Antioxidant/anti-inflammatory effects of melatonin

supplementation in strenuous exercise

Ivo F. Vicentini Bernardes,a*, Alexandre Abilio de S. Teixeira,b , José C. Rosa Neto,b , Antônio
Herbert Lancha Junior,a
a Nutrition and Metabolism Applied to Motor Activities Laboratory - School of Physical Education and Sport –
University of Sao Paulo (USP), São Paulo, Brazil
b Immunometabolism Research Group, Department of Cell Biology and Development – Institute of Biomedical

Sciences I – University of Sao Paulo (USP), São Paulo, Brazil;

*Address all correspondence to: Ivo F. Vicentini Bernardes, Nutrition and Metabolism Applied to Motor Activities Laboratory - School of Physical
Education and Sport – University of Sao Paulo (USP), São Paulo, Brazil – Av. Prof. Mello de Morais, 65; 05508-030 Phone/Fax: 55 14 997717134, E-
mail: [email protected]

ABSTRACT: Strenuous exercise, through oxidative stress and increase of inflammatory cytokines, leads
to fatigue, muscle damage, autophagy and mitochondrial fission in skeletal muscle. The anti-inflammatory
and immunomodulatory effects of melatonin could play a role against oxidative stress in strenuous
exercise background. Melatonin supplementation improved inflammatory and antioxidant profiles on
strenuous exercise by a decreasing of inflammatory cytokines, lipid peroxidation products, isoprostanes
and inflammation biomarkers; while increasing the activity of antioxidant enzymes and anti-inflammatory
cytokines. Melatonin supplementation appears to be effective in modulating oxidative stress and
inflammation parameters in subjects undergoing strenuous exercise. However, more studies are
necessary to elucidate the mechanisms associated to these effects.

KEY WORDS: melatonin, supplementation, strenuous exercise

I. STRENUOUS EXERCISE
Exercise training is an efficient strategy for treatment and prevention of lifestyle-related
diseases, such as obesity. Some of its effects are related to improving the profile of adipokines and
oxidative stress response modulation.(SAKURAI et.al, 2017). However, strenuous exercise leads to
fatigue, muscle damage, autophagy and mitochondrial fission in skeletal muscle (ESCAMES et.al,
2011). This kind of exercise affects immune system, guiding to immune suppression and elevation of
upper respiratory tract infection. (GLESSON, 2006; MCKUNE et.al, 2006; BERMON et.al, 2017).
Oxidative stress is one of the distress-related mechanisms during strenuous exercise. (MAARMAN &
REITER, 2018).

II. REACTIVE SPECIES AND PHYSICAL EXERCISE

Reactive species production during exercise was first investigated in 1978 by a research
whose objective was to evaluate the lipid peroxidation through pentane-exhaled levels in subjects
exercising on stationary bike. (DILLARD et.al, 1978).
Free radicals production occurs during exhausted physical exercise, leading to oxidative
stress. When oxygen consumption is elevated and the oxidative metabolism does not work
efficiently, 2% of the oxygen consumed by mitochondria is converted in reactive species, increasing
free radicals production. (VIÑA et.al, 2000). These free radicals can cause damage to all cellular
components such as proteins, lipids, carbohydrate and nucleic acids, leading to apoptosis. (VIÑA
et.al 2000, POWERS & JACKSON, 2007).
Skeletal muscle is the main source of reactive species during physical exercise
(PETERNELJ & COOMBES, 2011). Not only the mitochondria, but the sarcoplasmic reticulum, the
transverse tubules, the plasma membrane, phospholipase A2 and xanthine oxidase are endogenous
sites of free radical origin. Phagocytic cells that repair the damage to muscle fibers caused by
physical exercise also constitute a site of production of reactive species. Strenuous exercise leads
an expressive augment of circulating TNFα, IL-1β and IL-6. The magnitude of response varies
according to cytokine. (POWERS & JACKSON, 2007; STEINACKER et.al, 2004).

