Aerobic Exercise Does Not Predict Brain Derived Neurotrophic Factor And
Cortisol Alterations in Depressed Patients
Murilo Khede Lamego, Antonio Marcos de Souza Moura, Flávia Paes, Nuno Barbosa Ferreira
Rocha, Alberto Souza de Sá Filho, Eduardo Lattari, Ridson Rimes, João Manochio, Henning
Budde, Mirko Wegner, Gioia Mura, Oscar Arias-Carrión, Ti-Fei Yuan, Antonio Egidio Nardi and
Sergio Machado
Abstract: The pathophysiology of depression is related to neurobiological changes that occur in
the monoamine system, hypothalamic-pituitary-adrenal axis, neurogenesis system and the
neuroimmune system. In recent years, there has been a growing interest in the research of the
effects of exercise on brain function, with a special focus on its effects on brainderived
neurotrophic factor (BDNF), cortisol and other biomarkers. Thus, the aim of this study is to
present a review investigating the acute and chronic effects of aerobic exercise on BDNF and
cortisol levels in individuals with depression. It was not possible to establish an interaction
between aerobic exercise and concentration of BDNF and cortisol, which may actually be the
result of the divergence of methods, such as type of exercises, duration of the sessions, and
prescribed intensity and frequency of sessions.
Keywords: Aerobic exercise, biomarkers, brain derived neurotrophic factor, cognition, cortisol,
depression.
INTRODUCTION
Depression is related to several neurobiological changes [1, 2]. Research on the possible
molecular pathways of depression demonstrated that the increased cell dysfunction in cortical
and limbic areas of the brain can be observed in individuals suffering from depression [3, 4] and
is strongly related to the decrease in neurotrophic activity [5]. Therefore, the investigation of
biomarkers, such as brainderived neurotrophic factor (BDNF), has attracted great interest, in
order to clarify its role in the pathophysiology of depression [6]. BDNF is a protein expressed
mainly in the central nervous system (CNS), and it has an important role in the survival and
maintenance of neuronal function [7]. In fact, a low neurotrophic activity is associated with
reduced numbers of cells in the prefrontal cortex [8], amygdala [9, 10] and a decrease in
hippocampal volume [11, 12], indicating that the growth nerve factors, and more specifically,
the changes in BDNF may play an important role in the development of depression [3, 4, 13-15].
Furthermore, the dysfunction of the hypothalamuspituitary-adrenal (HPA) axis has been the
most valid neurobiological theory to explain the pathophysiology of depression. The HPA axis is
the interaction between the hypothalamus, pituitary gland, and the adrenal cortex, and is a
major part of the neuroendocrine system that controls reactions to stress [16]. The clinical
manifestation of its dysfunction in depression includes basal hypercortisolemia [17], elevated
cortisol secretion in the dexamethasone suppression test [18], and increased cortisol release in
the combined dexamethasone suppression-corticotropine releasing hormone stimulation test
[19, 20]. The first line of treatment for depression is the use of antidepressants [21]. However,
the remission rate with selective serotonin reuptake inhibitor (SSRI), which is currently the first-
line treatment for depression, is only 60% [22]. Exercise is a readily available therapeutic option,
effective as a treatment in mild to moderate depression [23] Regular exercise may bring
physiological, psychological and social benefits to its practitioners [24-26]. Given that sedentary
is a recognized risk factor [23] for many diseases, exercise has become a topic of great interest
to many researchers. Thus, the practice of exercises has been increasingly recommended in
health promotion programs by institutions such as the Center for Disease Control and
Prevention (CDP) and the American College of Sports Medicine (ACSM) as a non-
pharmacological means of prevention and treatment of psychiatric disorders such as depression
[27, 28]. The effectiveness of exercise on depression has been attributed to its impact on the
modification of certain neurobiological mechanisms such as: influence on monoamine
metabolism by increasing serotonin levels; regulating function of the HPA axis, with possible
reduction in cortisol secretion; increase in neurotrophic factors such as BDNF and hippocampal
neurogenesis and, finally, reducing neuroinflammation through a decrease in proinflammatory
mediators [29-38]. Ida et al. [21] examined the acute effects of aerobic exercise performed in
cycloergometer in the salivary cortisol levels as well as the scores of subjective symptoms of
