, which is observed before neuronal death. It induces BBB breakdown, upregulates adhesion molecule expression, and promotes the spread of toxic substances such as nitric oxide [42]. Consequently, TNF-α and IL-1β play a pivotal role in acute neuroinflammatory conditions such as ischemia, stroke, and brain injury, and in chronic neurodegenerative diseases such as AD and PD [43].

Mitochondrial dysfunction and ROS

Mitochondria are organelles of eukaryotic cells that contribute to bioenergetic metabolism and regulate cellular homeostasis. They are involved in the generation of ATP using electron transport and oxidative phosphorylation, the initiation and execution of mitochondria-mediated apoptosis, and the production of ROS [44]. Mitochondria are a vital source of ROS, which are produced from the electron transport chain. ROS can have a toxic impact on biological macromolecules and can activate several genes that initiate inflammatory signaling cascades [1]. Although physiological levels of ROS regulate cell metabolism, excessive levels of ROS cause mitochondrial dysfunction and tissue injury through oxidative damage, leading to neuroinflammation [1]. Specifically, mitochondrial dysfunction in microglia results in excessive production of ROS. This promotes redox imbalance and regulates pro-inflammatory gene transcription and the expression of cytokines, such as IL-6, IL-1β, monocyte chemotactic protein-1, and TNF-α, by encouraging the expression of oxidative stress-modified mitochondrial DNA and polynucleotides, which causes inflammatory signaling in astrocytes [1,45].

Neuroinflammatory Disease

Alzheimer disease

It is well known that neuroinflammation plays a vital role in the development and progression of AD, which is a fatal neurodegenerative disorder that affects more than 15 million people worldwide [46]. Extracellular and intracellular protein aggregation contributes to the development of AD. Specifically, AD is characterized by a sequence of major pathogenic events and the presence of amyloid-β peptide (Aβ) plaques and neurofibrillary tangles (NFTs), which result in the formation of the microtubuleassociated protein tau, and the onset of synaptic and neuronal dysfunction and loss [47]. The accumulation of Aβ plaques, tau protein, and NFTs in the brain induces neuroinflammation and plays a pivotal role in regulating the pathogenesis of AD [48]. This causes neuronal dysfunction and increased expression of inflammatory mediators around Aβ plaques and NFTs [49]. In the early stages of AD, microglia are activated, leading to the production and secretion of neurotoxic cytokines such as TNF-α and IL-1β, the generation of ROS, the inhibition of neuroprotective effects, and mitochondrial dysfunction [50,51].

Parkinson disease

PD is a common and complex neurological disorder. It is a neurodegenerative disease involving the early prominent death of dopaminergic neurons in the substantia nigra pars compacta [52]. In addition, PD is also associated with numerous nonmotor symptoms, some of which precede motor dysfunction by more than a decade [53]. Even though the etiology of PD is unknown, according to some studies, PD is induced by inflammatory reactions [3], oxidative stress [4], mitochondrial dysfunction [5], proteotoxic stress [6], and kinase dysfunction [7], resulting in movement disorders like bradykinesia, which is responsible for postural instability and resting tremor [54]. These physical disorders result from the accumulation of α-synuclein protein, which forms insoluble Lewy bodies, and the selective loss of dopaminergic neurons in the substantia nigra pars compacta region of the brain, which is responsible for limiting movements [54-56]. The α-synuclein clusters and neuronal necrosis eventually activate the microglia. These microglia produce ROS, cytokines such as TNF-α, and chemokines [57]. Postmortem studies of the brains of PD patients have shown significant astrocyte activation and increased levels of various cytokines and microglia [58-60]. In addition, the increase in the levels of TNF-α and TNF-α receptors is an essential mediator of PD. This increase triggers the onset of extrinsic neuronal apoptosis, which is one of the key factors that induces PD [61].

Amyotrophic lateral sclerosis

ALS, also called Lou Gehrig’s disease, is the most common chronic motor neuron disease. It is characterized by selective motor neuron loss, weakness, and atrophy [62]. ALS is characterized by muscle stiffness and twitching, which insidiously worsen due to decreased muscle size. Although the cause of ALS is still unknown, potential evidence suggests that the innate immune system may be a focal contributor that promotes the activation of macrophages/microglia [63], which leads to the production of pro-inflammatory neurotoxic cytokines such as IL‐1β, thereby promoting the death of motor neurons [64]. Protein aggregates play a central role in superoxide dismutase 1 (SOD1)‐mediated ALS pathogenesis [65] and wild-type SOD1 aggregates have also been recently linked to sporadic ALS pathology [66]. Furthermore, ALS protein aggregates are robust immune response mediators in microglia [64]. The NOD-like receptor and the pyrin domain containing receptor 3 (NLRP3) inflammasome, an intracellular signaling complex, are a key factor in the innate immune system. Expression of the NLRP3 inflammasome is promoted by the aggregation of proteins and has been associated with neurodegenerative diseases [67]. Activation of the inflammasome requires a priming signal for the upregulation of NLRP3 and cytokine precursors, such as pro‐IL‐1β and pro‐IL‐18, followed by an activation step, which contributes to the recruitment of the inflammasome adapter, apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC), the activation of caspase‐1 protease, and the cleavage and release of IL‐1β and IL‐18.

