Available online at www.sciencedirect.
com Current Opinion in
ScienceDirect
MedXercise: a promising strategy to promote
remyelination
Emily Wuerch, Brian Lozinski and V. Wee Yong
Abstract
Multiple sclerosis is an inflammatory and demyelinating dis-
ease of the central nervous system.
While remyelination facilitates functional recovery in animal
models, it is limited in people with multiple sclerosis. Thus,
multiple strategies have been put forth to promote remyelina-
tion, including exercise and medication. Exercise promotes the
release of growth factors and induces protein-level changes,
while remyelinating medications act through a variety of
mechanisms to promote oligodendrocyte maturation within the
lesion. In animal models, the combination of medication and
exercise (Medication + eXercise = MedXercise) has an addi-
tive effect on remyelination and other pathological features of
multiple sclerosis. In this review, we highlight the existing
literature on the effects of exercise and medication on remye-
lination both independently and in combination.
Addresses
Hotchkiss Brain Institute and the Department of Clinical Neurosci-
ences, University of Calgary, Calgary, AB, Canada
Corresponding author: Yong, V. Wee (vyong@ucalgary.ca)
Current Opinion in Pharmacology 2021, 61:120–126
This review comes from a themed issue on Neurosciences: Remyeli-
nation (2022)
Edited by Jeffrey Huang and Tara DeSilva
For complete overview about the section, refer Neurosciences:
Remyelination (2022)
Available online 21 October 2021
https://doi.org/10.1016/j.coph.2021.09.006
1471-4892/© 2021 Elsevier Ltd. All rights reserved.
Introduction
Multiple sclerosis (MS) is a chronic inflammatory dis-
ease of the central nervous system (CNS) character-
ized by demyelination and progressive
neurodegeneration. Demyelination impedes saltatory
conduction and leads to the loss of trophic support for
underlying axons, ultimately producing a range of
functional deficits [15]. Remyelination occurs when
oligodendrocyte progenitor cells (OPCs) migrate to the
lesion and differentiate into mature myelinating oligo-
dendrocytes [40,17]. Work in animal models has
demonstrated that remyelination produces thinner, yet
Current Opinion in Pharmacology 2021, 61:120–126
Pharmacology
functional myelin sheaths, and is associated with axon
survival [32,34]. Indeed, cessation of a demyelinating
diet in cats shows an association between remyelination
of the optic nerve and restoration of vision [13]. In
addition, positron emission tomography images
demonstrate that, in people with MS, an inverse cor-
relation exists between dynamic remyelination and
clinical disability [4]. Despite its benefits, remyelina-
tion is often insufficient in MS lesions leading to
chronic demyelination and subsequent axonal degen-
eration [16]. Thus, strategies to promote remyelination
are needed (see Figure 1).
Several medications enhance remyelination by targeting
OPCs and promoting their differentiation into mature
oligodendrocytes [44]. As well, exercise is a promising
non-pharmacological strategy to promote remyelination
in individuals with MS, potentially acting through the
release of growth factors and modulation of the immune
system [6,20]. Mice with access to a running wheel after
demyelination display numerous local protein changes
in the spinal cord [30]. Therefore, exercise may repre-
sent an opportunity to create a more receptive envi-
ronment for remyelination while medications enhance
the OPC response. Given that these therapeutic stra-
tegies appear to act through independent mechanisms,
it is possible that their combination
(Medication þ eXercise = MedXercise) may have an ad-
ditive effect on remyelination. Here, we will review
existing MedXercise literature examining the effect of
exercise and medication on remyelination both inde-
pendently and in combination.
Effects of exercise in the CNS
Exercise has many neuroprotective effects, as demon-
strated in both animal models and humans. Exercise is
known to exert an anti-inflammatory effect through
modulation of cytokine release [1,39], stimulate the
release of growth factors, and promote neurogenesis
[28,10]. Exercise also upregulates antioxidants and
protects against oxidative damage [47].
In animal models of MS, exercise enhances remyeli-
nation. For example, in the lysolecithin model of
demyelination, voluntary wheel running increases the
number of mature oligodendrocytes within the lesion
and promotes remyelination [23]. Furthermore, in
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 MedXercise for myelin repair Wuerch et al. 121

Figure 1

The effect of exercise and medication on MS lesions. MS lesions are characterized by infiltrating immune cells and dysregulated extracellular matrix
components. Examples of the latter include collagens, hyaluronan, laminins, chondroitin sulfate proteoglycans (CSPGs) and fibronectin. Exercise
modifies the lesion microenvironment through the release of growth factors and myokines, as well as through protein-level changes. These changes
create a regenerative environment that is more conducive for a medication to act on. OPCs within the lesion are targeted directly by remyelinating
medications. These medications bind to receptors on the surface of OPCs and promote their maturation into mature and myelinating oligodendrocytes.
