The impact of stress on body function: A review

Abstract

Any intrinsic or extrinsic stimulus that evokes a biological response is known as stress. The compensatory responses to these stresses are known as stress responses. Based on the type, timing and severity of the applied stimulus, stress can exert various actions on the body ranging from alterations in homeostasis to life-threatening effects and death. In many cases, the pathophysiological complications of disease arise from stress and the subjects exposed to stress, e.g. those that work or live in stressful environments, have a higher likelihood of many disorders. Stress can be either a triggering or aggravating factor for many diseases and pathological conditions. In this study, we have reviewed some of the major effects of stress on the primary physiological systems of humans.

Full text

EXCLI Journal 2017;16:1057-1072 – ISSN 1611-2156
Received: May 20, 2017, accepted: July 18, 2017, published: July 21, 2017
1057
Review article:
THE IMPACT OF STRESS ON BODY FUNCTION: A REVIEW
Habib Yaribeygi,1 Yunes Panahi,2* Hedayat Sahraei,1 Thomas P. Johnston,3
Amirhossein Sahebkar4*
1 Neurosciences Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
2 Clinical Pharmacy Department, Faculty of Pharmacy, Baqiyatallah University of Medical
Sciences, Tehran, Iran
3 Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas
City, Kansas City, Missouri, USA
4 Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
* Corresponding authors: Yunes Panahi, PhD, Clinical Pharmacy Department,
Faculty of Pharmacy, Baqiyatallah University of Medical Sciences, Tehran, Iran,
Tel/Fax: +982188211524; E-mail: yunespanahi@yahoo.com;
Amirhossein Sahebkar, PharmD, PhD, Department of Medical Biotechnology,
School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran,
P.O. Box: 91779-48564, Iran. Tel: 985118002288; Fax: 985118002287;
E-mail: sahebkara@mums.ac.ir; amir_saheb2000@yahoo.com
http://dx.doi.org/10.17179/excli2017-480
This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0/).
ABSTRACT
Any intrinsic or extrinsic stimulus that evokes a biological response is known as stress. The compensatory re-
sponses to these stresses are known as stress responses. Based on the type, timing and severity of the applied
stimulus, stress can exert various actions on the body ranging from alterations in homeostasis to life-threatening
effects and death. In many cases, the pathophysiological complications of disease arise from stress and the subjects
exposed to stress, e.g. those that work or live in stressful environments, have a higher likelihood of many disorders.
Stress can be either a triggering or aggravating factor for many diseases and pathological conditions. In this study,
we have reviewed some of the major effects of stress on the primary physiological systems of humans.
Keywords: stress, physiology, homeostasis
STRESS AND THE BRAIN FUNCTION
COMPLICATIONS
For a long time, researchers suggested
that hormones have receptors just in the pe-
ripheral tissues and do not gain access to the
central nervous system (CNS) (Lupien and
Lepage, 2001). However, observations have
demonstrated the effect of anti-inflammatory
drugs (which are considered synthetic hor-
mones) on behavioral and cognitive disorders
and the phenomenon called “Steroid psycho-
sis” (Clark et al., 1952). In the early sixties,
neuropeptides were recognized as compounds
devoid of effects on the peripheral endocrine
system. However, it was determined that hor-
mones are able to elicit biological effects on
different parts of the CNS and play an im-
portant role in behavior and cognition (De
Kloet, 2000). In 1968, McEven suggested for
the first time that the brain of rodents is capa-
ble of responding to glucocorticoid (as one of

EXCLI Journal 2017;16:1057-1072 – ISSN 1611-2156
Received: May 20, 2017, accepted: July 18, 2017, published: July 21, 2017
1058
the operators in the stress cascade). This hy-
pothesis that stress can cause functional
changes in the CNS was then accepted
(McEwen et al., 1968). From that time on, two
types of corticotropic receptors (glucocortico-
steroids and mineralocorticoids) were recog-
nized (de Kloet et al., 1999). It was deter-
mined that the affinity of glucocorticosteroid
receptors to cortisol and corticosterone was
about one tenth of that of mineralocorticoids
(de Kloet et al., 1999). The hippocampus area
has both types of receptors, while other points
of the brain have only glucocorticosteroid re-
ceptors (de Kloet et al., 1999).
The effects of stress on the nervous sys-
tem have been investigated for 50 years
(Thierry et al., 1968). Some studies have
shown that stress has many effects on the hu-
man nervous system and can cause structural
changes in different parts of the brain (Lupien
et al., 2009). Chronic stress can lead to atro-
phy of the brain mass and decrease its weight
(Sarahian et al., 2014). These structural
changes bring about differences in the re-
sponse to stress, cognition and memory
(Lupien et al., 2009). Of course, the amount
and intensity of the changes are different ac-
cording to the stress level and the duration of
stress (Lupien et al., 2009). However, it is
now obvious that stress can cause structural
changes in the brain with long-term effects on
the nervous system (Reznikov et al., 2007).
Thus, it is highly essential to investigate the
effects of stress on different aspects of the
nervous system (Table 1).
Table 1: Destructive effects of stress of CNS function
Aspects of
function Main Area
involved Structural Changes Functional Changes
Stress
and
brain
Memory
Hippocampus
(Glucocorticoid
receptors)
atrophy and neurogenesis
disorders (Lupien et al.,
2001), decreasing dendritic
branches (Woolley et al.,
1990), decreasing the num-
ber of neurons and synaptic
terminals altering (Sapolsky
et al., 1990), decreasing
neurogenesis in hypocam-
pus (Gould et al., 1998), re-
duction in hypocampus vol-
ume (Bremner, 1999), modi-
fying LTP (Seeman et al.,
1997)
declarative memory dis-
orders (Lupien et al.,
2001), reduction in spa-
tial memory (Luine et
al., 1994), weakening
verbal memory, disturb-
ance in hippocampus-
dependent loading data
(Bremner, 1999)
Amygdala (Nora-
drenaline)
Cognition
and Learn-
ing
hippocampus,
amygdala and
temporal lobe
neurodegenerative pro-
cesses activation (Li et al.,
2008)
reducing of cognition
(Scholey et al., 2014),
making behavioral, cog-
nitive and mood disor-
ders (Li et al., 2008),
disorders in hippocam-
pus-related cognition
(Borcel et al., 2008),
decreasing the reaction
time (Lupien et al.,
2002)