Multiple sclerosis

MS is a chronic autoimmune disease caused by CNS demyelination and inflammation, leading to damage of axons and myelin sheaths [4]. Although there might be a relationship between the development of the disease and systemic inflammation, there is little evidence supporting a relationship between inflammatory stimuli and the disrupted axons and myelin-producing cells [4]. Activation of the innate immune response, which involves the activation of microglia and macrophages, is responsible for the damaged axons observed during MS [68]. Systemic inflammation might contribute to the disruption of myelinated cells in MS. This explains the increased possibility of relapse following infection. Inflammation in MS results from the adaptive immune response, which involves T helper cells (Th1 and Th17) [69] and B cells [70]. Pro-inflammatory molecules generated by these glial cells and lymphocytes contribute to the initiation of MS [71].


Exercise in AD

Several studies have demonstrated that exercise is a positive regulator of AD (Table 1). For example, Kim et al. [72] found that treadmill running decreased the Aβ plaque burden, neuro-inflammation, and mitochondrial dysfunction, suggesting that exercise enhanced the cognitive performance of 3xTg-AD mice. Similarly, Kim et al. [73] showed that 20 weeks of treadmill running ameliorated neuroinflammation and apoptotic neuronal cell death in high-fat-diet (HFD)-induced 3xTg-AD mice. These results suggest that treadmill running protects against AD pathology and cognitive deficiency in HFD-induced 3xTg-AD mice. In another study, wheel running was reported to increase microglia activation [74], attenuate microglia cytokine production, and protect against the negative effects of immune system activation [75]. Tapia-Rojas et al. [76] showed that voluntary running decreased neuronal loss, Aβ burden, and spatial memory loss, and increased neurogenesis in an AD animal model. Rodriguez et al. [77] reported that voluntary wheel running affected microglial density and activation-associated changes in microglial morphology. Zhang et al. [78] suggested that treadmill exercise significantly inhibited neuroinflammation by reducing the expression of pro-inflammatory factors and increasing the expression of anti-inflammatory factors. Exercise also attenuated oxidative stress induced by methane dicarboxylic aldehyde and dramatically elevated SOD and Mn-SOD activity. Therefore, treadmill exercise is a positive regulator of neuroinflammation and oxidative stress in AD. Sixteen weeks of treadmill running decreased the level of β-amyloid precursor protein (β-APP or Aβ peptide) in transgenic (TgCRND8) mice with AD phenotypes [79]. Treadmill running ameliorated ROS generation and mtDNA oxidative damage, increased the activity of mitochondrial antioxidant enzymes, and prevented mitochondrial dysfunction in APP/PS1 transgenic mice with an AD phenotype [80].

The effects of exercise on Alzheimer disease (AD)

Stress deterioration on the hippocampal function, leading to short-term memory problems has been shown, also, to impair lower urinary tract functions [81]. Whereby, Heo et al. [82] investigated, not only CNS effects, but concomitant renal injuries associated with short-term memory disturbance. Treadmill exercise ameliorated short-term memory impairment, suppressed AChE expression and enhanced angiogenesis in mice with scopolamine-induced amnesia.

Exercise in PD

PD is a neurodegenerative disease characterized by the death of dopaminergic neurons, leading to decreased dopamine transmission and changes in motor and cognitive function [83,84]. Exercise may be one of the most promising therapeutic approaches because it inhibits the factors that promote neurodegenerative diseases and increases the levels of neurotrophic factors, resulting in a healthy CNS in the elderly population [85,86]. Real et al. [87] showed that 4 weeks of treadmill running reduced neuroinflammatory processes, thereby decreasing the risk of PD development, the activation of astrocytes and microglia, and the oxidative stress response. Tuon et al. [88] also reported that treadmill running modulated α-synuclein activity, brain-derived neurotrophic factor (BDNF), and sarcoplasmic reticulum Ca2+ ATPase (SERCA) II levels for 8 weeks in the striatum of a PD animal model. These results demonstrated that exercise protected the dopamine system in a 6-hydroxydopamine-induced PD animal model. Koo et al. [89] reported that 8 weeks of treadmill exercise inhibited TLR2 expression, microglial activation, neuroinflammation, ROS production, and apoptosis, and suppressed the expression of the nicotinamide adenine dinucleotide phosphate oxidase subunit, NF-κB, TNF-α, and IL-1β in a preclinical model of PD. The authors showed that treadmill exercise is a nonpharmacological tool for managing neurodegeneration in PD. Human studies confirmed the beneficial effect of exercise by demonstrating that intensive exercise resulted in a 16% increase in serum BDNF levels and improvements in scores on the Unified Parkinson’s Disease Rating Scale, which evaluates the benefits of therapeutic interventions [90]. In another study, moderate exercise for 8 weeks increased the level of serum BDNF, decreased the level of serum vascular cell adhesion molecule by 25%, and reduced the level of serum TNF-α in PD patient [91]. Bloomer et al. [92] reported that 8 weeks of resistance exercise decreased the oxidative stress caused by malondialdehyde and hydrogen peroxide. The study also confirmed an increase in the levels of SOD (9%) and glutathione peroxidase (15%), but these changes were not significant in PD patients. These central effects seem to propagate across to peripheral systems, as well. In a study applying treadmill exercise on PD rat models, Lee et al. [93] showed improvement of cerebellar functions by inhibiting Purkinje cell apoptosis. A summary of the effects of exercise on PD is shown in Table 2.