MS, multiple sclerosis; OPC, oligodendrocyte progenitor cell.

mice subjected to cuprizone-mediated demyelination,
exercise preserves myelin expression and reduces
axonal damage compared with controls [31]. In addi-
tion, research in healthy mice demonstrates that
voluntary wheel running increases myelin thickness
and the number of myelinated axons in the motor
cortex [55].
Studying the effect of exercise on remyelination in
people with MS presents unique challenges due to
disability and the Unthoff ’s phenomenon (worsening of
symptoms when the body is over-heated). Nonetheless,
promising data indicates that exercise is protective
against MS neuropathology. In individuals with MS,
increased cardiorespiratory fitness is associated with
preserved grey matter volume and increased white
matter integrity [45]. Furthermore, preliminary data
shows that aerobic exercise leads to an increase in hip-
pocampal volume from baseline in people with MS
suggesting a role for exercise in delaying MS-related
neurodegeneration [27]. In addition to neuro-
degeneration, exercise may also play a role in restoring
the integrity of the bloodebrain barrier (BBB). After a
high-intensity interval training regimen, people with
MS have reduced serum levels of MMP-2 compared
with baseline [57]. In normal-weight individuals with
MS, an eight-week exercise training program decreases
blood levels of S100b and neuron-specific enolase [37].
These markers indicate the degree of BBB integrity and
function; restoration of BBB integrity may decrease the
extent of immune cell infiltration and neuro-
inflammation that occurs in MS.
Taken together, these studies illustrate the beneficial
effects of exercise, both for general health as well as in
the context of MS and remyelination.
Mechanisms of exercise
Although not completely elucidated, exercise is thought
to exert its protective effects in part through modulation
of the CNS microenvironment. This is accomplished
through the release of growth factors and myokines
(cytokines released from contracting skeletal muscles),
as well as exercise-induced protein-level changes.

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122 Neurosciences: Remyelination
Brain-derived neurotrophic factor (BDNF) likely plays
a central role in the actions of exercise and is consis-
tently shown to be upregulated in both healthy humans
and people with MS following aerobic exercise
[5,11,37]. In addition to a role for BDNF in neuro-
genesis and long-term potentiation [36], it is also
implicated in MS pathology. In experimental autoim-
mune encephalomyelitis (EAE) mice that model MS,
intravenous administration of BDNF in combination
with the BBB modulator ADTC5 ameliorates clinical
disease, increases myelin staining, and promotes
oligodendrocyte maturation [25]. In addition, BDNF
knockdown mice fed a cuprizone diet have decreased
NG2þ OPCs compared with wildtype counterparts,
indicating a role for BDNF in OPC recruitment after
demyelination [51].
Irisin is a myokine released from contracting skeletal
muscles that may partially facilitate the neuro-
protective effects of exercise. During exercise, the
transcriptional coactivator PGC-1a (peroxisome
proliferator-activated receptor-gamma coactivator-1a)
upregulates the expression of FNDC5 (fibronectin
type III domain-containing protein 5); FNDC5 is then
cleaved, and the cleavage product that is secreted into
circulation is irisin [46]. Although not yet studied in
the context of MS, irisin is capable of crossing the BBB
[43] and has been shown to exert protective effects on
the CNS, including improved synaptic plasticity [29].
Studies performed on transgenic mice with down-
regulated FNDC5 expression have also demonstrated
a relationship between FNDC5 and BDNF expression,
suggesting that FNDC5/irisin may be an upstream
regulator of BDNF levels [54]. Thus, the exercise-
induced release of irisin may lead to BDNF-
dependent increases in OPC recruitment
and differentiation.
In addition to the above examples, exercise leads to the
release of several other factors, which may work to
mediate its effects on the CNS. These include the
ketone body b-hydroxybutyrate [50], a liver-derived
enzyme Gpld1 [22], the protease cathepsin B [38],
and an anti-inflammatory factor clusterin [9]. Taken
together, it is clear that exercise orchestrates a highly
complex release of local and systemic factors to partially
mediate its effects on the CNS.
A major consideration when it comes to exercise for
therapeutic intervention is the duration and onset of
exercise. Acute bouts of exercise following lysolecithin-
induced demyelination lead to the differential expres-
sion of over 150 proteins compared with sedentary
controls [30]. In the CNS, affected pathways involve
processes such as metabolism, antioxidant responses,
and synaptic transmission.