EXCLI Journal 2017;16:1057-1072 – ISSN 1611-2156
Received: May 20, 2017, accepted: July 18, 2017, published: July 21, 2017
1059
STRESS AND MEMORY
Memory is one of the important functional
aspects of the CNS and it is categorized as
sensory, short term, and long-term. Short term
memory is dependent on the function of the
frontal and parietal lobes, while long-term
memory depends on the function of large ar-
eas of the brain (Wood et al., 2000). However,
total function of memory and the conversion
of short term memory to long-term memory
are dependent on the hippocampus; an area of
the brain that has the highest density of gluco-
corticosteroid receptors and also represents
the highest level of response to stress (Sco-
ville and Milner, 1957; Asalgoo et al., 2015).
Therefore, during the past several decades,
the relationship between the hippocampus
and stress have been hotly debated (Asalgoo
et al., 2015; Lupien and Lepage, 2001). In
1968, it was proven that there were cortisol
receptors in the hippocampus of rats
(McEwen et al., 1968). Later, in 1982, by us-
ing specific agonists of glucocorticosteroid
and mineralocorticoid receptors, the existence
of these two receptors in the brain and hippo-
campus area of rats was proven (Veldhuis et
al., 1982). It should also be noted that the
amygdala is very important to assessing the
emotional experiences of memory (Roozen-
daal et al., 2009).
The results of past studies have demon-
strated the effect of stress on the process of
memory (Ghodrat et al., 2014). Various stud-
ies have shown that stress can cause func-
tional and structural changes in the hippocam-
pus section of the brain (McEwen, 1999).
These structural changes include atrophy and
neurogenesis disorders (Lupien and Lepage,
2001). Also, chronic stress and, consequently,
an increase in plasma cortisol, leads to a re-
duction in the number of dendritic branches
(Woolley et al., 1990) and the number of neu-
rons (Sapolsky et al., 1990), as well as struc-
tural changes in synaptic terminals (Sapolsky
et al., 1990) and decreased neurogenesis in
the hippocampus tissue (Gould et al., 1998).
Glucocorticosteroids can induce these
changes by either effecting the cellular metab-
olism of neurons (Lawrence and Sapolsky,
1994), or increasing the sensitivity of hippo-
campus cells to stimulatory amino acids
(Sapolsky and Pulsinelli, 1985) and/or in-
creasing the level of extracellular glutamate
(Sapolsky and Pulsinelli, 1985).
High concentrations of stress hormones
can cause declarative memory disorders
(Lupien and Lepage, 2001). Animal studies
have shown that stress can cause a reversible
reduction in spatial memory as a result of at-
rophy of the hippocampus (Luine et al.,
1994). In fact, high plasma concentrations of
glucocorticosteroids for extended periods of
time can cause atrophy of the hippocampus
leading to memory disorders (Issa et al.,
1990). Additionally, people with either Cush-
ing’s syndrome (with an increased secretion
of glucocorticosteroids), or people who re-
ceive high dosages of exogenous synthetic
anti-inflammatory drugs, are observed to have
atrophy of the hippocampus and associated
memory disorders (Ling et al., 1981). MRI
images taken from the brains of people with
post-traumatic stress disorder (PTSD) have
demonstrated a reduction in the volume of the
hippocampus along with neurophysiologic ef-
fects such as a weak verbal memory
(Bremner, 1999). Several human studies have
suggested that even common therapeutic
doses of glucocorticosteroids and dexame-
thasone can cause problems with explicit
memory (Keenan et al., 1995; Kirschbaum et
al., 1996). Thus, there is an inverse relation-
ship between the level of cortisol and memory
(Ling et al., 1981), such that increasing levels
of plasma cortisol following prolonged stress
leads to a reduction in memory (Kirschbaum
et al., 1996), which improves when the level
of plasma cortisol decreases (Seeman et al.,
1997).
Stress also has negative effects on learn-
ing. Results from hippocampus-dependent
loading data demonstrate that subjects are not
as familiar with a new environment after hav-
ing been exposed to a new environment
(Bremner, 1999). Moreover, adrenal steroids
lead to alteration in long-term potentiation
(LTP), which is an important process in
memory formation (Bliss and Lømo, 1973).

EXCLI Journal 2017;16:1057-1072 – ISSN 1611-2156
Received: May 20, 2017, accepted: July 18, 2017, published: July 21, 2017
1060
Two factors are involved in the memory
process during stress. The first is noradrena-
line, which creates emotional aspects of mem-
ories in the basolateral amygdala area (Joëls
et al., 2011). Secondly, this process is facili-
tated by corticosteroids. However, if the re-
lease of corticosteroids occurs a few hours
earlier, it causes inhibition of the amygdala
and corresponding behaviors (Joëls et al.,
2011). Thus, there is a mutual balance be-
tween these two hormones for creating a re-
sponse in the memory process (Joëls et al.,
2011).
Stress does not always affect memory.
Sometimes, under special conditions, stress
can actually improve memory (McEwen and
Lupien, 2002). These conditions include non-
familiarity, non-predictability, and life-threat-
ening aspects of imposed stimulation. Under
these specific conditions, stress can temporar-
ily improve the function of the brain and,
therefore, memory. In fact, it has been sug-
gested that stress can sharpen memory in
some situations (Schwabe et al., 2010). For
example, it has been shown that having to
take a written examination can improve
memory for a short period of time in exami-
nation participants. Interestingly, this condi-
tion is associated with a decrease in the level
of cortisol in the saliva (Vedhara et al., 2000).
Other studies have shown that impending
stress before learning occurs can also lead to
either an increase in the power of memory
(Domes et al., 2002; Schwabe et al., 2008), or
decrease in the capacity for memory
(Diamond et al., 2006; Kirschbaum et al.,
1996). This paradox results from the type of
imposed stress and either the degree of emo-
tional connection to the stressful event (Payne
et al., 2007; Diamond et al., 2007), or the pe-
riod of time between the imposing stress and
the process of learning (Diamond et al.,
2007).
The process of strengthening memory is
usually reinforced after stress (Schwabe et al.,
2012). Various studies on animal and human
models have shown that administration of ei-
ther glucocorticosteroids, or stress shortly af-
ter learning has occurred facilitates memory
(Schwabe et al., 2012). Also, it has been
shown that glucocorticosteroids (not mineral-
ocorticoids) are necessary to improve learn-
ing and memory (Lupien et al., 2002). How-
ever, the retrieval of events in memory after
exposure to stress will be decreased (Schwabe
et al., 2012), which may result from the com-
petition of updated data for storage in
memory in a stressful state (de Kloet et al.,
1999). Some investigations have shown that
either exposure to stress, or injection of glu-
cocorticosteroids before a test to assess reten-
tion, decreases the power of memory in hu-
mans and rodents (Schwabe and Wolf, 2009).
In summary, it has been concluded that
the effect of stress on memory is highly de-
pendent on the time of exposure to the stress-
ful stimulus and, in terms of the timing of the
imposed stress, memory can be either better
or worse (Schwabe et al., 2012). Moreover,
recent studies have shown that using a spe-
cific-timed schedule of exposure to stress not
only affects hippocampus-dependent
memory, but also striatum-dependent
memory, which highlights the role of timing
of the imposed stressful stimulus (Schwabe et
al., 2010).
STRESS, COGNITION AND
LEARNING
Cognition is another important feature of
brain function. Cognition means reception
and perception of perceived stimuli and its in-
terpretation, which includes learning, deci-
sion making, attention, and judgment (Sandi,
2013). Stress has many effects on cognition
that depend on its intensity, duration, origin,
and magnitude (Sandi, 2013). Similar to
memory, cognition is mainly formed in the
hippocampus, amygdala, and temporal lobe
(McEwen and Sapolsky, 1995). The net effect
of stress on cognition is a reduction in cogni-
tion and thus, it is said that any behavioral
steps undertaken to reduce stress leads to in-
crease in cognition (Scholey et al., 2014). In
fact, stress activates some physiological sys-
tems, such as the autonomic nervous system,
central neurotransmitter and neuropeptide