III. NUTRITIONAL INTERVENTIONS

Some nutritional interventions are considered as a way to minimize the deleterious effects
caused by reactive species during strenuous exercise. Vitamin C, vitamin E, carotenoids, CoQ10
and allopurinol are the most studied antioxidants as nutritional strategy in exercise oxidative stress
modulation. (PINGITORI et.al, 2015; COBLEY, 2015). However, evidences regarding the benefit of
supplementation of these compounds in exercise are still inconclusive. (PETERNELJ & COOMBES,
2011).

A. Melatonin
Melatonin, N-acetyl-5-methoxytryptamine, a neuroendocrine molecule, is cited among the
nutritional strategies studied to modulate oxidative stress. Its synthesis occurs from the metabolic
pathway of tryptophan, in absence of light, modulated by central biological clocks, with its peaks at
night. Melatonin has a fundamental role in modulation of sleep-awake cycle. (REITER et.al, 2010).
In humans, melatonin receptors have been found in the retina, brain, suprachiasmatic nucleus,
adenophobia, ovaries, peripheral and cerebral arteries, kidneys, pancreas, adipocytes and immune
cells. (KHOSTOGLOU-ATHANASIOU, 2013). It has high concentrations in mitochondria. There is
probably no organ or cell that is not impacted by the action of melatonin. (REITER et al., 2016).
The mechanisms of action of melatonin in reducing reactive species is associated with
multiple molecular actions within the cell: 1) Scavenger function of receptor-independent oxygen /
nitrogen reactive species, in order to reduce mitochondrial damage and apoptosis cascade; 2) via
cytosolic quinone reductase (MT3), reducing free radicals and oxidative damage; binding on
membrane receptors; 3) MT1 and MT2 by initiating a cascade of events that culminate in increased
transcriptional activity of antioxidant enzymes, modulation of pro-oxidant enzymes and reduction in
the synthesis of toxic cytokines. Melatonin can also regulate nitric oxide production via calmodulin
binding. (REITER et.al, 2016).
Some therapeutic applications of melatonin have been described in the literature, such as:
improvement in the oxidative profile in patients with type 2 diabetes mellitus (ZEPHY and AHMAD,
2015), improvement of the endogenous antioxidant system in patients with multiple sclerosis
(ADAMCZYK-SOWA et al , 2014; ALVAREZ-SANCHEZ et al., 2017); treatment of cardiovascular
and neurodegenerative diseases (ZISAPEL, 2018); circadian rhythm, sleep disturbances and jet-lag
regulation (SKENE et al., 1996, OKAWA et al 1998, TURK 2003, MC MORRIS, 2007; SNIRIVASAN
et.al 2007; DODSON & ZEE, 2010); treatment of memory problems and attention deficit
hyperactivity disorder (BAYDAS et al., 2005;BLOCH and MULQUEEN, 2014), improvement of
quality of life in aging (SADOWSKA-BARTOSZ and BARTOSZ, 2014; VURAL et al. (ANSIMOV,
2006; Hoover et al, 2007; BLOCK et al., 2008; NAJAFI et al., 2017) and modulation of the immune
system (BAUER et al. al., 2013).
The anti-inflammatory and immunomodulatory effects of melatonin may play an important
antioxidant and anti-inflammatory role in the context of strenuous physical exercise. (CARILLO-VICO
et al., 2013; SANCHEZ et al., 2015; MAARMAN & REITER, 2018).

