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Review
Possible contribution of IGF-1 to depressive
disorder
Ewa Szczêsny, Joanna Œlusarczyk, Katarzyna G³ombik, Bogus³awaBudziszewska, Marta Kubera, W³adys³aw Lasoñ, Agnieszka Basta-Kaim
Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences,Smêtna 12, PL 31-343 Kraków, Poland
Correspondence: Agnieszka Basta-Kaim, e-mail: basta@if-pan.krakow.pl
Abstract:
Depression is an illness of unknown origin and involves the dysregulation of many physiological processes disturbed in this disease.
It has been postulated that the pathomechanism of depression is complex, and apart from changes in neurotransmitters, a dysregula-
tion of the immune and endocrine systems also plays an important role in the development of this disorder. Recent studies indicate
that an impairment of synaptic plasticity in specific areas of the central nervous system (CNS), particularly the hippocampus, may be
an important factor in the pathogenesis of depression. The abnormal neural plasticity may be related to alterations in the levels of
neurotrophic factors. On this basis, a theory connecting the occurrence of depression with disturbances in neurotrophic factors has
gained great attention.
This review summarizes data suggesting a role for the neurotrophic factors – especially insulin-like-growth factor-1 (IGF-1) – as
possible targets for therapy in depression in the context of depressive behavior modulation, anti-inflammatory action and
neuroprotection.
Key words:
neurotrophic factors, insulin-like growth factor (IGF) family, depression, antidepressant and anti-inflammatory action,
neuroprotection
Abbreviations: BAD – Bcl-2-associated death promoter pro-
tein, BDNF – brain-derived neurotrophic factor, CNS – central
nervous system, CTNF – ciliary neurotrophic factor, GSK-3b –
glycogen synthase kinase-3b, HPA – hypothalamus-pituitary-
adrenal, IFN-g – interferon-g, IGFBP – insulin-like growth fac-
tor binding protein, IGF-1 – insulin-like growth factor-1,
IGF-1R – insulin-like growth factor-1 receptor, IGF-2 – insu-
lin-like growth factor-2, IL-1b – interleukin-1b, IL-4 –
interleukin-4, IL-10 – interleukin-10, iNOS – inducible NO
synthase, IR – insulin receptor, IRS-1 – insulin receptor
substrate-1, LIF – leukemia inhibitory factor, LPS – lipopoly-
saccharide, M6P/IGF-2R – mannose-6 phosphate/insulin-like
growth factor-2 receptor, MAPK/ERK – mitogen-activated
protein kinases/extracellular signal-regulated kinases, mTOR –
mammalian target of rapamycin, NGF – nerve growth factor,
NT-3 – neurotrophin-3, NT-4/5 – neurotrophin-4/5, PI3K/AKT
– phosphatidylinositide 3-kinase/protein kinase B, PLC –
phospholipase C, Src – proto-oncogene tyrosine-protein ki-
nase, TNF-a – tumor necrosis factor-a.
Introduction
Depression is a relatively common and serious mental
disorder affecting up to 15% of the population at least
once in their lifetime. It is a condition of unknown
origin and in severe cases may lead to suicidal at-
tempts and death. Over the years, many different di-
1622 Pharmacological Reports, 2013, 65, 1622�1631
Pharmacological Reports2013, 65, 1622�1631ISSN 1734-1140
Copyright © 2013by Institute of PharmacologyPolish Academy of Sciences
rections have been explored to investigate the mecha-
nisms of the onset of affective disorders such as major
depression, bipolar disorder or mania. Currently, it is
believed that interactions between genetic and envi-
ronmental factors are the most important factors in the
neurobiological mechanisms of affective illnesses.
Antidepressants used in the treatment of depression
are effective in only 50% of patients, and clinical data
show that patients respond to this medication only af-
ter weeks or months of chronic treatment [24]. It has
been postulated that the pathophysiology of depres-
sion is complex, and apart from changes in the neuro-
transmitter system, dysregulation of the immune and
endocrine systems also plays an important role in the
development of this disorder.