EXCLI Journal 2017;16:1057-1072 – ISSN 1611-2156
Received: May 20, 2017, accepted: July 18, 2017, published: July 21, 2017
1061
system, and the hypothalamus-pituitary-ad-
renal axis, which have direct effects on neural
circuits in the brain involved with data pro-
cessing (Sandi, 2013). Activation of stress re-
sults in the production and release of gluco-
corticosteroids. Because of the lipophilic
properties of glucocorticosteroids, they can
diffuse through the blood-brain barrier and
exert long-term effects on processing and
cognition (Sandi, 2013).
It appears that being exposed to stress can
cause pathophysiologic changes in the brain,
and these changes can be manifested as be-
havioral, cognitive, and mood disorders (Li et
al., 2008). In fact, studies have shown that
chronic stress can cause complications such
as increased IL-6 and plasma cortisol, but de-
creased amounts of cAMP responsive ele-
ment binding protein and brain-derived neu-
rotrophic factor (BDNF), which is very simi-
lar to what is observed in people with depres-
sion and mood disorders that exhibit a wide
range of cognitive problems (Song et al.,
2006). Additionally, the increased concentra-
tions of inflammatory factors, like interleu-
kins and TNF-α (which play an important role
in creating cognitive disorders), proves a
physiologic relationship between stress and
mood-based cognitive disorders (Solerte et
al., 2000; Marsland et al., 2006; Li et al.,
2008). Studies on animals suggest that cogni-
tive disorders resulting from stress are created
due to neuroendocrine and neuroamine fac-
tors and neurodegenerative processes (Li et
al., 2008). However, it should be noted that
depression may not always be due to the over
activation of the physiological-based stress
response (Osanloo et al., 2016).
Cognitive disorders following exposure to
stress have been reported in past studies
(Lupien and McEwen, 1997). Stress has ef-
fects on cognition both acutely (through cate-
cholamines) and chronically (through gluco-
corticosteroids) (McEwen and Sapolsky,
1995). Acute effects are mainly caused by
beta-adrenergic effects, while chronic effects
are induced in a long-term manner by changes
in gene expression mediated by steroids
(McEwen and Sapolsky, 1995). In general,
many mechanisms modulate the effects of
stress on cognition (McEwen and Sapolsky,
1995; Mendl, 1999). For instance, adrenal
steroids affect the function of the hippocam-
pus during cognition and memory retrieval in
a biphasic manner (McEwen and Sapolsky,
1995). In chronic stress, these steroids can de-
stroy neurons with other stimulatory neuro-
transmitters (Sandi, 2013). Exposure to stress
can also cause disorders in hippocampus-re-
lated cognition; specifically, spatial memory
(Borcel et al., 2008; Sandi et al., 2003). Addi-
tionally, stress can halt or decrease the genesis
of neurons in the dentate gyrus area of the hip-
pocampus (this area is one of the limited brain
areas in which neurogenesis occurs in adults)
(Gould and Tanapat, 1999; Köhler et al.,
2010). Although age is a factor known to af-
fect cognition, studies on animals have
demonstrated that young rats exposed to high
doses of adrenal steroids show the same level
of decline in their cognition as older adult an-
imals with normal plasma concentrations of
glucocorticoids (Landfield et al., 1978). Also,
a decrease in the secretion of glucocortico-
steroids causes preservation of spatial
memory in adults and has also been shown to
have neuroprotective effects (Montaron et al.,
2006). Other studies have shown that stress
(or the injection of adrenal steroids) results in
varied effects on cognition. For instance, in-
jection of hydrocortisone at the time of its
maximum plasma concentration (in the after-
noon) leads to a decrease in reaction time and
improves cognition and memory (Lupien et
al., 2002).
In summary, the adverse effects of stress
on cognition are diverse and depend on the
type, timing, intensity, and duration (Sandi,
2013). Generally, it is believed that mild
stress facilitates an improvement in cognitive
function, especially in the case of virtual or
verbal memory. However, if the intensity of
stress passes beyond a predetermined thresh-
old (which is different in each individual), it
causes cognitive disorders, especially in
memory and judgment. The disruption to
memory and judgment is due to the effects of

EXCLI Journal 2017;16:1057-1072 – ISSN 1611-2156
Received: May 20, 2017, accepted: July 18, 2017, published: July 21, 2017
1062
stress on the hippocampus and prefrontal cor-
tex (Sandi, 2013). Of course, it must be real-
ized that factors like age and gender may also
play a role in some cognitive disorders (Sandi,
2013). Importantly, it should be emphasized
that different people may exhibit varied re-
sponses in cognition when exposed to the
very same stressful stimulus (Hatef et al.,
2015).
STRESS AND IMMUNE SYSTEM
FUNCTIONS
The relationship between stress and the
immune system has been considered for dec-
ades (Khansari et al., 1990; Dantzer and
Kelley, 1989). The prevailing attitude be-
tween the association of stress and immune
system response has been that people under
stress are more likely to have an impaired im-
mune system and, as a result, suffer from
more frequent illness (Khansari et al., 1990).
Also, old anecdotes describing resistance of
some people to severe disease using the
power of the mind and their thought pro-
cesses, has promoted this attitude (Khansari et
al., 1990). In about 200 AC, Aelius Galenus
(Galen of Pergamon) declared that melan-
cholic women (who have high levels of stress
and, thus, impaired immune function) are
more likely to have cancer than women who
were more positive and exposed to less stress
(Reiche et al., 2004). This may be the first rec-
orded case about the relationship between the
immune system and stress. In an old study in
the early 1920’s, researchers found that the
activity of phagocytes in tuberculosis de-
creased when emotional stress was induced.
In fact, it was also suggested that living with
stress increases the risk of tuberculosis by
suppressing the immune system (Ishigami,
1919). Following this study, other researchers
suggested that the probability of disease ap-
pearance increases following a sudden, major,
and extremely stressful life style change
(Holmes and Rahe, 1967; Calabrese et al.,
1987).
Over the past several decades, there have
been many studies investigating the role of
stress on immune system function (Dantzer
and Kelley, 1989; Segerstrom and Miller,
2004). These studies have shown that stress
mediators can pass through the blood-brain
barrier and exert their effects on the immune
system (Khansari et al., 1990). Thus, the ef-
fect of stress on the immune system is now an
accepted relationship or association.
Stress can affect the function of the im-
mune system by modulating processes in the
CNS and neuroendocrine system (Khansari et
al., 1990; Kiecolt-Glaser and Glaser, 1991).
Following stress, some neuroendocrine and
neural responses result in the release of corti-
cotropin-releasing hormone (CRH), adreno-
corticotropic hormone (ACTH), and other
stress mediators (Carrasco and Van de Kar,
2003). However, evidence suggests that the
lymphatic system, which is a part of the im-
mune system, also plays a role in releasing
these mediators (Khansari et al., 1990). For
instance, thymus peptides, such as thymopen-
tine, thymopoietin, and thymosin fraction-5,
cause an increase in ACTH production (Goya
et al., 1993). Additionally, the existence of
CRH in thymus has been proven (Redei,
1992). It has also been proven that interleu-
kin-1 released from phagocytes has a role in
ACTH secretion (Berkenbosch et al., 1987).
On the other hand, natural or synthetic gluco-
corticosteroids (which are the final stress op-
erators) are known as anti-inflammatory
drugs and immune suppressants and their role
in the inhibition of lymphocytes and macro-
phages has been demonstrated as well
(Elenkov et al., 1999; Reiche et al., 2004).
Moreover, their role in inhibiting the produc-
tion of cytokines and other immune mediators
and decreasing their effect on target cells dur-
ing exposure to stress has also been deter-
mined (Reiche et al., 2004).
In addition to adrenal steroids, other hor-
mones are affected during stress. For exam-
ple, the secretion of growth hormone will be
halted during severe stress. A study showed
that long-term administration of CRH into the
brain ventricles leads to a cessation in the re-
lease of growth hormone (Rivier and Vale,
1985). Stress also causes the release of opioid
peptides to be changed during the time period