IV. MELATONIN SUPPLEMENTATION AND EXERCISE IN SEVERAL OUTCOMES

In the study conducted by RAHMAN et. al (2017), 75 rats were divided into 5 groups. The
variables of the groups were type 2 diabetes mellitus, physical exercise and melatonin
supplementation. It was possible to observe that diabetic rats supplemented with melatonin that
performed physical exercise obtained better score in the final performance test (P <0.001), better
glycemia and plasma insulin (P <0.001); lower MDA (P <0.01) and higher SOD and GSH (P <0.001
for both) comparing to the diabetic group without intervention. Exercise and melatonin significantly
improved the lipid profile, atherosclerotic index, leptin, adiponectin, urea and creatinine (P <0.001).
MOYAERI et.al (2017) investigated the effects of melatonin supplementation on
spermatogenesis in rats. Five groups of 10 animals were divided into control, melatonin solvent (1%
ethanol), melatonin (10mg / kg), exercise, melatonin (10mg / kg) plus exercise. A significant increase
of the antioxidant enzymes GPX, SOD, GR (P <0.05) was observed, but the same does not appear
to occur with CAT. No statistical differences were found in the TAC of the melatonin plus exercise
group compared to the exercise group; as well as MDA, although a downward trend was observed.
There were no statistical differences in the weight of the sex organs evaluated. The TUNEL test
revealed the influence of melatonin supplementation in reducing the extent of cellular apoptosis.
NASSAR et.al (2007) evaluated the effects of melatonin supplementation on GH and SST
secretion in trained men and women. In men, 5mg of melatonin supplementation before exercise
was better than placebo in increasing GH levels (P <0.017), with a trend at the dose of 0.5mg (P =
0.077). After exercise it was observed that both doses of melatonin were better than placebo (P =
0.042); and it tended to increase in women (P = 0.064). There was no impact of supplementation on
IGFBP-I levels, however the 5mg dose significantly increased IGFBP-3 levels in men (P = 0.017) and
decreased SST levels concomitantly.
BECK, SCARIOT and GOBATTO (2015) investigated the ergogenic effects of melatonin
supplementation in rats. It was possible to observe that the exercise time was improved in 169% in
the wake group and 90% in the group with the least spontaneous physical activity, representing an
important significance (P <0.01).
KAYA et al. (2010) investigated levels of plasma glucose and hepatic glycogen in rats
submitted to swimming exercise supplemented with melatonin (3mg / kg / day). It was possible to
observe that glucose levels in the group submitted to exercise and not supplemented were
significantly higher (P <0.05) than in the others. Regarding hepatic glycogen levels, it was possible to
observe that the exercise + melatonin group had the statistically higher values (P <0.01).
BRANDENBERG et.al (2017) investigated the possible ergogenic effects of melatonin
supplementation on physical exercise in 10 trained individuals in a double-blinded, placebo-
controlled study. The athletes underwent an ergometric exercise (32.2km course), whether or not
they received 5mg of melatonin. It was measured before the VO2 max test of the athletes, which
indicated to be similar to the range of variation used by other bicycle studies. Athletes were restricted
from food consumption in the last meal of the previous day until the time of testing. There were no
significant differences in time (P = 0.0682) and power output (P = 0.927) between the placebo and
melatonin groups.
BICER et al. (2015) conducted a study on 80 rats divided into 8 groups with the following
variables: control, diabetes, exercise (swimming for 30 minutes) and melatonin supplementation. The
results were considered statistically significant when P <0.01. From the obtained results, it was
possible to notice that the conditions of the variables influenced the distribution of several elements
of the liver as described in Table 1.
MENDES et. al (2013) investigated the effects of melatonin supplementation (1mg / kg) on
exercise adaptation parameters in elderly rats. There was a trend in reducing food intake in the
supplemented group and a significant one in the trained and supplemented group. In these groups, it
was possible to observe lower body weight and lower percentage of fat compared to sedentary
controls (P <0.05). No changes were observed in plasma glucose and cholesterol, but the melatonin
group and exercise + melatonin presented a reduction in triglycerides. The melatonin group showed
better tolerance to glucose, physical capacity, citrate synthase activity, glycogen content, activation
of PI3K, AMPK, MAPK and GLUT4 expression (P <0.05)