The effects of exercise on Parkinson disease (PD)

Exercise in ALS

Exercise is considered to be a key regulator in ALS, a chronic motor neuron disease. Exercise prevents ALS by regulating neuroinflammation. The effects of exercise in ALS are summarized in Table 3. Just-Borràs et al. [62] showed that moderate exercise, including running and swimming, maintained the BDNF/TrkB signaling pathway and downstream signaling for 45 days in an ALS animal model. These results are encouraging, since they show improvements even when therapy is started after the onset of the disease. Flis et al. [94] evaluated the effects of swimming exercise for 15 weeks on oxidative stress and mitochondrial function in an ALS animal model. They observed that mitochondrial function was maintained and oxidative stress was lowered, and that there was an exercise-induced deceleration in ALS development. Recently, Flis et al. [95] also reported that there were no significant changes in malondialdehyde, COX activity, and mitochondria oxygen consumption in an ALS mouse model after 15 weeks. In another study, Kassa et al. [96] reported treadmill running-induced increases in microglia activation and motor neuron counts in ALS mice. This suggests that exercise can ameliorate ALS symptoms and progression [97]. Taken together, exercise of various types and intensities can influence various aspects of ALS.

The effects of exercise on amyotrophic lateral sclerosis (ALS)

Exercise in MS

There is compelling evidence for the beneficial effects of exercise in MS. Accumulating evidence supports the role of exercise in neuroinflammation in MS (Table 4). For example, Kierkegaard et al. [98] reported that resistance exercise decreased plasma TNF-α level for 12 weeks in MS patients. Another study showed that resistance training significantly reduced serum levels of cytokines, including IL-4, IL-10, C-reactive protein, and interferon-gamma (IFN-γ) in MS patients [99]. In another study, Donia et al. [100] suggested that 1 hour of moderate aerobic exercise (60% of peak oxygen uptake) decreased plasma TNF-α levels in MS patients. Interestingly, combined aerobic training and Pilates training improved BDNF and physical performance, suggesting that combining forms of exercise might yield a beneficial effect in MS patients [101]. Castellano et al. [102] demonstrated that acute and long-term cycle exercise, which involved 60% of peak O2 uptake for 3 days per week over the course of 8 weeks reduced plasma TNF-α, IL-6, and IFN-γ levels in MS patients. Further investigations will help to elucidate the effects of exercise on neuroinflammation in MS.

The effects of exercise on multiple sclerosis (MS)


In this article, we highlighted neuroinflammation-related diseases, such as AD, PD, ALS, and MS. These diseases are associated with the activation of microglia, NF-κB, pro-inflammatory cytokines, mitochondrial dysfunction, and ROS. Even though further research is needed to confirm our findings, exercise might mitigate neuroinflammation in AD, PD, ALS, and MS. In order to elucidate the cellular and/or molecular mechanisms that underlie the role of exercise in attenuating the activation of microglia, NF-κB, pro-inflammatory cytokines, mitochondrial dysfunction, and ROS in the brain, further clinical and preclinical studies should be conducted.


Fund/Grant Support

This work was supported by the Ministry of Education of the Republic of Korea and the National Research Foundation of Korea (2016R1A2B4014240, 2018R1A2A3074577, 2019S1A5C2A03082727).

Conflict of Interest

No potential conflict of interest relevant to this article was reported.