EXCLI Journal 2017;16:1057-1072 – ISSN 1611-2156
Received: May 20, 2017, accepted: July 18, 2017, published: July 21, 2017
1063
over which the person is exposed to stress
(McCarthy et al., 2001). In fact, stress modi-
fies the secretion of hormones that play a crit-
ical role in the function of the immune system
(Khansari et al., 1990). To date, it has been
shown that various receptors for a variety of
hormones involved in immune system func-
tion are adversely affected by stress. For ex-
ample, ACTH, vasoactive intestinal peptide
(VIP), substance P, growth hormone, prolac-
tin, and steroids all have receptors in various
tissues of the immune system and can modu-
late its function (De la Fuente et al., 1996;
Gala, 1991; Mantyh, 1991). In addition, ac-
tive immune cells are also able to secrete sev-
eral hormones; thus, some researchers believe
that these hormones, as mediators of immune
system, play a significant role in balancing its
function (Blalock et al., 1985).
Severe stress can lead to malignancy by
suppressing the immune system (Reiche et al.,
2004). In fact, stress can decrease the activity
of cytotoxic T lymphocytes and natural killer
cells and lead to growth of malignant cells,
genetic instability, and tumor expansion
(Reiche et al., 2004). Studies have shown that
the plasma concentration of norepinephrine,
which increases after the induction stress, has
an inverse relationship with the immune func-
tion of phagocytes and lymphocytes (Reiche
et al., 2004). Lastly, catecholamines and opi-
oids that are released following stress have
immune-suppressing properties (Reiche et al.,
2004).
STRESS AND THE FUNCTION OF THE
CARDIOVASCULAR SYSTEM
The existence of a positive association be-
tween stress and cardiovascular disease has
been verified (Rozanski et al., 1999). Stress,
whether acute or chronic, has a deleterious ef-
fect on the function of the cardiovascular sys-
tem (Rozanski et al., 1999; Kario et al., 2003;
Herd, 1991). The effects of stress on the car-
diovascular system are not only stimulatory,
but also inhibitory in nature (Engler and
Engler, 1995). It can be postulated that stress
causes autonomic nervous system activation
and indirectly affects the function of the car-
diovascular system (Lazarus et al., 1963;
Vrijkotte et al., 2000). If these effects occur
upon activation of the sympathetic nervous
system, then it mainly results in an increase in
heart rate, strength of contraction, vasodila-
tion in the arteries of skeletal muscles, a nar-
rowing of the veins, contraction of the arteries
in the spleen and kidneys, and decreased so-
dium excretion by the kidneys (Herd, 1991).
Sometimes, stress activates the parasympa-
thetic nervous system (Pagani et al., 1991).
Specifically, if it leads to stimulation of the
limbic system, it results in a decrease, or even
a total stopping of the heart-beat, decreased
contractility, reduction in the guidance of im-
pulses by the heart stimulus-transmission net-
work, peripheral vasodilatation, and a decline
in blood pressure (Cohen et al., 2000). Fi-
nally, stress can modulate vascular endothe-
lial cell function and increase the risk of
thrombosis and ischemia, as well as increase
platelet aggregation (Rozanski et al., 1999).
The initial effect of stress on heart func-
tion is usually on the heart rate (Vrijkotte et
al., 2000). Depending upon the direction of
the shift in the sympatho-vagal response, the
heart beat will either increase or decrease
(Hall et al., 2004). The next significant effect
of stress on cardiovascular function is blood
pressure (Laitinen et al., 1999). Stress can
stimulate the autonomic sympathetic nervous
system to increase vasoconstriction, which
can mediate an increase in blood pressure, an
increase in blood lipids, disorders in blood
clotting, vascular changes, atherogenesis; all,
of which, can cause cardiac arrhythmias and
subsequent myocardial infarction (Rozanski
et al., 1999; Vrijkotte et al., 2000; Sgoifo et
al., 1998). These effects from stress are ob-
served clinically with atherosclerosis and
leads to an increase in coronary vasocon-
striction (Rozanski et al., 1999). Of course,
there are individual differences in terms of the
level of autonomic-based responses due to
stress, which depends on the personal charac-
teristics of a given individual (Rozanski et al.,
1999). Thus, training programs for stress

EXCLI Journal 2017;16:1057-1072 – ISSN 1611-2156
Received: May 20, 2017, accepted: July 18, 2017, published: July 21, 2017
1064
management are aimed at reducing the conse-
quences of stress and death resulting from
heart disease (Engler and Engler, 1995). In
addition, there are gender-dependent differ-
ences in the cardiovascular response to stress
and, accordingly, it has been estimated that
women begin to exhibit heart disease ten
years later that men, which has been attributed
to the protective effects of the estrogen hor-
mone (Rozanski et al., 1999).
Studies have shown that psychological
stress can cause alpha-adrenergic stimulation
and, consequently, increase heart rate and ox-
ygen demand (Rozanski et al., 1998, 1999;
Jiang et al., 1996). As a result, coronary vas-
oconstriction is enhanced, which may in-
crease the risk of myocardial infarction
(Yeung et al., 1991; Boltwood et al., 1993;
Dakak et al., 1995). Several studies have
demonstrated that psychological stress de-
creases the microcirculation in the coronary
arteries by an endothelium-dependent mecha-
nism and increases the risk of myocardial in-
farction (Dakak et al., 1995). On the other
hand, mental stress indirectly leads to poten-
tial engagement in risky behaviors for the
heart, such as smoking, and directly leads to
stimulation of the neuroendocrine system as
part of the autonomic nervous system
(Hornstein, 2004). It has been suggested that
severe mental stress can result in sudden
death (Pignalberi et al., 2002). Generally,
stress-mediated risky behaviors that impact
cardiovascular health can be summarized into
five categories: an increase in the stimulation
of the sympathetic nervous system, initiation
and progression of myocardial ischemia, de-
velopment of cardiac arrhythmias, stimula-
tion of platelet aggregation, and endothelial
dysfunction (Wu, 2001).
STRESS AND GASTROINTESTINAL
COMPLICATIONS
The effects of stress on nutrition and the
gastrointestinal (GI) system can be summa-
rized with two aspects of GI function.
First, stress can affect appetite (Bagheri
Nikoo et al., 2014; Halataei et al., 2011;
Ranjbaran et al., 2013). This effect is related
to involvement of either the ventral tegmental
area (VTA), or the amygdala via N-methyl-D-
aspartate (NMDA) glutamate receptors
(Nasihatkon et al., 2014; Sadeghi et al., 2015).
However, it should also be noted that nutrition
patterns have effects on the response to stress
(Ghanbari et al., 2015), and this suggests a bi-
lateral interaction between nutrition and
stress.
Second, stress adversely affects the nor-
mal function of GI tract. There are many stud-
ies concerning the effect of stress on the func-
tion of the GI system (Söderholm and Perdue,
2001; Collins, 2001). For instance, studies
have shown that stress affects the absorption
process, intestinal permeability, mucus and
stomach acid secretion, function of ion chan-
nels, and GI inflammation (Collins, 2001;
Nabavizadeh et al., 2011). Stress also in-
creases the response of the GI system to in-
flammation and may reactivate previous in-
flammation and accelerate the inflammation
process by secretion of mediators such as sub-
stance P (Collins, 2001). As a result, there is
an increase in the permeability of cells and re-
cruitment of T lymphocytes. Lymphocyte ag-
gregation leads to the production of inflam-
matory markers, activates key pathways in the
hypothalamus, and results in negative feed-
back due to CRH secretion, which ultimately
results in the appearance of GI inflammatory
diseases (Collins, 2001). This process can re-
activate previous silent colitis (Million et al.,
1999; Qiu et al., 1999). Mast cells play a cru-
cial role in stress-induced effects on the GI
system, because they cause neurotransmitters
and other chemical factors to be released that
affect the function of the GI system (Konturek
et al., 2011).
Stress can also alter the functional physi-
ology of the intestine (Kiliaan et al., 1998).
Many inflammatory diseases, such as Crohn’s
disease and other ulcerative-based diseases of
the GI tract, are associated with stress
(Hommes et al., 2002). It has been suggested
that even childhood stress can lead to these
diseases in adulthood (Schwartz and
Schwartz, 1983). Irritable bowel syndrome,
which is a disease with an inflammatory

EXCLI Journal 2017;16:1057-1072 – ISSN 1611-2156
Received: May 20, 2017, accepted: July 18, 2017, published: July 21, 2017
1065
origin, is highly related to stress
(Gonsalkorale et al., 2003). Studies on vari-
ous animals suggest the existence of inflam-
matory GI diseases following induction of se-
vere stress (Qiu et al., 1999; Collins et al.,
1996). Additionally, pharmacological inter-
ventions, in an attempt to decrease the re-
sponse of CRH to stress, have been shown to
result in an increase in GI diseases in rats
(Million et al., 1999).
Altering the permeability of the mucosal
membrane by perturbing the functions of mu-
cosal mast cells may be another way that
stress causes its effects on the GI system,
since this is a normal process by which harm-
ful and toxic substances are removed from the
intestinal lumen (Söderholm and Perdue,
2001). Also, stress can both decrease the re-
moval of water from the lumen, as well as in-
duce sodium and chloride secretion into the
lumen. This most likely occurs by increasing
the activity of the parasympathetic nervous
system (Barclay and Turnberg, 1987). More-
over, physical stress, such as trauma or sur-
gery, can increase luminal permeability
(Söderholm and Perdue, 2001) (Table 2).
Table 2: Stress has various effects on the function of GI system
Aspects of stress
effects on GI
Part, Area or
receptors
involved in Detailed effects
Stress and GI
system
Appetite Modifying
Ventral tegmen-
tal area, Amyg-
dala (NMDA Glu-
tamate recep-
tors)
Anorexia induction (Halataei et
al., 2011), Reduces food and
water intake (Ranjbaran et al.,
2013)
GI Tract Movement
CRH-2 receptors
in stomach,
CRH-1 and 5HT-
3 receptors in
Colon
Prevents stomach emptying,
accelerates the colon move-
ment (Mönnikes et al., 2001),
increases the movements of
terminal parts and decreases
the initial part of GI tract (Mön-
nikes et al., 2001)
Digestive functions Parasympathetic
system
Modifying absorption, intestinal
permeability, mucus and stom-
ach acid secretion and function
of ion channels (Collins, 2001;
Nabavizadeh et al., 2011), de-
creases the water reabsorption
from lumen and induces so-
dium and chloride secretion
into the lumen (Barclay and
Turnberg, 1987)
GI system inflammation T Lymphocytes
activation, cyto-
kines releasing
Increasing inflammation by
substance P secretion (Collins,
2001), retrieving T Lympho-
cytes (Collins, 2001), reactivate
silent previous colitis (Million et
al., 1999), induces irritable
bowel syndrome (Gonsalkorale
et al., 2003)