depression in patients diagnosed by Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV). The salivary cortisol levels were measured pre-exercise and postexercise. The same
patients returned after a month for a control session (sitting quietly), where the salivary cortisol
levels were measured pre- and post-session. The authors concluded that a session of 15 minutes
of moderate intensity aerobic exercise could reduce salivary cortisol levels. In addition, a
decrease in salivary cortisol level was statistically correlated with a decrease in the scores of
subjective symptoms of depression. It is noteworthy that all patients were being treated with
antidepressant medications during the study, and in addition, subjective depression scores used
in this study have not yet been validated on a large scale. A new view on the benefits of regular
practice of physical exercise has been discussed in some studies that show the anti-inflammatory
effects of exercise [21, 39]. There is evidence that shows that exercise performed at a moderate
intensity may be an important factor in prevention and treatment, not only of metabolic
diseases [26, 40, 41], but also of symptomatology and cognitive function in mood disorders [42,
43], although its physiological effects still remain uncertain. Thus, in recent years there has been
increasing interest in research on the effects of exercise on brain function, with a special focus
on its effects on BDNF, cortisol and other biomarkers [44]. This study aimed to review the acute
and chronic of aerobic exercise on BDNF and cortisol levels in depressed patients. Here, we will
review the basic foundation of BDNF and cortisol, their role in healthy and depressed people
and the experimental advances of aerobic exercise on BDNF and cortisol in depressed patients
that can become viable as clinical applications in the coming years for major depression (MD). A
literature search was conducted using the databases PubMed, ISI Web of Knowledge and
PsycInfo using the following terms and their combinations: “aerobic exercise”, “depression”,
“brain derived neurotrophic factor”, “cortisol”, and "biomarkers". All articles were published
between 1995 and 2015 and in English. Additional references were identified through hand
search of the possessed articles.
BDNF: ISOFORMS AND RECEPTORS The neurotrophic growth factors, known as neurotrophins,
are proteins whose main function is the development of neurons, contributing for their survival,
growth and characterization [45, 46]. The family of neurotrophins includes the nerve growth
factor (NGF), the neurotrophic growth factor derived from the BDNF, the neurotrophin-3 (NT-3)
and the neurotrophin-4/5 (NT-4/5) [45, 47]. Their biologically active forms show about 50%
amino acid identity. The genes encoding neurotrophins are expressed not only during
development but also in the adulthood, in a variety of tissues, including the CNS [48].
Neurotrophins sustain the neuroplasticity (i.e., ability of the CNS to adapt to environmental
changes, respond to injury and acquire new information, modifying neural connectivity and
function) and are capable of signaling neurons to survive, differentiate, or grow [49, 50].
Neurotrophins interact with two distinct classes of receptors [47]. The first to be discovered was
the neurotrophin receptor 75 p-(p-75NTR) [51, 52], which belongs to the family of receptors of
the tumor necrosis factor (TNF) [47]. The second class of neurotrophin receptors includes the
receptors for tropomyosin-related kinase (TrK, tyrosine kinase). All neurotrophins bind to the
receptor p-75NTR, but neurotrophins bind with greater affinity to its specific receptor TrK [52].
In particular, NGF binds to TrkA, BDNF and NT-4/5 bind to and NT3 binds with greater affinity
to TrkC [53]. Among these neurotrophins, BDNF has attracted great interest as a functional
candidate gene in several mental disorders. The BDNF gene is located on chromosome 11p13
reverse strand and encodes a precursor peptide pro-BDNF [54]. In fact, all neurotrophins,
including BDNF, are synthesized as a pre-pro neurotrophic precursor. In particular, pro-BDNF
preferably activates p75NTR to mediate the programmed neuronal death [55], to reduce the
complexity and density of the dendrites of hippocampal neurons [56] and to induce long-term
depression of synaptic transmission [57, 58]. The function of a receptor for BDNF (i.e., TrkB) is
also regulated in an activity-dependent manner, as TrkB is mainly located in synapses. In
addition, BDNF can be found in synapses after neuronal activity [59]. The neuronal activity,
however, is essential for the synthesis and intracellular targeting of TrkB receptors. Thus, the
release of BDNF and TrkB receptors expression in a coordinated manner are important for
optimal synaptic response [60].