·Full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis: DYS, HBK

·Study concept and design: DYS, HBK

·Acquisition of data: JWH, JRK

·Analysis and interpretation of data: JWH, JRK

·Drafting of the manuscript: DYS, HBK

·Critical revision of the manuscript for important intellectual content: HBK

·Administrative, technical, or material support: HBK

·Study supervision: HBK


1. Shabab T, Khanabdali R, Moghadamtousi SZ, Kadir HA, Mohan G. Neuroinflammation pathways: a general review. Int J Neurosci 2017;127:624–33.
2. Carson MJ, Thrash JC, Walter B. The cellular response in neuroinflammation: the role of leukocytes, microglia and astrocytes in neuronal death and survival. Clin Neurosci Res 2006;6:237–45.
3. Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 2009;458:509–13.
4. Lyman M, Lloyd DG, Ji X, Vizcaychipi MP, Ma D. Neuroinflammation: the role and consequences. Neurosci Res 2014;79:1–12.
5. Ebert SE, Jensen P, Ozenne B, Armand S, Svarer C, Stenbaek DS, et al. Molecular imaging of neuroinflammation in patients after mild traumatic brain injury: a longitudinal (123) I-CLINDE single photon emission computed tomography study. Eur J Neurol 2019;26:1426–32.
6. Gendelman HE. Neural immunity: Friend or foe? J Neurovirol 2002;8:474–9.
7. Schain M, Kreisl WC. Neuroinflammation in neurodegenerative disorders-a review. Curr Neurol Neurosci Rep 2017;17:25.
8. Das Sarma J. Microglia-mediated neuroinflammation is an amplifier of virus-induced neuropathology. J Neurovirol 2014;20:122–36.
9. de Vries HE, Blom-Roosemalen MC, van Oosten M, de Boer AG, van Berkel TJ, Breimer DD, et al. The influence of cytokines on the integrity of the blood-brain barrier in vitro. J Neuroimmunol 1996;64:37–43.
10. Laflamme N, Lacroix S, Rivest S. An essential role of interleukin-1β in mediating NF-kappaB activity and COX-2 transcription in cells of the blood-brain barrier in response to a systemic and localized inflammation but not during endotoxemia. J Neurosci 1999;19:10923–30.
11. Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM. Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer’s disease. J Neurosci 2005;25:8843–53.
12. Cunningham AJ, Murray CA, O’Neill LA, Lynch MA, O’Connor JJ. Interleukin-1β (IL-1 beta) and tumour necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro. Neurosci Lett 1996;203:17–20.
13. Ortiz GG, Pacheco-Moises FP, Macias-Islas MA, Flores-Alvarado LJ, Mireles-Ramirez MA, Gonzalez-Renovato ED, et al. Role of the blood-brain barrier in multiple sclerosis. Arch Med Res 2014;45:687–97.
14. Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 2018;14:133–50.
15. Desai BS, Monahan AJ, Carvey PM, Hendey B. Blood-brain barrier pathology in Alzheimer’s and Parkinson’s disease: implications for drug therapy. Cell Transplant 2007;16:285–99.
16. Garbuzova-Davis S, Sanberg PR. Blood-CNS Barrier Impairment in ALS patients versus an animal model. Front Cell Neurosci 2014;8:21.
17. Harry GJ, Kraft AD. Microglia in the developing brain: a potential target with lifetime effects. Neurotoxicology 2012;33:191–206.
18. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell 2010;140:918–34.
19. Akbar M, Essa MM, Daradkeh G, Abdelmegeed MA, Choi Y, Mahmood L, et al. Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress. Brain Res 2016;1637:34–55.
20. Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 2007;30:464–72.
21. Rothman SM, Griffioen KJ, Wan R, Mattson MP. Brain-derived neurotrophic factor as a regulator of systemic and brain energy metabolism and cardiovascular health. Ann N Y Acad Sci 2012;1264:49–63.
22. Voss MW, Vivar C, Kramer AF, van Praag H. Bridging animal and human models of exercise-induced brain plasticity. Trends Cogn Sci 2013;17:525–44.
23. Yoo SZ, No MH, Heo JW, Park DH, Kang JH, Kim JH, et al. Effects of acute exercise on mitochondrial function, dynamics, and mitophagy in rat cardiac and skeletal muscles. Int Neurourol J 2019;23:S22–31.
24. Mee-Inta O, Zhao ZW, Kuo YM. Physical exercise inhibits inflammation and microglial activation. 2019;8(7)pii: E691. https://doi.org/10.3390/cells8070691.
25. Yoo SZ, No MH, Heo JW, Chang E, Park DH, Kang JH, et al. Effects of a single bout of exercise on mitochondria-mediated apoptotic signaling in rat cardiac and skeletal muscles. J Exerc Rehabil 2019;15:512–7.
26. Yoo SZ, No MH, Heo JW, Park DH, Kang JH, Kim SH, et al. Role of exercise in age-related sarcopenia. J Exerc Rehabil 2018;14:551–8.
27. Nagamatsu LS, Flicker L, Kramer AF, Voss MW, Erickson KI, Hsu CL, et al. Exercise is medicine, for the body and the brain. Br J Sports Med 2014;48:943–4.
28. Gomez-Cabrera MC, Domenech E, Vina J. Moderate exercise is an antioxidant: upregulation of antioxidant genes by training. Free Radic Biol Med 2008;44:126–31.
29. Ferreira GD, Costa AC, Plentz RD, Coronel CC, Sbruzzi G. Respiratory training improved ventilatory function and respiratory muscle strength in patients with multiple sclerosis and lateral amyotrophic sclerosis: systematic review and meta-analysis. Physiotherapy 2016;102:221–8.
30. Braga ACM, Pinto A, Pinto S, de Carvalho M. The role of moderate aerobic exercise as determined by cardiopulmonary exercise testing in ALS. Neurol Res Int 2018;2018:8218697.
31. Park SS, Park HS, Jeong H, Kwak HB, No MH, Heo JW, et al. Treadmill exercise ameliorates chemotherapy-induced muscle weakness and central fatigue by enhancing mitochondrial function and inhibiting apoptosis. Int Neurourol J 2019;23:S32–9.
32. Filiano AJ, Gadani SP, Kipnis J. Interactions of innate and adaptive immunity in brain development and function. Brain Res 2015;1617:18–27.
33. Gehrmann J, Matsumoto Y, Kreutzberg GW. Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 1995;20:269–87.
34. Park SE, Sapkota K, Kim S, Kim H, Kim SJ. Kaempferol acts through mitogen-activated protein kinases and protein kinase B/AKT to elicit protection in a model of neuroinflammation in BV2 microglial cells. Br J Pharmacol 2011;164:1008–25.
35. Gilmore TD. Introduction to NF-kappaB: players, pathways, perspectives. Oncogene 2006;25:6680–4.
36. Huang WC, Hung MC. Beyond NF-kappaB activation: nuclear functions of IkappaB kinase alpha. J Biomed Sci 2013;20:3.