Current Opinion in Pharmacology 2021, 61:120–126
Exercise may also promote remyelination through its
effects on neuronal activity. Exercise increases neuronal
activity in the hippocampi of rodents, and increased
duration and intensity of exercise are associated with
greater neuronal activation [48]. In people with
Parkinson’s disease, physical activity leads to increased
neuronal activity in the prefrontal cortex and substantia
nigra, as detected using functional MRI [24]. In animal
models of MS, neuronal activity has been shown to in-
crease remyelination. After lysolecithin-induced demy-
elination, repeated optogenetic activation of neurons in
the corpus callosum enhances oligodendrocyte differ-
entiation and increases remyelination within the lesion
site [42]. In mice subject to ethidium bromide-induced
demyelination, inhibition of neuronal activity prevents
remyelination and increases the number of undifferen-
tiated OPCs in the lesion [19]. Thus, there may be a
link between exercise and neuronal activity, which
works to promote remyelination.
In sum, these findings demonstrate a role for exercise in
remyelination and neuroprotection, likely through a
wide range of mechanisms, including modulation of the
CNS microenvironment and release of various factors.
Of note, further elucidation of the specific molecules
and signalling pathways upregulated because exercise
may allow for the development of an exercise mimetic
that recapitulates the protective effects of exercise.
Such therapeutics would be of particular interest in
diseases such as MS, where individuals often experience
limited mobility.
Remyelinating medications
There are several theories as to why remyelination fails in
MS. Generally, these can be broken into the failure of
OPCs to migrate, proliferate, or mature in the lesion. The
evidence suggests that the rate-limiting step for remye-
lination occurs due to OPC failure to mature into myeli-
nating oligodendrocytes [53]. Furthermore, previous
studies have also demonstrated that OPCs can be present
in sufficient numbers in MS lesions [52,26]; thus, most
medications aim to promote OPC differentiation into
mature and myelinating oligodendrocytes. In addition to
lifestyle-based approaches such as exercise, success has
been found with pharmacological strategies that aim to
promote remyelination by targeting OPCs directly.
Among these OPC-targeting therapeutics are clemas-
tine, first identified in a micropillar assay for its potential
to enhance remyelination [33]. Clemastine is an anti-
cholinergic agent which acts to antagonize the M1
muscarinic receptor found on the surface of OPCs [
[8,34]]. In the lysolecithin model, treatment with
clemastine increases the number of mature oligoden-
drocytes when compared with controls [23]. Moreover,
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treatment with clemastine reduces clinical score and
promotes remyelination in EAE mice [35].
U-50488 is among a group of k-opioid receptor agonists
that bind receptors found on OPCs and promote their
differentiation into mature oligodendrocytes [34,2].
Application of U-50488 to OPCs in culture leads to
increased remyelination, as indicated by an elegant
micropillar assay. Furthermore, U-50488 leads to
decreased demyelination in the EAE model and
increased remyelination in mice subjected to cuprizone
[12]. In the lysolecithin model, treatment with U-50488
increases the proportion of myelinated axons when
compared with vehicle controls [34].
In addition to these examples, there are many additional
medications that exert their effects on OPCs, including
domperidone [56], thyroid hormone [21] and metfor-
min [41]. In sum, these findings demonstrate the po-
tential for therapeutics to enhance remyelination by
acting directly on OPC differentiation.
Medxercise
Research in animal models of MS suggests that medi-
cation and exercise may promote remyelination to a
greater extent than either therapy on its own.
When combined with voluntary wheel running, clem-
astine has an additive effect on remyelination in the
lysolecithin model of demyelination [23]. Compared to
individual treatments of either exercise or medication,
combination therapy leads to enhanced myelin thick-
ness and an increase in the proportion of surviving axons
that are remyelinated. Furthermore, this combination
increases the number of mature oligodendrocytes pre-
sent within the lesion.
In EAE mice, four weeks of prior treadmill exercise was
combined with the immunomodulatory therapeutics
glatiramer acetate or dimethyl fumarate [3]. When
compared to exercise on its own, exercise and glatiramer
acetate together lead to reduced astrocyte immunoreac-
tivity in the spinal cord. In addition, the combination of
dimethyl fumarate and exercise ameliorates clinical
symptoms and increases Iba1 immunoreactivity compared
with mice that receive dimethyl fumarate on their own.
One possible explanation is that exercise and dimethyl
fumarate work additively to modulate the microglia/
macrophage population, promoting a neuroprotective
phenotype. This data suggests that a lifestyle consisting of
regular exercise can work in conjunction with disease-
modifying therapeutics to ameliorate disease.
In the EAE model of MS, there is increased apoptosis in
the CNS [7]. In rats with EAE, the combination treat-
ment of exercise and galantamine elevates expression of
the anti-apoptotic factor Bcl-2 and reduces the
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MedXercise for myelin repair Wuerch et al. 123
apoptosis-inducing factor Bax [14]. This has implica-
tions for MS, as apoptosis has been associated with
neurodegeneration [18,49].