BDNF: ISOFORMS AND RECEPTORS
The neurotrophic growth factors, known as neurotrophins, are proteins whose main function is
the development of neurons, contributing for their survival, growth and characterization [45,
46]. The family of neurotrophins includes the nerve growth factor (NGF), the neurotrophic
growth factor derived from the BDNF, the neurotrophin-3 (NT-3) and the neurotrophin-4/5 (NT-
4/5) [45, 47]. Their biologically active forms show about 50% amino acid identity. The genes
encoding neurotrophins are expressed not only during development but also in the adulthood,
in a variety of tissues, including the CNS [48]. Neurotrophins sustain the neuroplasticity (i.e.,
ability of the CNS to adapt to environmental changes, respond to injury and acquire new
information, modifying neural connectivity and function) and are capable of signaling neurons
to survive, differentiate, or grow [49, 50]. Neurotrophins interact with two distinct classes of
receptors [47]. The first to be discovered was the neurotrophin receptor 75 p-(p-75NTR) [51,
52], which belongs to the family of receptors of the tumor necrosis factor (TNF) [47]. The second
class of neurotrophin receptors includes the receptors for tropomyosin-related kinase (TrK,
tyrosine kinase). All neurotrophins bind to the receptor p-75NTR, but neurotrophins bind with
greater affinity to its specific receptor TrK [52]. In particular, NGF binds to TrkA, BDNF and NT-
4/5 bind to and NT3 binds with greater affinity to TrkC [53]. Among these neurotrophins,
BDNF has attracted great interest as a functional candidate gene in several mental disorders.
The BDNF gene is located on chromosome 11p13 reverse strand and encodes a precursor
peptide pro-BDNF [54]. In fact, all neurotrophins, including BDNF, are synthesized as a pre-pro
neurotrophic precursor. In particular, pro-BDNF preferably activates p75NTR to mediate the
programmed neuronal death [55], to reduce the complexity and density of the dendrites of
hippocampal neurons [56] and to induce long-term depression of synaptic transmission [57, 58].
The function of a receptor for BDNF (i.e., TrkB) is also regulated in an activity-dependent
manner, as TrkB is mainly located in synapses. In addition, BDNF can be found in synapses after
neuronal activity [59]. The neuronal activity, however, is essential for the synthesis and
intracellular targeting of TrkB receptors. Thus, the release of BDNF and TrkB receptors
expression in a coordinated manner are important for optimal synaptic response [60].
THE ROLE OF BDNF AND CORTISOL IN HEALTHY HUMANS
BDNF, which is an essential neurotrophin connected directly to the central and peripheral
molecular processes of energy metabolism and homeostasis, may play a key role in these
induced mechanisms [61]. BDNF has a repertoire of neurotrophic and neuroprotective
properties in the CNS and the periphery [62- 64]. The effect of BDNF on the plasticity of the CNS
involves elements of cellular energy metabolism and in the periphery participates in metabolic
processes. Prime examples come from studies of transgenic mice heterozygous for BDNF, which
suffer from hyperphagia, obesity and hyperinsulinemia [65, 66]. Tonra [67] demonstrated that
central or peripheral administration of BDNF reduces body weight and improves glycemic
control in obese diabetics. BDNF also appears to be a positive regulator of energy expenditure,
and BDNF has shown to be effective in preventing reduction in body temperature during cold
exposure or food deprivation [68]. Furthermore, Wu et al. [69] reported that increase in
oxidative stress, which would be a consequence of aberrant energy metabolism, result in
decreased BDNF levels. BDNF works toward neuronal protection and survival, axonal and
dendritic growth and remodeling, neuronal differentiation and synaptic activity
(synaptogenesis) and has efficacy in synaptic transmission [70, 71]. In the periphery, BDNF
function is to increase lipid oxidation in skeletal muscle through the activation of activated
kinase protein (AMPK) [72]. A human case study showed a clinical phenotype of impaired
cognitive function, hyperactivity and severe obesity associated with a chromosomal inversion of
a region encompassing the BDNF gene, and a reduction in serum BDNF [73]. Furthermore, Araya
et al. [74] demonstrated that plasma BDNF was increased in insulin resistant individuals,
overweight subjects and obese subjects following a reducedcalorie diet. These findings reinforce
the fact that BDNF is essential not only in the neuronal system, but are also strongly linked to
the central and peripheral molecular processes of energy metabolism and homeostasis [75, 76].
With regard to cortisol, which is released by the cortex of the adrenal gland, it is the main
glucocorticoid to be directly involved in the regulation of plasma glucose [77]. Glucocorticoids
are widely distributed in the brain, specifically concentrated in the hippocampus, amygdala and
hypothalamus [78]. Cortisol is not only part of the circadian system, but helps to organize it.