EXCLI Journal 2017;16:1057-1072 – ISSN 1611-2156
Received: May 20, 2017, accepted: July 18, 2017, published: July 21, 2017
1066
Stress also affects movement of the GI
tract. In this way, it prevents stomach empty-
ing and accelerates colonic motility
(Mönnikes et al., 2001). In the case of irritable
bowel syndrome, stress increases the move-
ment (contractility and motility) of the large
intestine (Mönnikes et al., 2001). Previous
studies have revealed that CRH increases
movement in the terminal sections of the GI
tract and decreases the movements in the
proximal sections of the GI tract (Mönnikes et
al., 2001). A delay in stomach emptying is
likely accomplished through CRH-2 recep-
tors, while type 1 receptors affect the colon
(Mönnikes et al., 2001). The effects produced
by CRH are so prominent that CRH is now
considered an ideal candidate for the treat-
ment of irritable bowel syndrome (Martinez
and Taché, 2006). When serotonin is released
in response to stress (Chaouloff, 2000), it
leads to an increase in the motility of the co-
lon by stimulating 5HT-3 receptors
(Mönnikes et al., 2001). Moreover, it has also
been suggested that stress, especially mental
and emotional types of stress, increase vis-
ceral sensitivity and activate mucosal mast
cells (Mönnikes et al., 2001). Stimulation of
the CNS by stress has a direct effect on GI-
specific nervous system (i.e., the myenteric
system or plexus) and causes the above men-
tioned changes in the movements of the GI
tract (Bhatia and Tandon, 2005). In fact, stress
has a direct effect on the brain-bowel axis
(Konturek et al., 2011). Various clinical stud-
ies have suggested a direct effect of stress on
irritable bowel syndrome, intestinal inflam-
mation, and peptic ulcers (Konturek et al.,
2011).
In conclusion, the effects of stress on the
GI system can be classified into six different
actions: GI tract movement disorders, in-
creased visceral irritability, altered rate and
extent of various GI secretions, modified per-
meability of the intestinal barrier, negative ef-
fects on blood flow to the GI tract, and in-
creased intestinal bacteria counts (Konturek
et al., 2011).
STRESS AND THE ENDOCRINE
SYSTEM
There is a broad and mutual relationship
between stress and the endocrine system. On
one hand, stress has many subtle and complex
effects on the activity of the endocrine system
(Sapolsky, 2002; Charmandari et al., 2005),
while on the other hand, the endocrine system
has many effects on the response to stress
(Ulrich-Lai and Herman, 2009; Selye, 1956).
Stress can either activate, or change the activ-
ity of, many endocrine processes associated
with the hypothalamus, pituitary and adrenal
glands, the adrenergic system, gonads, thy-
roid, and the pancreas (Tilbrook et al., 2000;
Brown-Grant et al., 1954; Thierry et al., 1968;
Lupien and McEwen, 1997). In fact, it has
been suggested that it is impossible to sepa-
rate the response to stress from the functions
of the endocrine system. This premise has
been advanced due to the fact that even a min-
imal amount of stress can activate the hypo-
thalamic-pituitary-adrenal axis, which itself is
intricately involved with the activation of sev-
eral different hormone secreting systems
(Sapolsky, 2002). In different locations
throughout this article, we have already dis-
cussed the effects of stress on hormones and
various endocrine factors and, thus, they will
not be further addressed.
CONCLUSION
Altogether, stress may induce both bene-
ficial and harmful effects. The beneficial ef-
fects of stress involve preserving homeostasis
of cells/species, which leads to continued sur-
vival. However, in many cases, the harmful
effects of stress may receive more attention or
recognition by an individual due to their role
in various pathological conditions and dis-
eases. As has been discussed in this review,
various factors, for example, hormones, neu-
roendocrine mediators, peptides, and neuro-
transmitters are involved in the body’s re-
sponse to stress. Many disorders originate
from stress, especially if the stress is severe
and prolonged. The medical community
needs to have a greater appreciation for the

EXCLI Journal 2017;16:1057-1072 – ISSN 1611-2156
Received: May 20, 2017, accepted: July 18, 2017, published: July 21, 2017
1067
significant role that stress may play in various
diseases and then treat the patient accordingly
using both pharmacological (medications
and/or nutraceuticals) and non-pharmacolog-
ical (change in lifestyle, daily exercise,
healthy nutrition, and stress reduction pro-
grams) therapeutic interventions. Important
for the physician providing treatment for
stress is the fact that all individuals vary in
their response to stress, so a particular treat-
ment strategy or intervention appropriate for
one patient may not be suitable or optimal for
a different patient.
Conflict of interest
The authors declare that have no conflict
of interest in this study.
Acknowledgment
The authors would like to thank the "Neu-
rosciences Research Center of Baqiyatallah
University of Medical Sciences" and the
“Clinical Research Development Center of
Baqiyatallah (a.s.) Hospital” for providing
technical supports.
Abbreviations
ACTH Adrenocorticotropic hormone
CNS Central nervous system
CRH Corticotropin releasing hormone
GI Gastrointestinal
LTP Long-term potentiation
NMDA N-methyl-D-aspartate
VTA Ventral tegmental area
REFERENCES
Asalgoo S, Jahromi G, Meftahi G, Sahraei H. Posttrau-
matic stress disorder (PTSD): mechanisms and possi-
ble treatments. Neurophysiology. 2015;47:482-9.
Bagheri Nikoo G, Khosravi M, Sahraei H, Ranjbaran
M, Sarahian N, Zardooz H, et al. Effects of systemic
and intra-accumbal memantine administration on the
impacts of plantar electrical shock in male NMRI mice.
Physiol Pharmacol. 2014;18:61-71.
Barclay G, Turnberg L. Effect of psychological stress
on salt and water transport in the human jejunum. Gas-
troenterology. 1987;93:91-7.
Berkenbosch F, Van Oers J, Del Rey A, Tilders F,
Besedovsky H. Corticotropin-releasing factor-produc-
ing neurons in the rat activated by interleukin-1. Sci-
ence. 1987;238(4826):524-6.
Bhatia V, Tandon RK. Stress and the gastrointestinal
tract. J Gastroenterol Hepatol. 2005;20:332-9.
Blalock JE, Harbour-McMenamin D, Smith EM. Pep-
tide hormones shared by the neuroendocrine and im-
munologic systems. J Immunol. 1985;13:858s-61s.
Bliss TV, Lømo T. Long‐lasting potentiation of synap-
tic transmission in the dentate area of the anaesthetized
rabbit following stimulation of the perforant path. J
Physiol. 1973;232:331-56.
Boltwood MD, Taylor CB, Burke MB, Grogin H,
Giacomini J. Anger report predicts coronary artery vas-
omotor response to mental stress in atherosclerotic seg-
ments. Am J Cardiol. 1993;72:1361-5.
Borcel E, Pérez-Alvarez L, Herrero AI, Brionne T,
Varea E, Berezin V, et al. Chronic stress in adulthood
followed by intermittent stress impairs spatial memory
and the survival of newborn hippocampal cells in aging
animals: prevention by FGL, a peptide mimetic of neu-
ral cell adhesion molecule. Behav Pharmacol. 2008;19:
41-9.
Bremner JD. Does stress damage the brain? Biol Psy-
chiatry. 1999;45:797-805.
Brown-Grant K, Harris G, Reichlin S. The effect of
emotional and physical stress on thyroid activity in the
rabbit. J Physiol. 1954;126:29-40.
Calabrese JR, Kling MA, Gold PW. Alterations in im-
munocompetence during stress, bereavement, and de-
pression: focus on neuroendocrine regulation. Am J
Psychiatry. 1987;144:1123-34.
Carrasco GA, Van de Kar LD. Neuroendocrine phar-
macology of stress. Eur J Pharmacol. 2003;463:235-
72.
Chaouloff F. Serotonin, stress and corticoids. J Psycho-
pharmacol. 2000;14:139-51.
Charmandari E, Tsigos C, Chrousos G. Endocrinology
of the stress response. Ann Rev Physiol. 2005;67:259-
84.
Clark LD, Bauer W, Cobb S. Preliminary observations
on mental disturbances occurring in patients under
therapy with cortisone and ACTH. N Engl J Med.
1952;246:205-16.