Although current data regarding the effect of MedXer-
cise on remyelination is somewhat limited, it is indeed
promising. Further investigation is needed to elucidate
the neuroprotective mechanisms of MedXercise before
its translation into clinical trials for MS.
Conclusions and future directions
In conclusion, studies in animal models have demon-
strated that exercise and medication are independently
capable of promoting remyelination. Emerging data also
support the idea that combination therapy of medica-
tion and exercise (MedXercise) may have an additive
effect and promote remyelination and neuroprotection
better than either therapy on its own.
Before MedXercise can be translated into human trials,
there are several unanswered questions that must be
resolved. First, whether or not different types of exercise
provide different levels of neuroprotection is unclear.
Although aerobic exercise is most commonly studied in
animal models, the types of exercise that could be
employed by individuals with MS are variable; this could
include but is not limited to aerobic, strength, or balance
training. Thus, this field would benefit from additional
studies examining a range of exercise paradigms.
In addition, the minimum intensity of exercise required
to obtain neuroprotection is not well-understood.
Although some studies have indicated that higher in-
tensity exercise may confer greater benefit than mod-
erate intensity, this may not be feasible for individuals
with MS that experience fatigue or reduced motor
function and may not be able to participate in rigorous
exercise paradigms. Thus, the minimum intensity of
exercise, that is, required to obtain a therapeutic effect
is unclear but of great interest to this population.
Furthermore, the development of an exercise mimetic is
another promising strategy to promote exercise-induced
remyelination in individuals with limited capacity for
intense physical activity.
Finally, thus far only clemastine, dimethyl fumarate,
glatiramer acetate, and galantamine have been tested in
conjunction with exercise. There exists a range of MS
medications that act through different mechanisms,
such as regulation of the immune system, promotion of
OPC differentiation, and inhibition of non-permissive
factors. Whether one drug category interacts most
ideally with exercise is still yet to be determined. In
addition, the optimal dose and temporal administration
of both exercise and medication are important factors
that must be elucidated before the translation of
MedXercise into MS clinical trials.
Current Opinion in Pharmacology 2021, 61:120–126
124 Neurosciences: Remyelination
Despite these remaining questions, MedXercise is a
promising strategy to promote remyelination, one that
warrants further investigation.
Conflict of interest statement
Nothing declared.
Acknowledgements
The authors acknowledge operating grant support from the Canadian In-
stitutes of Health Research and the MS Society of Canada. EW is
supported by studentships from the Hotchkiss Brain Institute and the
Province of Alberta. BL is supported by a studentship from the MS Society
of Canada. VWY acknowledges salary support from the Canada Research
Chair (Tier 1) program.
References
Papers of particular interest, published within the period of review,
have been highlighted as:
* of special interest
1. Agarwal D, Welsch MA, Keller JN, Francis J: Chronic exercise
modulates RAS components and improves balance between
pro- and anti-inflammatory cytokines in the brain of SHR.
Basic Res Cardiol 2011, 106:1069–1085, https://doi.org/10.1007/
s00395-011-0231-7.
2. Beck TC, Hapstack MA, Beck KR, Dix TA: Therapeutic potential
of kappa opioid agonists. Pharmaceuticals 2019, 12:95, https://
doi.org/10.3390/ph12020095.
3. Bernardes D, Oliveira A L R de: Regular exercise modifies
histopathological outcomes of pharmacological treatment in
experimental autoimmune encephalomyelitis. Front Neurol
2018, 9:950, https://doi.org/10.3389/fneur.2018.00950.
4. Bodini B, Veronese M, García-Lorenzo D, Battaglini M, Poirion E,
Chardain A, Freeman L, Louapre C, Tchikviladze M, Papeix C,
Dollé F, Zalc B, Lubetzki C, Bottlaender M, Turkheimer F,
Stankoff B: Dynamic imaging of individual remyelination
profiles in multiple sclerosis. Ann Neurol 2016, 79, https://
doi.org/10.1002/ana.24620.
5. Briken S, Rosenkranz SC, Keminer O, Patra S, Ketels G,
Heesen C, Hellweg R, Pless O, Schulz K-H, Gold SM: Effects of
exercise on Irisin, BDNF and IL-6 serum levels in patients
with progressive multiple sclerosis. J Neuroimmunol 2016,
299:53–58, https://doi.org/10.1016/j.jneuroim.2016.08.007.
6. Cotman CW, Berchtold NC, Christie L-A: Exercise builds brain
health: key roles of growth factor cascades and inflamma-
tion. Trends Neurosci 2007, 30, https://doi.org/10.1016/
j.tins.2007.06.011. 464 472.