Corticosteroids act on the glucocorticoid and mineralocorticoid receptors [79]. Steroids also act
over receptors linked to genomic membrane, which may play a role on neuronal function [80].
HPA axis responds quickly to a range of environmental and internal factors, which are often
associated to stress [16]. Although cortisol performs a feedback function at the level of the
pituitary gland, hypothalamus and hippocampus, prolonged stress can stimulate secretion over
several hours. After stimulation by adrenocorticotropin (ACTH), cortisol is synthesized and
secreted by the adrenal gland and released into the blood, circulating quickly on carriers such as
corticosteroid-binding globulin, albumin and erythrocytes. Only a small fraction of cortisol (2-
15%) remains free. It is just that fraction of free hormone that causes the multitude of cortisol
related genomic effects in peripheral tissues and the brain [81]. It is also known that about 30
to 60 minutes after awakening, there is an increase in cortisol secretion [82], but the area or the
type of receptor that may be involved in the risk posed by this change has not yet been
established [83].
THE ROLE OF BDNF AND CORTISOL IN DEPRESSION
The pathophysiology of depression has been associated with dysregulation of the HPA axis [84].
Hyperactivity of the HPA is one of the most robust and consistent neurobiological findings in
patients with MD, and cortisol have been suggested as a potential biomarker of this disease [85,
86]. The cortisol contributes to genetic variants increasing the risk of developing MD, so that
environmental events may extend such a risk. The influence of corticosteroids begins prenatally,
but continues during adulthood. The impact of cortisol in each phase depends not only on their
interaction with other factors, such as psychological traits and genetic variants, but also on the
events that have or not previously occurred [87]. There is little doubt that cortisol plays a central
role in the onset and course of depression, but there is still considerable uncertainty about what
exactly that role is [87]. The daily cortisol rhythms are disturbed in about half the cases of MD
[88]. There is an increase of resistance to the action of glucocorticoid feedback on the HPA
activity in a proportion of cases of DM [89, 90]. The post-awakening cortisol increase and
prolonged excessive levels can result in DM [91-96]. Cortisol levels in excess can put the brain at
risk, making it more vulnerable to harmful agents that in the absence of corticoids would not
necessarily be harmful [97, 98]. This notion can be translated to the MD, since that adversity
predisposes to this disorder [99, 100], and increased cortisol can potentiate the
psychopathological actions of these agents in a similar way [101]. The development and
maintenance of the vertebrate nervous system requires continuous operation of a number of
proteins called neurotrophins. It has been shown that in the adult brain occurs the proliferation
and maturation of neurons in discrete areas including the hippocampus and the striatal
subventricular area. Exposure to psychotropic substances or stressors mediates the process of
adult neurogenesis by regulating the expression and function of some growth factors, suggesting
a possible role of neurogenesis in the pathophysiology of MD [102, 103]. The physiological role
of BDNF is to stimulate the development and stabilization of connections between neurons. This
growth factor influences the expression levels of reelin, a molecule of the extracellular matrix
that plays an important role in the processes of neural plasticity in important areas for plasticity
and memory, such as the hippocampus and cortex, as well as other components of the limbic
system and amygdala [104]. Furthermore, both BDNF as well as glutamate are involved in the
process of synaptic plasticity, neurogenesis and neural survival in the adult brain. In fact, both
signals are co-regulated: glutamate stimulates the expression of BDNF, so that there is an
increase in the growth and survival of glutamatergic neurons [105]. There is much evidence of a
possible validity of BDNF as a biomarker of MD, as follows: low levels of this marker in the blood
of depressed individuals; a negative correlation between blood levels of BDNF and Hamilton
scale score of patients with depression; as well as increases in hippocampal BDNF expression in
subjects treated with antidepressants compared to healthy controls [106, 107]. The basic
assumption is that MD is caused by a maladaptation to the plasticity of the brain, and
antidepressants act allowing renewed plasticity that somehow restores normal function [108].
Exactly where and how this occurs and how could explain the MD was not specified, although
the hippocampus is an obvious target in this process, which contains high concentrations of both
BDNF and its main receptor, TkrB.
THE EFFECT OF AEROBIC EXERCISE ON THE PLASMA OR SERUM CORTISOL CONCENTRATIONS IN
DEPRESSIVE PATIENTS
Few studies have analyzed the relationship between serum cortisol levels and aerobic exercise
in patients with depression [21, 32, 109-112]. Krogh et al. [109] investigated whether an exercise