Recent studies have indicated that impairment in
synaptic plasticity, i.e., axon branching, dendritogene-
sis and neurogenesis in specific areas of the central
nervous system (CNS), particularly in the hippocam-
pus, may be an important factor in the pathogenesis of
depression. Abnormal neural plasticity may be related
to alterations in the levels of neurotrophic factors. On
this basis, a theory connecting the occurrence of de-
pression with disturbances in neurotrophic factors has
been the subject of increased attention. In fact, patients
suffering from affective disorders exhibit not only mor-
phological changes in the CNS but also functional im-
pairment in some brain areas [27]. Alterations of the
hippocampus, prefrontal cortex or amygdala have been
linked to changes in the expression or levels of neuro-
trophic factors such as brain-derived neurotrophic fac-
tor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5
(NT-4/5), nerve growth factor (NGF) and recently
insulin-like growth factor (IGF-1) [9].
This paper reviews data suggesting a role for the
neurotrophic factors, particularly IGF-1, as possible
targets for the therapy of depression, in light of evi-
dence suggesting their involvement in depressive be-
havior modulation, anti-inflammatory action and
downstream signaling activation, all of which lead to
neuroprotection.
The role of neurotrophic factors
in the brain
Neurotrophic factors are a family of proteins involved
in neuronal growth, differentiation, maturation and
survival. Therefore, their contribution to proper func-
tioning of both the central and peripheral nervous sys-
tems cannot be overestimated. These factors are syn-
thesized and secreted not only by neuronal cells of the
brain and spinal cord but also by cells or tissues that
depend on peripheral sensory, motor and sympathetic
neurons. Neurotrophins fulfill modulatory functions
on synapse formation and neuronal growth, both dur-
ing embryogenesis and in adulthood. In addition to
the classical neurotrophins BDNF, NGF, NT-3 and
NT-4/5, neuropoietins such as ciliary neurotrophic
factor (CTNF), leukemia inhibitory factor (LIF),
transforming growth factors and the growth factors
IGF-1 and IGF-2 are also considered neurotrophic
factors [43].
Neurotrophic factors play an important role in the
regulation of a large spectrum of brain processes, and
the equilibrium between neuroregeneration and neuro-
degeneration is largely dependent on the availability
and activity of specific growth factors. Apart from ex-
hibiting “classic” neurotrophic actions, these agents
may also affect synaptic transmission, modulate the ac-
tivity of different types of neurons or influence mem-
ory formation. However, there are still many undiscov-
ered potential actions of neurotrophins in the brain.
Neurotrophic factors and depression
BDNF, which plays an important role in brain plastic-
ity particularly in the hippocampus, is the most exten-
sively studied member of the neurotrophic factor fam-
ily in depression. The hippocampus is smaller in de-
pressed patients, but it is unclear whether its
diminished size is a consequence of the illness or
rather a result of the prior action of factors that lead to
the onset of depression. It is known that excessive ac-
tivation of the hypothalamic-pituitary-adrenal (HPA)
axis (often observed in patients suffering from depres-
sion) leads to a sustained elevation of corticosteroids
and chronic neuroinflammation. The HPA axis is also
capable of downregulating hippocampal neurogene-
sis, and all of these factors may lead to depression.
Data from human brain tissue (obtained from subjects
with depression) studied post mortem showed
a downregulation of BDNF mRNA, which is thought
to be one of the essential causes of plasticity impair-
ments and changes in the hippocampus that lead to
behavioral disturbances.
Pharmacological Reports, 2013, 65, 1622�1631 1623
The IGF system and depressionEwa Szczêsny et al.
Moreover, BDNF levels are altered in peripheral
blood lymphocytes and in mononuclear cells [16].
Additionally, a recent report showing decreased se-
rum BDNF levels also demonstrated changes in mi-
croRNAs responsible for Bdnf gene regulation [21].
Many studies have investigated the contribution of
BDNF dysfunction in depression-like disorders using
animal models of depression involving stressful pro-
cedures. Although the influence of stress on brain
BDNF expression depended on the stress procedure
applied, there was a clear trend towards a decrease in
expression. For example, in mice, psychosocial stress
induces a long-lasting increase in histone H3-K27 di-
methylation in the hippocampus, repressing the ex-
pression of BDNF [41]. Additionally, chronic unpre-
dictable stress reduces hippocampal BDNF mRNA
expression in rats [7]. Furthermore, it has been found
that the use of efficient antidepressant therapies such
as zinc plus imipramine increases BDNF expression
in the hippocampi of stressed animals [7], thus pro-
viding support for the potential antidepressant effects
of this neurotrophic factor. The presented results sug-
gest a dysregulation of BDNF in stress-related disor-
ders. This finding is supported by the fact that BDNF
is able to reverse most depression-like behaviors
when administered centrally [15], often by direct
modulation of serotonergic activity.