7. Dasgupta A, Zheng J, Perrone-Bizzozero NI, Bizzozero OA:
Increased carbonylation, protein aggregation and apoptosis
in the spinal cord of mice with experimental autoimmune
encephalomyelitis. ASN Neuro 2013, 5, https://doi.org/10.1042/
AN20120088. AN20120088.
8. De Angelis F, Bernardo A, Magnaghi V, Minghetti L, Tata AM:
Muscarinic receptor subtypes as potential targets to modu-
late oligodendrocyte progenitor survival, proliferation, and
differentiation. Develop Neurobiol 2012, 72:713–728, https://
doi.org/10.1002/dneu.20976.
9. De Miguel Z, Betley MJ, Willoughby D, Lehallier B, Olsson N,
Bonanno L, Fairchild KJ, Contrepois K, Elias JE, Rando TA,
Wyss-Coray T: Exercise conditioned plasma dampens
inflammation via clusterin and boosts memory [Preprint].
Neuroscience 2019, https://doi.org/10.1101/775288.
10. Di Liegro, Schiera Proia, Di Liegro: Physical activity and brain
health. Genes 2019, 10:720, https://doi.org/10.3390/
genes10090720.
11. Dinoff A, Herrmann N, Swardfager W, Liu CS, Sherman C,
Chan S, Lanctôt KL: The effect of exercise training on resting
concentrations of peripheral brain derived neurotrophic
Current Opinion in Pharmacology 2021, 61:120–126
factor (BDNF): a Meta-Analysis. PloS One 2016, 11, e0163037,
https://doi.org/10.1371/journal.pone.0163037.
12. Du C, Duan Y, Wei W, Cai Y, Chai H, Lv J, Du X, Zhu J, Xie X:
Kappa opioid receptor activation alleviates experimental
autoimmune encephalomyelitis and promotes
oligodendrocyte-mediated remyelination. Nat Commun 2016,
7:11120, https://doi.org/10.1038/ncomms11120.
13. Duncan ID, Brower A, Kondo Y, Curlee JF, Schultz RD: Exten-
sive remyelination of the CNS leads to functional recovery.
Proc Natl Acad Sci Unit States Am 2009, 106:6832–6836, https://
doi.org/10.1073/pnas.0812500106.
14. El-Emam MA, El Achy S, Abdallah DM, El-Abhar HS,
* Gowayed MA: Neuroprotective role of galantamine with/
without physical exercise in experimental autoimmune
encephalomyelitis in rats. Life Sci 2021, 277:119459, https://
doi.org/10.1016/j.lfs.2021.119459.
This study highlights the concept of MedXercise by demonstrating that
galantamine and exercise have an additive effect on modulation of
apoptotic factors in the EAE model of MS.
15. Ettle B, Schlachetzki JCM, Winkler J: Oligodendroglia and
myelin in neurodegenerative diseases: more than just by-
standers? Mol Neurobiol 2016, 53:3046–3062, https://doi.org/
10.1007/s12035-015-9205-3.
16. Fancy SPJ, Kotter MR, Harrington EP, Huang JK, Zhao C,
Rowitch DH, Franklin RJM: Overcoming remyelination failure
in multiple sclerosis and other myelin disorders. Exp Neurol
2010, 225:18–23, https://doi.org/10.1016/
j.expneurol.2009.12.020.
17. Franklin RJM, ffrench-Constant C: Regenerating CNS
myelin—from mechanisms to experimental medicines. Nat
Rev Neurosci 2017, 18:753–769, https://doi.org/10.1038/
nrn.2017.136.
18. Friese MA, Schattling B, Fugger L: Mechanisms of neuro-
degeneration and axonal dysfunction in multiple sclerosis.
Nat Rev Neurol 2014, 10:225–238, https://doi.org/10.1038/
nrneurol.2014.37.
19. Gautier HOB, Evans KA, Volbracht K, James R, Sitnikov S,
Lundgaard I, James F, Lao-Peregrin C, Reynolds R,
Franklin RJM, Káradóttir RT: Neuronal activity regulates
remyelination via glutamate signalling to oligodendrocyte
progenitors. Nat Commun 2015, 6:8518, https://doi.org/10.1038/
ncomms9518.
20. Gentile A, Musella A, De Vito F, Rizzo FR, Fresegna D, Bullitta S,
* Vanni V, Guadalupi L, Stampanoni Bassi M, Buttari F,
Centonze D, Mandolesi G: Immunomodulatory effects of ex-
ercise in experimental multiple sclerosis. Front Immunol 2019,
10:2197, https://doi.org/10.3389/fimmu.2019.02197.