V. EFFECTS OF MELATONIN SUPPLEMENTATION ON STRENUOUS EXERCISE

In the study proposed by JOHE and OSTERUD (2005), the supplemented group received
3mg of melatonin; changes were observed in the samples collected. Immediately after exercise,
melatonin significantly reduced LPS-induced monocyte activation by 48% (P <0.01), lymphocyte
count by 30% (P <0.01) and decreased erythrocytes and hemoglobin (5% and 3-4% ); at this time, a
trend was observed in suppression of the leukocyte increase in 10% and greater platelet activity in
8%. After two hours of exercise, melatonin significantly decreased LPS-induced monocyte activation
by 44% (P <0.02); and a trend in reducing leukotriene B4 by 30% was observed. IL-8 and TNF-α
tended to decrease in the group supplemented with melatonin. In this study, the production of
thromboxane B2 did not change.
OCHOA et al. (2011) tested the efficacy of melatonin supplementation in Sierra Nevada race
participants. The hemoglobin count decreased in both groups (P <0.001), as well as the plasma
viscosity (P <0.05); and an increase in urinary creatinine excretion was observed in both groups (P
<0.001). Bilirubin levels were significantly lower in the melatonin group before and after the race (P
<0.001); as well as levels of phospholipids (P <0.05) and cholesterol (P <0.01 before and P <0.001
after the run). The activity of CAT and GPx enzymes and TAS increased significantly after exercise
(P <0.01) in the supplemented group. The levels of isoprostanes and 8-OHdG increased significantly
after exercise in both groups, although in the melatonin group it was significantly lower (P <0.001).
Despite significant increases in TNF-α and IL-6 after exercise in both groups, the melatonin group
was significantly lower (P <0.001 in both). There was a significant increase in IL1ra (P <0.001) and
sTNF-RII (P <0.01) in the melatonin group after exercise.
MALDONADO et.al (2012) performed a study in 16 soccer players. 6mg of melatonin were
administered 30 minutes before exercise in the intervention group. In the supplemented group of
melatonin, a significant reduction of the number of moles of MDA / ml 15 minutes (P <0.05) and 60
minutes (P <0.001) after the beginning of the activity was observed; as well as a significant increase
in TAS 15 and 60 respectively (P <0.05 and P <0.001). Plasma triglycerides showed a significant
reduction in melatonin group 15 and 60 minutes after exercise (P <0.001). IgA only increased
statistically significantly in the melatonin group (P <0.05) 60 minutes after activity. The authors did
not find significant differences in the other parameters evaluated: cortisol, DHEA, free and total
testosterone, GOT, GPT, GGT, alkaline phosphatase, calcium, phosphorus, sodium, potassium,
LDH, CPK, complete blood count, CD3 +, CD4 + , CD8 +, CD19 +, NK, HLA-DR; and IgM / IgG.
BECK et.al (2015) studied in animal model (120 rats) the effect of intraperitoneal
supplementation of melatonin in rats submitted to strenuous exercise. The groups were divided into
eight, including the following variables: circadian cycle of day / night; melatonin supplementation /
placebo; submitted to strenuous exercise without exercise. The nocturnal group submitted to
exercise with melatonin intervention presented a better performance in the exercise compared to the
other groups. There were no changes in pIKKβ, Ikβ-α, leukocytes and lymphocytes in the groups
supplemented with melatonin and exposed to exercise. An increase in CK-MM (P <0.01) and LDH (P
<0.01) was observed in melatonin / night / exercise. Resting plasma lactate concentrations were
influenced by time of day and supplementation condition, but not by exercise (P <0.05).
In the study proposed by BORGES et.al (2015), performed in rats, it was possible to observe
that the control group experienced a 3.1x increase in IL-1β cytokine, while the melatonin group 2.0x
(P <0.001); plasma L-selectin was significantly reduced in the melatonin group after two hours of
exercise (P <0.05) compared to the control. Reagrding the control group, a significant reduction of IL-
6, TNF-α and TBARS (P <0.05 in both) was observed in the melatonin group; and an increase in
VEGF (P <0.05) and SOD (P <0.001). CAT and GPx did not undergo significant changes with
treatment.
FRANCO et al. (2017) evaluated the efficacy of melatonin supplementation in 14 male
athletes. An increased concentration of TAC (P <0.05) and GPx (P <0.05) was observed in the
melatonin group compared to the placebo group immediately and 24 hours after exercise. No
differences were observed in SOD enzymes. DNA damage was significantly lower in the melatonin
group (P <0.05) after exercise.
CIMEN et.al (2017) studied the melatonin supplementation in rats submitted to strenuous
exercise. It was divided in two groups (melatonin and placebo) of 15 albino rats submitted to intense
acute exercise. The energetic charge was significantly higher in the melatonin group (P <0.01). The
levels of 3-NT and MDA were lower in the melatonin group compared to the control group (P
<0.001). There were no significant differences in SOD, CAT and GPx between the control and
melatonin groups.
LEONARDO-MENDONÇA et al. (2017) evaluated the efficacy of melatonin supplementation
(100 mg / day) before bedtime for 4 weeks in 24 athletes. There was a significant increase in total
ORAC (P <0.01) and reduction of LPO (P <0.001), AOPP (P <0.001), NOx (P <0.01), GPx / Grd
ratio, GSSG / GSH ratio of melatonin group . Melatonin supplementation significantly reduced CK,
LDH, creatinine and cholesterol levels (both P <0.05).