There is some evidence that the expression of not
only BDNF but also other neurotrophic factors may
be altered in patients suffering from affective disor-
ders. Although the availability of studies investigating
the serum levels of NGF in depressed patients is lim-
ited, it is generally accepted that the level of NGF is
decreased in untreated patients suffering from major
depression. This may be a result of increased cortisol
levels [23]. In animal experiments using different
types of stressors such as forced movement and rough
handling followed by a painful injection, NGF levels
were altered in the frontal cortex, amygdala or hippo-
campus. On the basis of these experiments, the
authors hypothesized that the decrease in NGF ex-
pression was most likely evoked by an overactivation
of the HPA axis and brain overproduction of inflam-
matory cytokines in response to stress.
Thus far, only a few papers examining the changes
in NGF levels in response to antidepressant treatment
have been published. Hellweg and colleagues [13]
demonstrated an increase in NGF levels in the rat
frontal cortex, hippocampus and limbic forebrain after
subchronic lithium treatment. Furthermore, the influ-
ence of duloxetine treatment on NGF levels in differ-
ent brain areas has been tested. Astonishingly, this
drug caused a decrease in NGF expression. According
to a recent hypothesis, this observation was due to an
increase in serotonin and a normalization of cortisol
in the basal forebrain and an increase in NGF uptake
in brain tissue [23]. Nevertheless, these findings pro-
vided more evidence implicating disturbances in this
growth factor in the etiology of depression.
Additionally, the levels and function of other clas-
sical neurotrophic factors, i.e., NT-3, NT-4/5, are
thought to influence the changes accompanying affec-
tive disorders. To date, only a few papers have de-
scribed the levels of NT-4/5 in the blood of depressed
patients. Unfortunately, the clinical data are inconclu-
sive and have certain limitations because the exam-
ined patients were on medication. Thus, the effect of
affective disorder on basal levels of NT-4/5 still re-
mains unknown. However, adult mother-separated
rats, in addition to exhibiting behavioral disturbances
(increased immobility time and decreased climbing)
and a decrease in BDNF levels in the amygdala,
showed a dampening of NT-3 expression in both the
amygdala and the hippocampus [36]. It is possible
that the changes in NT-3 or NT-4/5 levels (together
with BDNF alterations) may be responsible for the
behavioral disturbances observed in this animal
model of depression.
Insulin-like growth factor (IGF)
– an overview
Recently, IGF-1 has gained great attention in diseases
affecting the CNS. First, IGF-1 is known to increase
the synthesis and activity of BDNF, and both factors
are required to enhance neuronal survival and plastic-
ity in the brain [40]. Second, IGF-1 alone is a potent
regulator of cell growth, survival and differentiation
and exhibits neurotrophic, neurogenic and neuropro-
tective actions [37]. Finally, IGF-1 is the only neuro-
trophic factor that may be regulated by the immune
system, the dysfunction of which has been widely ac-
cepted in the pathogenesis of depression.
IGF-1 is a small polypeptide with a molecular
weight of 7.5 kDa. IGF-1 together with IGF-2, insulin
and their respective receptors: IGF-1R, mannose-6
phosphate/IGF-2 (M6P/IGF-2R), IR, hybrid receptor
1624 Pharmacological Reports, 2013, 65, 1622�1631
(IR/IGF-1R) and a group of six binding proteins
(IGFBP-1–6), constitute the so-called Insulin-like
Growth Factor family [3]. After the discovery of their
presence in serum, IGFs were called “sulfation fac-
tors” (because they were first defined by their in-
volvement in cartilage sulfation), and later this name
was changed to the somatomedins (due to their ability
to mediate growth hormone actions) [37]. The term
“insulin-like,” introduced in 1954, is not precise, and
its origin refers to the ability of the IGFs to stimulate
glucose uptake in muscle and adipose tissue [35].