EXCLI Journal 2017;16:1057-1072 – ISSN 1611-2156
Received: May 20, 2017, accepted: July 18, 2017, published: July 21, 2017
1068
Cohen H, Benjamin J, Geva AB, Matar MA, Kaplan Z,
Kotler M. Autonomic dysregulation in panic disorder
and in post-traumatic stress disorder: application of
power spectrum analysis of heart rate variability at rest
and in response to recollection of trauma or panic at-
tacks. Psychiatry Res. 2000;96:1-13.
Collins SM. Modulation of intestinal inflammation by
stress: basic mechanisms and clinical relevance (IV).
Am J Physiol. 2001;280:G315-8.
Collins SM, McHugh K, Jacobson K, Khan I, Riddell
R, Murase K, et al. Previous inflammation alters the
response of the rat colon to stress. Gastroenterology.
1996;111:1509-15.
Dakak N, Quyyumi AA, Eisenhofer G, Goldstein DS,
Cannon RO. Sympathetically mediated effects of men-
tal stress on the cardiac microcirculation of patients
with coronary artery disease. Am J Cardiol. 1995;76:
125-30.
Dantzer R, Kelley KW. Stress and immunity: an inte-
grated view of relationships between the brain and the
immune system. Life Sci. 1989;44:1995-2008.
de Kloet ER. Stress in the brain. Eur J Pharmacol.
2000;405:187-98.
de Kloet ER, Oitzl MS, Joëls M. Stress and cognition:
are corticosteroids good or bad guys? Trends Neurosci.
1999;22:422-6.
De la Fuente M, Delgado M, Gomariz RP. VIP modu-
lation of immune cell functions. Adv Neuroimmunol.
1996;6:75-91.
Diamond DM, Campbell AM, Park CR, Woodson JC,
Conrad CD, Bachstetter AD, et al. Influence of preda-
tor stress on the consolidation versus retrieval of long‐
term spatial memory and hippocampal spinogenesis.
Hippocampus. 2006;16:571-6.
Diamond DM, Campbell AM, Park CR, Halonen J, Zo-
ladz PR. The temporal dynamics model of emotional
memory processing: a synthesis on the neurobiological
basis of stress-induced amnesia, flashbulb and trau-
matic memories, and the Yerkes-Dodson law. Neural
Plast. 2007;2007:60803.
Domes G, Heinrichs M, Reichwald U, Hautzinger M.
Hypothalamic–pituitary–adrenal axis reactivity to psy-
chological stress and memory in middle-aged women:
High responders exhibit enhanced declarative memory
performance. Psychoneuroendocrinology. 2002;27:
843-53.
Elenkov IJ, Webster EL, Torpy DJ, Chrousos GP.
Stress, corticotropin - releasing hormone, glucocorti-
coids, and the immune/inflammatory response: acute
and chronic effects. Ann NY Acad Sci. 1999;876:1-13.
Engler MB, Engler MM. Assessment of the cardiovas-
cular effects of stress. J Cardiovasc Nurs. 1995;10:51-
63.
Gala RR. Prolactin and growth hormone in the regula-
tion of the immune system. Exp Biol Med. 1991;198:
513-27.
Ghanbari Z, Khosravi M, Hoseini Namvar FS, Zarrin
Ehteram B, Sarahian N, Sahraei H. Effect of intermit-
tent feeding on metabolic symptoms of chronic stress
in female NMRI mice. Iranian South Med J. 2015;18:
982-91.
Ghodrat M, Sahraei H, Razjouyan J, Meftahi G. Effects
of a saffron alcoholic extract on visual short-term
memory in humans: a psychophysical study. Neuro-
physiology. 2014;46:247-53.
Gonsalkorale W, Perrey C, Pravica V, Whorwell P,
Hutchinson I. Interleukin 10 genotypes in irritable
bowel syndrome: evidence for an inflammatory com-
ponent? Gut. 2003;52:91-3.
Gould E, Tanapat P. Stress and hippocampal neurogen-
esis. Biol Psychiatry. 1999;46:1472-9.
Gould E, Tanapat P, McEwen BS, Flügge G, Fuchs E.
Proliferation of granule cell precursors in the dentate
gyrus of adult monkeys is diminished by stress. Proc
Natl Acad Sci. 1998;95:3168-71.
Goya R, Castro M, Hannah M, Sosa Y, Lowry P. Thy-
mosin peptides stimulate corticotropin release by a cal-
cium-dependent mechanism. Neuroendocrinology.
1993;57:230-5.
Halataei BA, Khosravi M, Arbabian S, Sahraei H,
Golmanesh L, Zardooz H, et al. Saffron (Crocus sa-
tivus) Aqueous Extract and its Constituent Crocin Re-
duces Stress‐induced Anorexia in Mice. Phytother Res.
2011;25:1833-8.
Hall M, Vasko R, Buysse D, Ombao H, Chen Q, Cash-
mere JD, et al. Acute stress affects heart rate variability
during sleep. Psychosomatic Med. 2004;66:56-62.
Hatef B, Shiri S, Sahraei H. Why human react differ-
ently to the same sensory experiences: an emotion-cog-
nition interaction. Neurosci J Shefaye Khatam. 2015;4:
63-72.
Herd JA. Cardiovascular response to stress. Physiol
Rev. 1991;71:305-30.
Holmes TH, Rahe RH. The social readjustment rating
scale. J Psychosomatic Res. 1967;11:213-8.