37. Okun E, Griffioen KJ, Lathia JD, Tang SC, Mattson MP, Arumugam TV. Toll-like receptors in neurodegeneration. Brain Res Rev 2009;59:278–92.
38. Wang L, Kou MC, Weng CY, Hu LW, Wang YJ, Wu MJ. Arsenic modulates heme oxygenase-1, interleukin-6, and vascular endothelial growth factor expression in endothelial cells: roles of ROS, NF-kappaB, and MAPK pathways. Arch Toxicol 2012;86:879–96.
39. Allan SM, Rothwell NJ. Inflammation in central nervous system injury. Philos Trans R Soc Lond B Biol Sci 2003;358:1669–77.
40. Cumiskey D, Curran BP, Herron CE, O’Connor JJ. A role for inflammatory mediators in the IL-18 mediated attenuation of LTP in the rat dentate gyrus. Neuropharmacology 2007;52:1616–23.
41. Nitsch R, Bechmann I, Deisz RA, Haas D, Lehmann TN, Wendling U, et al. Human brain-cell death induced by tumournecrosis-factor-related apoptosis-inducing ligand (TRAIL). Lancet 2000;356:827–8.
42. Blamire AM, Anthony DC, Rajagopalan B, Sibson NR, Perry VH, Styles P. Interleukin-1β-induced changes in blood-brain barrier permeability, apparent diffusion coefficient, and cerebral blood volume in the rat brain: a magnetic resonance study. J Neurosci 2000;20:8153–9.
43. Swaroop S, Sengupta N, Suryawanshi AR, Adlakha YK, Basu A. HSP60 plays a regulatory role in IL-1β-induced microglial inflammation via TLR4-p38 MAPK axis. J Neuroinflammation 2016;13:27.
44. Galluzzi L, Kepp O, Kroemer G. Mitochondria: master regulators of danger signalling. Nat Rev Mol Cell Biol 2012;13:780–8.
45. Mathew A, Lindsley TA, Sheridan A, Bhoiwala DL, Hushmendy SF, Yager EJ, et al. Degraded mitochondrial DNA is a newly identified subtype of the damage associated molecular pattern (DAMP) family and possible trigger of neurodegeneration. J Alzheimers Dis 2012;30:617–27.
46. Andreeva TV, Lukiw WJ, Rogaev EI. Biological basis for amyloidogenesis in Alzheimer’s disease. Biochemistry (Mosc) 2017;82:122–39.
47. Trovato Salinaro A, Pennisi M, Di Paola R, Scuto M, Crupi R, Cambria MT, et al. Neuroinflammation and neurohormesis in the pathogenesis of Alzheimer’s disease and Alzheimer-linked pathologies: modulation by nutritional mushrooms. Immun Ageing 2018;15:8.
48. Calsolaro V, Edison P. Neuroinflammation in Alzheimer’s disease: current evidence and future directions. Alzheimers Dement 2016;12:719–32.
49. Morales I, Guzman-Martinez L, Cerda-Troncoso C, Farias GA, Maccioni RB. Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci 2014;8:112.
50. McNaull BB, Todd S, McGuinness B, Passmore AP. Inflammation and anti-inflammatory strategies for Alzheimer’s disease--a minireview. Gerontology 2010;56:3–14.
51. Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol 2014;14:463–77.
52. Tansey MG, McCoy MK, Frank-Cannon TC. Neuroinflammatory mechanisms in Parkinson’s disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol 2007;208:1–25.
53. Kalia LV, Lang AE. Parkinson’s disease. Lancet 2015;386:896–912.
54. Mahlknecht P, Poewe W. Is there a need to redefine Parkinson’s disease? J Neural Transm (Vienna) 2013;120 Suppl 1:S9–17.
55. Marques O, Outeiro TF. Alpha-synuclein: from secretion to dysfunction and death. Cell Death Dis 2012;3:e350.
56. Morris JK, Bomhoff GL, Gorres BK, Davis VA, Kim J, Lee PP, et al. Insulin resistance impairs nigrostriatal dopamine function. Exp Neurol 2011;231:171–80.
57. Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, et al. Aggregated α-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 2005;19:533–42.
58. Banati RB, Daniel SE, Blunt SB. Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson’s disease. Mov Disord 1998;13:221–7.
59. Nagatsu T, Mogi M, Ichinose H, Togari A. Cytokines in Parkinson’s disease. J Neural Transm Suppl 2000;(58):143–51.
60. Reynolds AD, Glanzer JG, Kadiu I, Ricardo-Dukelow M, Chaudhuri A, Ciborowski P, et al. Nitrated alpha-synuclein-activated microglial profiling for Parkinson’s disease. J Neurochem 2008;104:1504–25.
61. Ruberg M, France-Lanord V, Brugg B, Lambeng N, Michel PP, Anglade P, et al. Neuronal death caused by apoptosis in Parkinson disease. Rev Neurol (Paris) 1997;153:499–508.
62. Just-Borràs L, Hurtado E, Cilleros-Mane V, Biondi O, Charbonnier F, Tomas M, et al. Running and swimming prevent the deregulation of the BDNF/TrkB neurotrophic signalling at the neuromuscular junction in mice with amyotrophic lateral sclerosis. Cell Mol Life Sci Cell Mol Life Sci 2019;Oct. 23. [Epub]. https://doi.org/10.1007/s00018-019-03337-5.
63. Brites D, Vaz AR. Microglia centered pathogenesis in ALS: insights in cell interconnectivity. Front Cell Neurosci 2014;8:117.
64. Meissner F, Molawi K, Zychlinsky A. Mutant superoxide dismutase 1-induced IL-1β accelerates ALS pathogenesis. Proc Natl Acad Sci U S A 2010;107:13046–50.
65. Watanabe M, Dykes-Hoberg M, Culotta VC, Price DL, Wong PC, Rothstein JD. Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. Neurobiol Dis 2001;8:933–41.
66. Forsberg K, Graffmo K, Pakkenberg B, Weber M, Nielsen M, Marklund S, et al. Misfolded SOD1 inclusions in patients with mutations in C9orf72 and other ALS/FTD-associated genes. J Neurol Neurosurg Psychiatry 2019;90:861–9.
67. Gordon R, Albornoz EA, Christie DC, Langley MR, Kumar V, Mantovani S, et al. Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med 2018;10(465)pii: eaah4066. https://doi.org/10.1126/scitranslmed.aah4066.
68. Moreno B, Jukes JP, Vergara-Irigaray N, Errea O, Villoslada P, Perry VH, et al. Systemic inflammation induces axon injury during brain inflammation. Ann Neurol 2011;70:932–42.
69. Fransson ME, Liljenfeldt LS, Fagius J, Totterman TH, Loskog AS. The T-cell pool is anergized in patients with multiple sclerosis in remission. Immunology 2009;126:92–101.
70. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008;358:676–88.
71. Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, et al. Interleukin-17 production in central nervous systeminfiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 2008;172:146–55.
72. Kim D, Cho J, Kang H. Protective effect of exercise training against the progression of Alzheimer’s disease in 3xTg-AD mice. Behav Brain Res 2019;374:112105.
73. Kim D, Cho J, Lee I, Jin Y, Kang H. Exercise attenuates high-fat diet-induced disease progression in 3xTg-AD mice. Med Sci Sports Exerc 2017;49:676–86.