This paper summarizes current literature regarding exercise in exper-
imental models of MS.
21. Hartley MD, Banerji T, Tagge IJ, Kirkemo LL, Chaudhary P,
Calkins E, Galipeau D, Shokat MD, DeBell MJ, Van Leuven S,
Miller H, Marracci G, Pocius E, Banerji T, Ferrara SJ, Meinig JM,
Emery B, Bourdette D, Scanlan TS: Myelin repair stimulated by
CNS-selective thyroid hormone action. JCI Insight 2019, 4,
e126329, https://doi.org/10.1172/jci.insight.126329.
22. Horowitz AM, Fan X, Bieri G, Smith LK, Sanchez-Diaz CI,
Schroer AB, Gontier G, Casaletto KB, Kramer JH, Williams KE,
Villeda SA: Blood factors transfer beneficial effects of exer-
cise on neurogenesis and cognition to the aged brain. Sci-
ence 2020, 369:167–173, https://doi.org/10.1126/
science.aaw2622.
23. Jensen SK, Michaels NJ, Ilyntskyy S, Keough MB, Kovalchuk O,
Yong VW: Multimodal enhancement of remyelination by ex-
ercise with a pivotal role for oligodendroglial PGC1a. Cell Rep
2018, 24:3167–3179, https://doi.org/10.1016/
j.celrep.2018.08.060.
24. Kelly NA, Wood KH, Allendorfer JB, Ford MP, Bickel CS,
Marstrander J, Amara AW, Anthony T, Bamman MM,
Skidmore FM: High-intensity exercise acutely increases
substantia nigra and prefrontal brain activity in Parkinson’s
disease. Med Sci Mon Int Med J Exp Clin Res 2017, 23:
6064–6071, https://doi.org/10.12659/MSM.906179.
www.sciencedirect.com

25. Kopec BM, Kiptoo P, Zhao L, Rosa-Molinar E, Siahaan TJ:
* Noninvasive brain delivery and efficacy of BDNF to stimulate
neuroregeneration and suppression of disease relapse in
EAE mice. Mol Pharmaceut ACS Molpharmaceut 2020, https://
doi.org/10.1021/acs.molpharmaceut.9b00644. 9b00644.
This paper shows that intravenous administration of BDNF can alle-
viate disease and promote oligodendrocyte maturation in the EAE
model, providing a potential mechanism through which exercise exerts
protective effects.
26. Kuhlmann T, Miron V, Cuo Q, Wegner C, Antel J, Bruck W: Dif-
ferentiation block of oligodendroglial progenitor cells as a
cause for remyelination failure in chronic multiple sclerosis.
Brain 2008, 131:1749–1758, https://doi.org/10.1093/brain/
awn096.
27. Leavitt VM, Cirnigliaro C, Cohen A, Farag A, Brooks M, Wecht JM,
Wylie GR, Chiaravalloti ND, DeLuca J, Sumowski JF: Aerobic
exercise increases hippocampal volume and improves
memory in multiple sclerosis: preliminary findings. Neuro-
case 2014, 20:695–697, https://doi.org/10.1080/
13554794.2013.841951.
28. Liu PZ, Nusslock R: Exercise-mediated neurogenesis in the
hippocampus via BDNF. Front Neurosci 2018, 12:52, https://
doi.org/10.3389/fnins.2018.00052.
29. Lourenco MV, Frozza RL, de Freitas GB, Zhang H, Kincheski GC,
* Ribeiro FC, Gonçalves RA, Clarke JR, Beckman D,
Staniszewski A, Berman H, Guerra LA, Forny-Germano L,
Meier S, Wilcock DM, de Souza JM, Alves-Leon S, Prado VF,
Prado MAM, De Felice FG: Exercise-linked FNDC5/irisin res-
cues synaptic plasticity and memory defects in Alzheimer’s
models. Nat Med 2019, 25:165–175, https://doi.org/10.1038/
s41591-018-0275-4.
This paper demonstrates the role of FNDC5/irisin in mediating
exercise-induced neuroprotection.
30. Lozinski BM, de Almeida LGN, Silva C, Dong Y, Brown D,
Chopra S, Yong VW, Dufour A: Exercise rapidly alters
proteomes in mice following spinal cord demyelination. Sci
Rep 2021, 11:7239, https://doi.org/10.1038/s41598-021-86593-5.
By characterizing proteomic changes that occur acutely following ex-
ercise, this study outlines a potential mechanism whereby exercise
alters the non-permissive microenvironment of the CNS.
31. Mandolesi G, Bullitta S, Fresegna D, De Vito F, Rizzo FR,
Musella A, Guadalupi L, Vanni V, Stampanoni Bassi M, Buttari F,
Viscomi MT, Centonze D, Gentile A: Voluntary running wheel
attenuates motor deterioration and brain damage in
cuprizone-induced demyelination. Neurobiol Dis 2019, 129:
102–117, https://doi.org/10.1016/j.nbd.2019.05.010.