EXCLI Journal 2017;16:1057-1072 – ISSN 1611-2156
Received: May 20, 2017, accepted: July 18, 2017, published: July 21, 2017
1069
Hommes D, Van Den Blink B, Plasse T, Bartelsman J,
Xu C, Macpherson B, et al. Inhibition of stress-acti-
vated MAP kinases induces clinical improvement in
moderate to severe Crohn's disease. Gastroenterology.
2002;122:7-14.
Hornstein C. [Stress, anxiety and cardiovascular dis-
ease: an interdisciplinary approach] (article in Span-
ish). Vertex (Buenos Aires, Argentina). 2004;15(Suppl
1):21-31.
Ishigami T. The influence of psychic acts on the pro-
gress of pulmonary tuberculosis. Am Rev Tuberculo-
sis. 1919;2:470-84.
Issa AM, Rowe W, Gauthier S, Meaney MJ. Hypotha-
lamic-pituitary-adrenal activity in aged, cognitively
impaired and cognitively unimpaired rats. J Neurosci.
1990;10:3247-54.
Jiang W, Babyak M, Krantz DS, Waugh RA, Coleman
RE, Hanson MM, et al. Mental stress - induced myo-
cardial ischemia and cardiac events. JAMA. 1996;275:
1651-6.
Joëls M, Fernandez G, Roozendaal B. Stress and emo-
tional memory: a matter of timing. Trends Cognit Sci.
2011;15:280-8.
Kario K, McEwen B, Pickering T. Disasters and the
heart: a review of the effects of earthquake-induced
stress on cardiovascular disease. Hypertension Res.
2003;26:355-67.
Keenan P, Jacobson M, Soleymani R, Newcomer J.
Commonly used therapeutic doses of glucocorticoids
impair explicit memory. Ann NY Acad Sci. 1995;761:
400-2.
Khansari DN, Murgo AJ, Faith RE. Effects of stress on
the immune system. Immunol Today. 1990;11:170-5.
Kiecolt-Glaser JK, Glaser R. Stress and immune func-
tion in humans. In: Ader R (ed.). Psychoneuroim-
munology. 2nd ed. (pp 849–867). London: Academic
Press, 1991.
Kiliaan AJ, Saunders PR, Bijlsma PB, Berin MC, Ta-
miniau JA, Groot JA, et al. Stress stimulates transepi-
thelial macromolecular uptake in rat jejunum. Am J
Physiol. 1998;275:G1037-44.
Kirschbaum C, Wolf OT, May M, Wippich W,
Hellhammer DH. Stress-and treatment-induced eleva-
tions of cortisol levels associated with impaired declar-
ative memory in healthy adults. Life Sci. 1996;58:
1475-83.
Köhler S, Thomas AJ, Lloyd A, Barber R, Almeida OP,
O’Brien JT. White matter hyperintensities, cortisol lev-
els, brain atrophy and continuing cognitive deficits in
late-life depression. Brit J Psychiatry. 2010;196:143-9.
Konturek PC, Brzozowski T, Konturek SJ. Stress and
the gut: pathophysiology, clinical consequences, diag-
nostic approach and treatment options. J Physiol Phar-
macol. 2011;62:591-9.
Laitinen T, Hartikainen J, Niskanen L, Geelen G, Län-
simies E. Sympathovagal balance is major determinant
of short-term blood pressure variability in healthy sub-
jects. Am J Physiol. 1999;276:H1245-52.
Landfield PW, Waymire J, Lynch G. Hippocampal ag-
ing and adrenocorticoids: quantitative correlations.
Science. 1978;202:1098-102.
Lawrence MS, Sapolsky RM. Glucocorticoids acceler-
ate ATP loss following metabolic insults in cultured
hippocampal neurons. Brain Res. 1994;646:303-6.
Lazarus RS, Speisman JC, Mordkoff AM. The rela-
tionship between autonomic indicators of psychologi-
cal stress: Heart rate and skin conductance. Psychoso-
matic Med. 1963;25:19-30.
Li S, Wang C, Wang W, Dong H, Hou P, Tang Y.
Chronic mild stress impairs cognition in mice: from
brain homeostasis to behavior. Life Sci. 2008;82:934-
42.
Ling MH, Perry PJ, Tsuang MT. Side effects of corti-
costeroid therapy. Psychiatric aspects. Arch Gen Psy-
chiatry. 1981;38:471-7.
Luine V, Villegas M, Martinez C, McEwen BS. Re-
peated stress causes reversible impairments of spatial
memory performance. Brain Res. 1994;639:167-70.
Lupien SJ, Lepage M. Stress, memory, and the hippo-
campus: can't live with it, can't live without it. Behav
Brain Res. 2001;127:137-58.
Lupien SJ, McEwen BS. The acute effects of cortico-
steroids on cognition: integration of animal and human
model studies. Brain Res Rev. 1997;24:1-27.
Lupien SJ, Wilkinson CW, Brière S, Ménard C, Kin
NNY, Nair N. The modulatory effects of corticoster-
oids on cognition: studies in young human populations.
Psychoneuroendocrinology. 2002;27:401-16.
Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects
of stress throughout the lifespan on the brain, behav-
iour and cognition. Nat Rev Neurosci. 2009;10:434-45.
Mantyh PW. Substance P and the inflammatory and
immune response. Ann NY Acad Sci. 1991;632:71.

EXCLI Journal 2017;16:1057-1072 – ISSN 1611-2156
Received: May 20, 2017, accepted: July 18, 2017, published: July 21, 2017
1070
Marsland AL, Petersen KL, Sathanoori R, Muldoon
MF, Neumann SA, Ryan C, et al. Interleukin-6 cova-
ries inversely with cognitive performance among mid-
dle-aged community volunteers. Psychosomatic Med.
2006;68:895-903.
Martinez V, Taché Y. CRF1 receptors as a therapeutic
target for irritable bowel syndrome. Curr Pharm Des.
2006;12:4071-88.
McCarthy L, Wetzel M, Sliker JK, Eisenstein TK,
Rogers TJ. Opioids, opioid receptors, and the immune
response. Drug Alcohol Depend. 2001;62:111-23.
McEwen BS. Stress and hippocampal plasticity. Ann
Rev Neurosci. 1999;22:105-22.
McEwen B, Lupien S. Stress: hormonal and neural as-
pects. In: Ramachandran VS (ed.). Encyclopedia of the
human brain (pp 463-74). Amsterdam: Elsevier, 2002.
McEwen BS, Sapolsky RM. Stress and cognitive func-
tion. Curr Opin Neurobiol. 1995;5:205-16.
McEwen BS, Weiss JM, Schwartz LS. Selective reten-
tion of corticosterone by limbic structures in rat brain.
Nature. 1968;220(5170):911-2.
Mendl M. Performing under pressure: stress and cog-
nitive function. Appl Animal Behav Sci. 1999;65:221-
44.
Million M, Taché Y, Anton P. Susceptibility of Lewis
and Fischer rats to stress-induced worsening of TNB-
colitis: protective role of brain CRF. Am J Physiol.
1999;276:G1027-36.
Mönnikes H, Tebbe J, Hildebrandt M, Arck P, Os-
manoglou E, Rose M, et al. Role of stress in functional
gastrointestinal disorders. Digest Dis. 2001;19:201-11.
Montaron M, Drapeau E, Dupret D, Kitchener P, Au-
rousseau C, Le Moal M, et al. Lifelong corticosterone
level determines age-related decline in neurogenesis
and memory. Neurobiol Aging. 2006;27:645-54.
Nabavizadeh F, Vahedian M, Sahraei H, Adeli S,
Salimi E. Physical and psychological stress have simi-
lar effects on gastric acid and pepsin secretions in rat.
J Stress Physiol Biochem. 2011;7:164-74.
Nasihatkon ZS, Khosravi M, Bourbour Z, Sahraei H,
Ranjbaran M, Hassantash SM, et al. Inhibitory effect
of nmda receptors in the ventral tegmental area on hor-
monal and eating behavior responses to stress in rats.
Behav Neurol. 2014;2014:294149.
Osanloo N, Najafi-Abedi A, Jafari F, Javid F, Pirpiran
M, Memar-Jafari MR, et al. Papaver rhoeas L. hydroal-
coholic extract exacerbates forced swimming test-in-
duced depression in mice. Basic Clin Neurosci.
2016;7:195-202.
Pagani M, Mazzuero G, Ferrari A, Liberati D, Cerutti
S, Vaitl D, et al. Sympathovagal interaction during
mental stress. A study using spectral analysis of heart
rate variability in healthy control subjects and patients
with a prior myocardial infarction. Circulation.
1991;83:II43-51.
Payne JD, Jackson ED, Hoscheidt S, Ryan L, Jacobs
WJ, Nadel L. Stress administered prior to encoding im-
pairs neutral but enhances emotional long-term epi-
sodic memories. Learning & Memory. 2007;14:861-8.
Pignalberi C, Ricci R, Santini M. Psychological stress
and sudden death. Ital Heart J (Suppl). 2002;3:1011-
21.
Qiu B, Vallance B, Blennerhassett P, Collins S. The
role of CD4+ lymphocytes in the susceptibility of mice
to stress-induced reactivation of experimental colitis.
Nat Med. 1999;5:1178-82.
Ranjbaran M, Mirzaei P, Lotfi F, Behzadi S, Sahraei
H. Reduction of metabolic signs of acute stress in male
mice by papaver Rhoaes hydro-alcoholic extract. Paki-
stan J Biol Sci. 2013;16:1016-21.
Redei E. Immuno-reactive and bioactive corticotropin-
releasing factor in rat thymus. Neuroendocrinology.
1992;55:115-8.
Reiche EMV, Nunes SOV, Morimoto HK. Stress, de-
pression, the immune system, and cancer. Lancet On-
col. 2004;5:617-25.
Reznikov LR, Grillo CA, Piroli GG, Pasumarthi RK,
Reagan LP, Fadel J. Acute stress‐mediated increases in
extracellular glutamate levels in the rat amygdala: dif-
ferential effects of antidepressant treatment. Eur J Neu-
rosci. 2007;25:3109-14.
Rivier C, Vale W. Effect of the long-term administra-
tion of corticotropin-releasing factor on the pituitary-
adrenal and pituitary-gonadal axis in the male rat. J
Clin Invest. 1985;75:689.
Roozendaal B, McEwen BS, Chattarji S. Stress,
memory and the amygdala. Nat Rev Neurosci.
2009;10:423-33.
Rozanski A, Bairey CN, Krantz DS, Friedman J,
Resser KJ, Morell M, et al. Mental stress and the in-
duction of silent myocardial ischemia in patients with
coronary artery disease. N Engl J Med. 1988;318:1005-
12.