74. Kohman RA, DeYoung EK, Bhattacharya TK, Peterson LN, Rhodes JS. Wheel running attenuates microglia proliferation and increases expression of a proneurogenic phenotype in the hippocampus of aged mice. Brain Behav Immun 2012;26:803–10.
75. Barrientos RM, Frank MG, Crysdale NY, Chapman TR, Ahrendsen JT, Day HE, et al. Little exercise, big effects: reversing aging and infection-induced memory deficits, and underlying processes. J Neurosci 2011;31:11578–86.
76. Tapia-Rojas C, Aranguiz F, Varela-Nallar L, Inestrosa NC. Voluntary running attenuates memory loss, decreases neuropathological changes and induces neurogenesis in a mouse model of Alzheimer’s disease. Brain Pathol 2016;26:62–74.
77. Rodriguez JJ, Noristani HN, Verkhratsky A. Microglial response to Alzheimer’s disease is differentially modulated by voluntary wheel running and enriched environments. Brain Struct Funct 2015;220:941–53.
78. Zhang X, He Q, Huang T, Zhao N, Liang F, Xu B, et al. Treadmill exercise decreases abeta deposition and counteracts cognitive decline in APP/PS1 mice, possibly via hippocampal microglia modifications. Front Aging Neurosci 2019;11:78.
79. Um HS, Kang EB, Leem YH, Cho IH, Yang CH, Chae KR, et al. Exercise training acts as a therapeutic strategy for reduction of the pathogenic phenotypes for Alzheimer’s disease in an NSE/APPsw-transgenic model. Int J Mol Med 2008;22:529–39.
80. Bo H, Kang W, Jiang N, Wang X, Zhang Y, Ji LL. Exercise-induced neuroprotection of hippocampus in APP/PS1 transgenic mice via upregulation of mitochondrial 8-oxoguanine DNA glycosylase. Oxid Med Cell Longev 2014;2014:834502.
81. Kim BK, Ko IG, Kim SE, Kim CJ, Yoon JS, Baik HH, et al. Impact of several types of stresses on short-term memory and apoptosis in the hippocampus of rats. Int Neurourol J 2013;17:114–20.
82. Heo YM, Shin MS, Lee JM, Kim CJ, Baek SB, Kim KH, et al. Treadmill exercise ameliorates short-term memory disturbance in scopolamine-induced amnesia rats. Int Neurourol J 2014;18:16–22.
83. Ba F, Obaid M, Wieler M, Camicioli R, Martin WR. Parkinson disease: the relationship between non-motor symptoms and motor phenotype. Can J Neurol Sci 2016;43:261–7.
84. Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron 2003;39:889–909.
85. van der Kolk NM, de Vries NM, Kessels RPC, Joosten H, Zwinderman AH, Post B, et al. Effectiveness of home-based and remotely supervised aerobic exercise in Parkinson’s disease: a double-blind, randomised controlled trial. Lancet Neurol 2019;18:998–1008.
86. Tang L, Fang Y, Yin J. The effects of exercise interventions on Parkinson’s disease: a Bayesian network meta-analysis. J Clin Neurosci 2019;70:47–54.
87. Real CC, Garcia PC, Britto LRG. Treadmill exercise prevents increase of neuroinflammation markers involved in the dopaminergic damage of the 6-OHDA Parkinson’s disease model. J Mol Neurosci 2017;63:36–49.
88. Tuon T, Valvassori SS, Lopes-Borges J, Luciano T, Trom CB, Silva LA, et al. Physical training exerts neuroprotective effects in the regulation of neurochemical factors in an animal model of Parkinson’s disease. Neuroscience 2012;227:305–12.
89. Koo JH, Jang YC, Hwang DJ, Um HS, Lee NH, Jung JH, et al. Treadmill exercise produces neuroprotective effects in a murine model of Parkinson’s disease by regulating the TLR2/MyD88/NFkappaB signaling pathway. Neuroscience 2017;356:102–13.
90. Frazzitta G, Maestri R, Bertotti G, Riboldazzi G, Boveri N, Perini M, et al. Intensive rehabilitation treatment in early Parkinson’s disease: a randomized pilot study with a 2-year follow-up. Neurorehabil Neural Repair 2015;29:123–31.
91. Zoladz JA, Majerczak J, Zeligowska E, Mencel J, Jaskolski A, Jaskolska A, et al. Moderate-intensity interval training increases serum brain-derived neurotrophic factor level and decreases inflammation in Parkinson’s disease patients. J Physiol Pharmacol 2014;65:441–8.
92. Bloomer RJ, Schilling BK, Karlage RE, Ledoux MS, Pfeiffer RF, Callegari J. Effect of resistance training on blood oxidative stress in Parkinson disease. Med Sci Sports Exerc 2008;40:1385–9.
93. Lee JM, Kim TW, Park SS, Han JH, Shin MS, Lim BV, et al. Treadmill exercise improves motor function by suppressing purkinje cell loss in Parkinson disease rats. Int Neurourol J 2018;22(Suppl 3):S147–55.
94. Flis DJ, Dzik K, Kaczor JJ, Halon-Golabek M, Antosiewicz J, Wieckowski MR, et al. Swim training modulates skeletal muscle energy metabolism, oxidative stress, and mitochondrial cholesterol content in amyotrophic lateral sclerosis mice. Oxid Med Cell Longev 2018;2018:5940748.
95. Flis DJ, Dzik K, Kaczor JJ, Cieminski K, Halon-Golabek M, Antosiewicz J, et al. Swim training modulates mouse skeletal muscle energy metabolism and ameliorates reduction in grip strength in a mouse model of amyotrophic lateral sclerosis. Int J Mol Sci 2019;20(2)pii: E233. https://doi.org/10.3390/ijms20020233.
96. Kassa RM, Bonafede R, Boschi F, Bentivoglio M, Mariotti R. Effect of physical exercise and anabolic steroid treatment on spinal motoneurons and surrounding glia of wild-type and ALS mice. Brain Res 2017;1657:269–78.
97. Lisle S, Tennison M. Amyotrophic lateral sclerosis: the role of exercise. Curr Sports Med Rep 2015;14:45–6.
98. Kierkegaard M, Lundberg IE, Olsson T, Johansson S, Ygberg S, Opava C, et al. 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. J Neurol Sci 2016;362:251–7.
99. White LJ, Castellano V, Mc Coy SC. Cytokine responses to resistance training in people with multiple sclerosis. J Sports Sci 2006;24:911–4.
100. Donia SA, Allison DJ, Gammage KL, Ditor DS. The effects of acute aerobic exercise on mood and inflammation in individuals with multiple sclerosis and incomplete spinal cord injury. Neuro-Rehabilitation 2019;45:117–24.
101. Ozkul C, Guclu-Gunduz A, Irkec C, Fidan I, Aydin Y, Ozkan T, et al. Effect of combined exercise training on serum brain-derived neurotrophic factor, suppressors of cytokine signaling 1 and 3 in patients with multiple sclerosis. J Neuroimmunol 2018;316:121–9.
102. Castellano V, Patel DI, White LJ. Cytokine responses to acute and chronic exercise in multiple sclerosis. J Appl Physiol (1985) 2008;104:1697–702.