32. Matsushima GK, Morell P: The neurotoxicant, cuprizone, as a
model to study demyelination and remyelination in the cen-
tral nervous system. Brain Pathol 2001, 11:107–116, https://
doi.org/10.1111/j.1750-3639.2001.tb00385.x.
33. Mei F, Fancy SPJ, Shen Y-AA, Niu J, Zhao C, Presley B, Miao E,
Lee S, Mayoral SR, Redmond SA, Etxeberria A, Xiao L,
Franklin RJM, Green A, Hauser SL, Chan JR: Micropillar arrays
as a high-throughput screening platform for therapeutics in
multiple sclerosis. Nat Med 2014, 20:954–960, https://doi.org/
10.1038/nm.3618.
34. Mei F, Lehmann-Horn K, Shen Y-AA, Rankin KA, Stebbins KJ,
Lorrain DS, Pekarek K, A Sagan S, Xiao L, Teuscher C, von
Büdingen H-C, Wess J, Lawrence JJ, Green AJ, Fancy SP,
Zamvil SS, Chan JR: Accelerated remyelination during in-
flammatory demyelination prevents axonal loss and im-
proves functional recovery. ELife 2016, 5, e18246, https://
doi.org/10.7554/eLife.18246.
35. Mei F, Mayoral SR, Nobuta H, Wang F, Desponts C, Lorrain DS,
Xiao L, Green AJ, Rowitch D, Whistler J, Chan JR: Identification
of the kappa-opioid receptor as a therapeutic target for
oligodendrocyte remyelination. J Neurosci 2016, 36:
7925–7935, https://doi.org/10.1523/JNEUROSCI.1493-16.2016.
36. Miranda M, Morici JF, Zanoni MB, Bekinschtein P: Brain-derived
neurotrophic factor: a key molecule for memory in the
healthy and the pathological brain. Front Cell Neurosci 2019,
13:363, https://doi.org/10.3389/fncel.2019.00363.
37. Mokhtarzade M, Motl R, Negaresh R, Zimmer P, Khodadoost M,
Baker JS, Patel D, Majdinasab N, Ranjbar R: Exercise-induced
www.sciencedirect.com
MedXercise for myelin repair Wuerch et al. 125
changes in neurotrophic factors and markers of blood-brain
barrier permeability are moderated by weight status in mul-
tiple sclerosis. Neuropeptides 2018, 70:93–100, https://doi.org/
10.1016/j.npep.2018.05.010.
38. Moon HY, Becke A, Berron D, Becker B, Sah N, Benoni G,
Janke E, Lubejko ST, Greig NH, Mattison JA, Duzel E, van
Praag H: Running-induced systemic cathepsin B secretion is
associated with memory function. Cell Metabol 2016, 24:
332–340, https://doi.org/10.1016/j.cmet.2016.05.025.
39. Nascimento C, Pereira J, Andrade L, Garuffi M, Talib L,
Forlenza O, Cancela J, Cominetti M, Stella F: Physical exercise
in MCI elderly promotes reduction of pro-inflammatory cyto-
kines and improvements on cognition and BDNF peripheral
levels. Curr Alzheimer Res 2014, 11:799–805, https://doi.org/
10.2174/156720501108140910122849.
40. Nave K-A, Werner HB: Myelination of the nervous system:
mechanisms and functions. Annu Rev Cell Dev Biol 2014, 30:
503–533, https://doi.org/10.1146/annurev-cellbio-100913-
013101.
41. Neumann B, Baror R, Zhao C, Segel M, Dietmann S, Rawji KS,
Foerster S, McClain CR, Chalut K, van Wijngaarden P,
Franklin RJM: Metformin restores CNS remyelination capacity
by rejuvenating aged stem cells. Cell Stem Cell 2019, 25:
473–485, https://doi.org/10.1016/j.stem.2019.08.015. e8.
42. Ortiz FC, Habermacher C, Graciarena M, Houry P-Y,
Nishiyama A, Oumesmar BN, Angulo MC: Neuronal activity
in vivo enhances functional myelin repair. JCI Insight 2019, 4,
https://doi.org/10.1172/jci.insight.123434. e123434.
43. Phillips C, Baktir MA, Srivatsan M, Salehi A: Neuroprotective
effects of physical activity on the brain: a closer look at tro-
phic factor signaling. Front Cell Neurosci 2014, 8, https://
doi.org/10.3389/fncel.2014.00170.