VI. DISCUSSION
Through studies, it was possible to observe an improvement in the inflammatory and
antioxidant profile with the use of melatonin in physical exercise through the reduction of
inflammatory cytokines, lipid peroxidation products, isoprostanes, markers of inflammation and
increased activity of anti-inflammatory enzymes and cytokines.
Endogenous enzymes from antioxidant system, when exposed to an oxidizing stimulus such
as physical exercise, act to reduce the reactive species produced. It is called hormesis, when this
antioxidant action is sufficient to maintain controlled levels of reactive species. Strenuous exercise-
induced oxidative stress leads the production of exacerbated reactive species and enzymatic
function diminished (PINGITORI et.al, 2015). OCHOA et. al (2011) and FRANCO et al. (2017)
observed an increase in SAD and GPx; however, in the second study there were no significant
differences in SOD activity. BORGES et. al (2015) observed melatonin impact on SOD but without
changes in CAT and GPx. CIMEN et.al (2017) did not observe significant changes in both SOD, GPx
and CAT. The fact that the studies present different methodologies (animal x human model, dose
used and exercise) may imply the results obtained. In the animal model, melatonin supplementation
may influences different enzyme sites.
Bilirubin, among the endogenous compounds, came to be understood by its antioxidant role
besides the already known function of excretion (WAGNER et al., 2015). For this justification, two
studies evaluated bilirubin levels. Ochoa et al. observed a decrease in bilirubin levels in melatonin-
supplemented group, indicating a lower need for its use and lower hepatotoxicity (OCHOA et al.,
2011). Maldonado et.al related no significant changes in total bilirubin. The methodologies used were
different. OCHOA et.al used 15mg of melatonin administered 2 days before the experiment, while
MALDONADO et.al administered 6mg minutes before exercise; it is possible that the dose offered in
the second study was not enough to observe significant differences in bilirubin levels.
Lipid peroxidation indicates damage to membrane structures, serving as a marker of
oxidative stress. Melatonin supplementation decreased lipid peroxidation by significantly reducing
levels of malonaldehyde (MDA) and thiobarbituric acid reactive substances (TBARS), and increased
activity of antioxidant enzymes such as GPx and CAT. Therefore, it was possible to observe in these
studies an impact of the melatonin supply on the modulation of the oxidative stress induced by
physical exercise.
Mitochondrial DNA is the main target of ROS during exercise (OCHOA et al., 2011).
Melatonin supplementation reduced DNA damage by reducing isoprostanes, 8-OHdG and reactive
oxygen species (ROS). Intense exercise, through its oxidant insult, can cause mitochondrial damage
and decrease the expression of PGC-1α (ESCAMES et.al, 2011), melatonin supplementation
seemed to prevent this deleterious effect.
Intense exercise causes overproduction of inflammatory cytokines (STEINACKER et.al,
2004). Melatonin supplementation was significant in the modulation of exacerbated inflammation
caused by an inflammatory insult (strenuous exercise). It was possible to observe a decrease in
inflammatory cytokines (IL-6, TNF-α and IL-1β) and reduction of inflammation parameters such as
LPS-induced monocyte activation and advanced oxidation protein (AOPP) products. One of the
mechanisms related to this event is the modulation of the inflammatory cytokines expression via
NFκB-activation/translocation inhibition through the melatonin binding to MT1-A and TLR-4 receptors
in the myocyte. (MAMAN and REITER, 2018).
MALDONADO et.al noticed a significant increase in immunoglobulin A (IgA) levels in athletes