Article information Continued

Table 1.

The effects of exercise on Alzheimer disease (AD)

Subjects Exercise protocol Effect Reference
3xTG-AD mice Treadmill running ↓Aβ plaque burden Kim et al. [72]
6 m/min to 20 m/min for 40 min, 5 days per week for 12 weeks ↓Neuroinflammation
↓Mitochondrial dysfunction
HFD with 3xTG-AD mice Treadmill running ↓Neuroinflammation Kim et al. [73]
5 m/min to 10 m/min for 30 min, 5 days per week for 20 weeks ↓Apoptotic neuronal cell death
BALB/c mice Wheel running for 8 weeks ↑Microglia expression Kohman et al. [74]
↑IGF expression
APPswe/PSEN1ΔE9 mice Voluntary running for 10 weeks ↓Neuronal loss Tapia-Rojas et al. [76]
↓Spatial memory loss
3xTg-AD mouse model of AD Voluntary wheel running for 9 months ↑Microglia surface, volume, and soma volume Rodriguez et al. [77]
APP/PS1 mice Treadmill running at 12 m/min for 45 min, 5 days/week for 12 weeks ↓Pro-inflammatory factors Zhang et al. [78]
↑SOD and Mn-SOD
APP/PS1 Tg mice with AD phenotype Treadmill running at 11 m/min for 30 min, 5 days/week for 20 weeks ↓ROS generation Bo et al. [80]
↓mtDNA oxidative damage
↑Mitochondrial antioxidant enzymes