EXCLI Journal 2017;16:1057-1072 – ISSN 1611-2156
Received: May 20, 2017, accepted: July 18, 2017, published: July 21, 2017
1071
Rozanski A, Blumenthal JA, Kaplan J. Impact of psy-
chological factors on the pathogenesis of cardiovascu-
lar disease and implications for therapy. Circulation.
1999;99:2192-217.
Sadeghi B, Sahraei H, Zardooz H, Alibeik H, Sarahian
N. Effects of intra-amygdala memantine infusion on
metabolic symptoms induced by chronic stress in male
NMRI mice. Koomesh. 2015;16:Pe376-83, En350.
Sandi C. Stress and cognition. Wiley Interdisciplinary
Reviews: Cognitive Science. 2013;4:245-61.
Sandi C, Davies HA, Cordero MI, Rodriguez JJ, Popov
VI, Stewart MG. Rapid reversal of stress induced loss
of synapses in CA3 of rat hippocampus following wa-
ter maze training. Eur J Neurosci. 2003;17:2447-56.
Sapolsky RM. Endocrinology of the stress-response.
In: Becker JB, Breedlove SM, Crews D, McCarthy
MM (eds.). Behavioral endocrinology. 2nd ed. (pp 409-
50). Cambridge, MA: MIT Press, 2002.
Sapolsky RM, Pulsinelli WA. Glucocorticoids potenti-
ate ischemic injury to neurons: therapeutic implica-
tions. Science. 1985;229:1397-400.
Sapolsky RM, Uno H, Rebert CS, Finch CE. Hippo-
campal damage associated with prolonged glucocorti-
coid exposure in primates. J Neurosci. 1990;10:2897-
902.
Sarahian N, Sahraei H, Zardooz H, Alibeik H, Sadeghi
B. Effect of memantine administration within the nu-
cleus accumbens on changes in weight and volume of
the brain and adrenal gland during chronic stress in fe-
male mice. Modares J Med Sci: Pathobiology. 2014;
17:71-82.
Scholey A, Gibbs A, Neale C, Perry N, Ossoukhova A,
Bilog V, et al. Anti-stress effects of lemon balm-con-
taining foods. Nutrients. 2014;6:4805-21.
Schwabe L, Bohringer A, Chatterjee M, Schachinger
H. Effects of pre-learning stress on memory for neutral,
positive and negative words: Different roles of cortisol
and autonomic arousal. Neurobiol Learn Mem. 2008;
90:44-53.
Schwabe L, Wolf OT. The context counts: congruent
learning and testing environments prevent memory re-
trieval impairment following stress. Cogn Affect Be-
hav Neurosci. 2009;9:229-36.
Schwabe L, Wolf OT, Oitzl MS. Memory formation
under stress: quantity and quality. Neurosci Biobehav
Rev. 2010;34:584-91.
Schwabe L, Joëls M, Roozendaal B, Wolf OT, Oitzl
MS. Stress effects on memory: an update and integra-
tion. Neurosci Biobehav Rev. 2012;36:1740-9.
Schwartz RA, Schwartz IK. Psychiatric disorders asso-
ciated with Crohn's disease. Int J Psychiat Med.
1983;12:67-73.
Scoville WB, Milner B. Loss of recent memory after
bilateral hippocampal lesions. J Neurol Neurosurg Psy-
chiatry. 1957;20:11-21.
Seeman TE, McEwen BS, Singer BH, Albert MS,
Rowe JW. Increase in urinary cortisol excretion and
memory declines: MacArthur studies of successful ag-
ing. J Clin Endocrinol Metab. 1997;82:2458-65.
Segerstrom SC, Miller GE. Psychological stress and
the human immune system: a meta-analytic study of 30
years of inquiry. Psychol Bull. 2004;130:601-30.
Selye H. Endocrine reactions during stress. Anesthesia
& Analgesia. 1956;35:182-93.
Sgoifo A, De Boer SF, Buwalda B, Korte-Bouws G,
Tuma J, Bohus B, et al. Vulnerability to arrhythmias
during social stress in rats with different sympathova-
gal balance. Am J Physiol. 1998;275:H460-6.
Söderholm JD, Perdue MH II. Stress and intestinal bar-
rier function. Am J Physiol. 2001;280:G7-G13.
Solerte S, Cravello L, Ferrari E, Fioravanti M. Over-
production of IFN‐γ and TNF‐α from natural killer
(NK) cells is associated with abnormal NK reactivity
and cognitive derangement in Alzheimer's disease.
Ann NY Acad Sci. 2000;917:331-40.
Song L, Che W, Min-Wei W, Murakami Y, Matsumoto
K. Impairment of the spatial learning and memory in-
duced by learned helplessness and chronic mild stress.
Pharmacol Biochem Behav. 2006;83:186-93.
Thierry A-M, Javoy F, Glowinski J, Kety SS. Effects
of stress on the metabolism of norepinephrine, dopa-
mine and serotonin in the central nervous system of the
rat. I. Modifications of norepinephrine turnover. J
Pharmacol Exp Ther. 1968;163:163-71.
Tilbrook A, Turner A, Clarke I. Effects of stress on re-
production in non-rodent mammals: the role of gluco-
corticoids and sex differences. Rev Reprod. 2000;5:
105-13.
Ulrich-Lai YM, Herman JP. Neural regulation of endo-
crine and autonomic stress responses. Nat Rev Neuro-
sci. 2009;10:397-409.
Vedhara K, Hyde J, Gilchrist I, Tytherleigh M, Plum-
mer S. Acute stress, memory, attention and cortisol.
Psychoneuroendocrinology. 2000;25:535-49.

EXCLI Journal 2017;16:1057-1072 – ISSN 1611-2156
Received: May 20, 2017, accepted: July 18, 2017, published: July 21, 2017
1072
Veldhuis HD, Van Koppen C, Van Ittersum M, de
Kloet RE. Specificity of the adrenal steroid receptor
system in rat hippocampus. Endocrinology. 1982;110:
2044-51.
Vrijkotte TG, Van Doornen LJ, De Geus EJ. Effects of
work stress on ambulatory blood pressure, heart rate,
and heart rate variability. Hypertension. 2000;35:880-
6.
Wood ER, Dudchenko PA, Robitsek RJ, Eichenbaum
H. Hippocampal neurons encode information about
different types of memory episodes occurring in the
same location. Neuron. 2000;27:623-33.
Woolley CS, Gould E, McEwen BS. Exposure to ex-
cess glucocorticoids alters dendritic morphology of
adult hippocampal pyramidal neurons. Brain Res.
1990;531:225-31.
Wu Z. Epidemiological studies on the relationship be-
tween psychosocial factors and cardiovascular disease.
Zhongguo yi xue ke xue yuan xue bao. Acta Acad Med
Sin. 2001;23:73-7, 82.
Yeung AC, Vekshtein VI, Krantz DS, Vita JA, Ryan Jr
TJ, Ganz P, et al. The effect of atherosclerosis on the
vasomotor response of coronary arteries to mental
stress. N Engl J Med. 1991;325:1551-6.