melatonin-supplemented compared to the control group. Intensive physical exercise may lead to
temporary immunosuppression, predisposing the individual to opportunistic infections (GLESSON,
2006). In this study there were no significant changes in other immunoglobulins; therefore, studies
that investigate the impact of melatonin on parameters of the immune system in individuals
submitted to strenuous physical exercise are still lacking. BECK et.al (2015) found no significant
difference in local and systemic inflammatory markers (pIKβ, IkB-α, leukocytes and lymphocytes) in
the melatonin-supplemented group, although the authors observed a decrease in tissue damage
markers (muscle creatine kinase, creatinine and urea).
BORGES et.al (2015) observed a significant increase in vascular endothelial growth factor
(VEGF-α) in melatonin-supplemented group, favoring the metabolic adaptation process induced by
aerobic exercise. MENDES et. al (2013) reported a significant impact of melatonin supplementation
on the process of adaptation to exercise in elderly rats by increasing PI3K and MAPK. RAHMAN et.
al (2017) noted a significant increase in PGC1-α expression in mice supplemented with melatonin
compared to the control group. In contrast to studies that indicate some antioxidants
supplementation such as vitamins C and E, may compromise the process of adaptation to exercise
(BRAAKHUIS et.al, 2014; GOMEZ-CABRERA et al, 2015, PINGITORI et al, 2015), the melatonin
supplementation seems to exert a positive effect on adaptation parameters.
In some studies, a change in lipid profile has been noted through melatonin supplementation.
LEONARDO-GONÇALVEZ et.al (2017), OCHOA et.al (2011) and MALDONADO et. al (2012)
observed changes in plasma lipids. The supplemented group with melatonin presented a reduction
of triglycerides, phospholipids and total cholesterol in relation to the control group. One of the
mechanisms that could explain these findings is the increase in the enzymatic action of lecithin-
cholesterol-acyltransferase by melatonin (ESQUIFINO et.al, 1997). The hypolipidemic action
observed in the studies seems to be important for greater clearance of endogenous cholesterol,
greater tissue uptake of lipids and reduction of risks of cardiovascular diseases in athletes. (OCHOA
et al., 2011).
Few studies in the literature have evaluated the ergogenic effects of melatonin
supplementation. BECK et al (2015) have concluded melatonin supplementation had more impact on
performance than on the anti-inflammatory / antioxidant effect. In this study, supplemented rats
performed more effort compared to those who did not receive melatonin; it is possible that this
difference in exercise protocol influenced the evaluation of the inflammation of the groups.
BRANDENBERG et. al (2017) verified in trained athletes that the melatonin supplementation did not
significantly alter the performance; while RAHMAN et. al (2017) noticed an improvement in the stress
test after the supply of melatonin in diabetic rats. Therefore, the hypothesis that melatonin
supplementation positively affects sports performance is still contradictory.
The lack of studies and disparity of methodologies compose the limitations found in this
review. The doses of melatonin used and the administration protocol varied. The lowest dose
administered was 3mg and the highest dose was 100mg. Despite the disparate characteristic of the
dosage, which used remained in the range established by phase 1 studies (GALLEY et.al 2014).

V. CONCLUSION
Melatonin supplementation appears to be effective in modulating oxidative stress and
inflammation parameters in subjects undergoing intense physical exercise. However, more studies
are necessary to elucidate the mechanisms associated to these effects.

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