Aβ, amyloid beta; HFD, high-fat-diet; IGF, insulin-like growth factor; APP, amyloid precursor protein; MDA, malondialdehyde; SOD, superoxide dismutase; ROS, reactive oxygen species; ↑, increase; ↓, decrease.

Table 2.

The effects of exercise on Parkinson disease (PD)

Subjects Exercise protocol Effect Reference
6-OHDA-induced rats Treadmill running at 10 m/min for 40 min, 3 days per week for 30 days ↑Motor behavior Real et al. [87]
↑CD-11c/b expression
↑GFAP immunostaining
MPTP-injected C57BL6J mice Treadmill running at 10 m/min for 60 min, 5 days per week for 8 weeks ↓TLR2 expression Koo et al. [89]
↓Microglial activation
↓ROS, apoptosis
↓NADPH oxidase subunit expression
↓TNF-α, NF-κB, and IL-1β
6-OHDA-induced rats Treadmill running at 13–17 m/min, 3 or 4 days/week for 8 weeks ↑BNDF, SERCA II, Tuon et al. [88]
↑SOD and CAT
↓Oxidative damage
PD patients Treadmill exercise, heart rate reserve of 60%–70% at maximal speed of treadmill ↑Serum BDNF by 16% Frazzitta et al. [90]
Scrolling of 3.5 km/h for 30 min, every day for 4 weeks ↓UPDRS
PD patients Moderate-intensity interval training using cycling at 60%–75% of patients’ individualized maximum heartrate ↓Serum soluble vascular cell adhesion molecule 1 Zoladz et al. [91]
↓Serum BDNF
↓TNF-α level
PD patients Resistance exercise, 3 to 5 times of a 1-repetition maximum for 8 weeks. ↓Oxidative stress Bloomer et al. [92]
No change in SOD
No change in glutathione peroxidase

CD-11c/b, microglial activation; GFAP, glial fibrillary acidic protein; TLR2, toll-like receptor 2; ROS, reactive oxygen species; NADPH, nicotinamide adenine dinucleotide phosphate; TNF-α, tumor necrosis factor-α; NF-κB, nuclear transcription factor-κB; IL-1β, interleukin-1β; BNDF, brain-derived neurotrophic factor; SERCA, sarcoplasmic reticulum Ca2+ ATPase; SOD, superoxide dismutase; CAT, catalase; UPDRS, Unified Parkinson’s Disease Rating Scale; ↑, increase; ↓, decrease.

Table 3.

The effects of exercise on amyotrophic lateral sclerosis (ALS)

Subjects Exercise protocol Effect Reference
ALS mice Running (13 m/min) or swimming for 40 min, 5 days/wk for 45 days ↑BDNF Just-Borràs et al. [62]
↑PKA activation
ALS mice Swimming training for 30 min, 5 days/wk for 15 weeks ↑Citrate synthase Flis et al. [95]
No MDH or COX activity, and mitochondrial consumption
ALS mice Treadmill running ↑Microglia activation Kassa et al. [96]
20 m/min for 45 min, 5 days/wk for 7 weeks ↑Motor neuron counts

BNDF, brain-derived neurotrophic factor; TrkB.T1, truncated trkB receptor; PKA, protein kinase A; MDH, malate dehydrogenase; COX, cyclooxygenase; ↑, increase; ↓, decrease.

Table 4.

The effects of exercise on multiple sclerosis (MS)

Subjects Exercise protocol Effect Reference
MS patients Resistance exercise twice a week for 60 min for 12 weeks ↓Plasma TNF- α Kierkegaard et al. [98]
No change in IL-6 and IL-17
MS patients Acute aerobic exercise 30 minutes of exercise at 60% of their previous VO2 peak ↓Plasma TNF-α Donia et al. [100]
MS patients Combined exercise training consisting of aerobic training and Pilates training, at 60%–70% of MHR during the first 4 weeks, and 70%–80% of MHR during the last 4 weeks ↑BDNF Ozkul et al. [101]
↑Physical performance
No change in SOCS1 or SOCS3
MS patients Cycle ergometry at 60% of peak O2 uptake, 3 days/wk for 8 weeks ↓Plasma TNF-α, IL-6, and IFN-γ Castellano et al. [102]
MS patients 50%–70% of MVC, one set of 10–15 repetitions for 8 weeks ↓IL-4, IL-10, CRP and IFN-γ White et al. [99]

TNF-α, tumor necrosis factor-α; IL, interleukin; MHR, maximum heart rate; SOCS, suppressors of cytokine signaling; MVC, maximal voluntary isometric contraction; CRP, C-reactive protein; IFN, interferon; ↑, increase; ↓, decrease.