44. Plemel JR, Liu W-Q, Yong VW: Remyelination therapies: a
new direction and challenge in multiple sclerosis. Nat Rev
Drug Discov 2017, 16:617 – 634, https://doi.org/10.1038/
nrd.2017.115.
45. Prakash RS, Snook EM, Motl RW, Kramer AF: Aerobic fitness is
associated with gray matter volume and white matter integ-
rity in multiple sclerosis. Brain Res 2010, 1341:41–51, https://
doi.org/10.1016/j.brainres.2009.06.063.
46. Rabiee F, Lachinani L, Ghaedi S, Nasr-Esfahani MH, Megraw TL,
Ghaedi K: New insights into the cellular activities of Fndc5/
Irisin and its signaling pathways. Cell Biosci 2020, 10:51,
https://doi.org/10.1186/s13578-020-00413-3.
47. Radak Z, Suzuki K, Higuchi M, Balogh L, Boldogh I, Koltai E:
Physical exercise, reactive oxygen species and neuro-
protection. Free Radic Biol Med 2016, 98:187–196, https://
doi.org/10.1016/j.freeradbiomed.2016.01.024.
48. Rendeiro C, Rhodes JS: A new perspective of the hippocam-
pus in the origin of exercise–brain interactions. Brain Struct
Funct 2018, 223:2527–2545, https://doi.org/10.1007/s00429-018-
1665-6.
49. Rossi S, Motta C, Studer V, Macchiarulo G, Volpe E, Barbieri F,
Ruocco G, Buttari F, Finardi A, Mancino R, Weiss S, Battistini L,
Martino G, Furlan R, Drulovic J, Centonze D: Interleukin-1b
causes excitotoxic neurodegeneration and multiple sclerosis
disease progression by activating the apoptotic protein p53.
Mol Neurodegener 2014, 9:56, https://doi.org/10.1186/1750-
1326-9-56.
50. Sleiman SF, Henry J, Al-Haddad R, El Hayek L, Abou Haidar E,
Stringer T, Ulja D, Karuppagounder SS, Holson EB, Ratan RR,
Ninan I, Chao MV: Exercise promotes the expression of brain
derived neurotrophic factor (BDNF) through the action of the
ketone body b-hydroxybutyrate. ELife 2016, 5, https://doi.org/
10.7554/eLife.15092. e15092.
51. VonDran MW, Singh H, Honeywell JZ, Dreyfus CF: Levels of
BDNF impact oligodendrocyte lineage cells following a
cuprizone lesion. J Neurosci 2011, 31:14182–14190, https://
doi.org/10.1523/JNEUROSCI.6595-10.2011.
52. Wolswijk G: Chronic stage multiple sclerosis lesions contain a
relatively quiescent population of oligodendrocyte precursor
Current Opinion in Pharmacology 2021, 61:120–126
126 Neurosciences: Remyelination
cells. J Neurosci 1998, 18:601–609, https://doi.org/10.1523/
JNEUROSCI.18-02-00601.1998.
53. Woodruff RH, Fruttiger M, Richardson WD, Franklin RJM:
Platelet-derived growth factor regulates oligodendrocyte
progenitor numbers in adult CNS and their response
following CNS demyelination. Mol Cell Neurosci 2004, 25:
252–262, https://doi.org/10.1016/j.mcn.2003.10.014.
54. Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D,
Wu J, Ma D, Lin JD, Greenberg ME, Spiegelman BM: Exercise
induces hippocampal BDNF through a PGC-1a/FNDC5
pathway. Cell Metabol 2013, 18:649–659, https://doi.org/
10.1016/j.cmet.2013.09.008.
55. Zheng J, Sun X, Ma C, Li B, Luo F: Voluntary wheel running
promotes myelination in the motor cortex through Wnt
Current Opinion in Pharmacology 2021, 61:120–126
signaling in mice. Mol Brain 2019, 12:85, https://doi.org/10.1186/
s13041-019-0506-8.
56. Zhornitsky S, Johnson TA, Metz LM, Weiss S, Yong V: Prolactin
in combination with interferon-b reduces disease severity in
an animal model of multiple sclerosis. J Neuroinflammation
2015, 12:55, https://doi.org/10.1186/s12974-015 0278-8.
57. Zimmer Philipp, Bloch Wilhelm, Schenk Alexander, Oberste Max,
Riedel Stefan, Kool Jan, Langdon Dawn, Dalgas Ulrik,
Kesselring Jürg, Bansi Jens: High-intensity interval exercise
improves cognitive performance and reduces matrix metal-
loproteinases-2 serum levels in persons with multiple scle-
rosis: A randomized controlled trial. Mult Scler J 2018:
1635–1644, https://doi.org/10.1177/1352458517728342.
www.sciencedirect.com