In humans, the Igf-1 gene is located on chromosome
12q22-q23, whereas in the rat, it is on chromosome 7.
Previous studies have indicated the existence of two
isoforms of IGF known as IGF-1 and IGF-2. Tissue-
specific alternative splicing patterns have been shown
to exist, but of these, IGF-1Ea and IGF-1Eb are the
most extensively studied. The first alternate form IGF-
1Ea is secreted as IGF-1, consisting of 70 amino acids
and sharing 40% identity with insulin [25].
In the periphery, the liver is the main source of IGF-1,
and its expression is regulated by growth hormone.
IGF-1 is also synthesized by other organs, and all cell
types respond to IGF-1 signaling. Thus, IGF-1 exerts
endocrine as well as paracrine effects [3]. Although this
factor has the ability to cross the barrier between the
blood and other tissues, many reports have documented
that IGF-1 is also produced by different cells in the cen-
tral and peripheral nervous systems [40].
The most important role of IGF-1 in the brain is to
control cell growth, differentiation, maturation (by
stimulation of mitosis, DNA synthesis) and metabolic
processes (i.e., glucose uptake and protein produc-
tion) at different developmental stages. During early
organogenesis, IGF-1 mRNA expression in the CNS
is low but significantly increases at later developmen-
tal stages. In adults, its expression remains very high,
especially in brain areas with large projection neurons
such as the cerebellum, olfactory bulb, hypothalamus,
hippocampus, cortex and retina. Additionally, accord-
ing to some papers, IGF-1 is also expressed in the
brain stem and spinal cord [37].
The role of IGF-1 in neurodevelopment
IGF-1 influences CNS development by its ability to
stimulate the proliferation of embryonic progenitors.
Studies using in vitro cultures showed that IGF-1 in-
creased the total number of progenitor cells and pro-
moted the development of the neuronal lineage from
precursors. Furthermore, IGF-1 has been proposed to
regulate the actions of other growth agents such as fi-
broblast growth factor (FGF) or epidermal growth
factor (EGF) in striatal neural stem cells [39].
By acting as a neurotrophic factor, IGF-1 stimu-
lates the growth and differentiation of sensory, motor
and sympathetic neurons and is the only growth factor
that enhances the regeneration of both sensory and
motor nerves in adult animals [37]. A study of hippo-
campal progenitors revealed a greater rate of neuro-
genesis in cell cultures treated with IGF-1. Moreover,
Aberg et al. [1] found that in hypophysectomized rats
infused with IGF-1, a six-day treatment significantly
increased the proliferation of neural progenitors in the
hippocampus of adult animals. Finally, IGF-1 is also
involved in synaptic plasticity, viz. it controls the effi-
ciency of synapses by influencing processes involved
in their formation, the release of neurotransmitters
and the excitation of neurons [37].
IGF-1 receptor as the target for
the actions of IGF-1 in the brain
IGF-1 exerts its biological functions mainly through
the IGF-1 receptor (IGF-1R), which is a transmem-
brane heterotetramer consisting of two extracellular a
subunits containing an IGF-binding site and two intra-
cellular b subunits exhibiting tyrosine kinase activity
[3] (Fig. 1). The binding of IGF-1 to the receptor re-
Pharmacological Reports, 2013, 65, 1622�1631 1625
The IGF system and depressionEwa Szczêsny et al.
Fig. 1. Schematic illustration of IGF-1 receptor structure
sults in conformational changes in the a subunits and
autophosphorylation of the b subunits. Subsequently,
this leads to the phosphorylation of insulin receptor
substrate-1 (IRS-1) and to the activation of one of two
main intracellular signaling pathways, mitogen-
activated protein kinase (MAPK) or phosphatidyl-
inositide 3-kinase/protein kinase B (PI3K/AKT) [37].
Apart from IGF-1, the IGF-1R can bind insulin and
IGF-2, but with a lower affinity. In some cell types,
IGF-1R subunits may merge with insulin receptor
subunits and form a hybrid receptor with comparable
affinities for insulin and IGF-1 and a lower affinity
for IGF-2. However, the function of this complex has
not yet been understood in detail.
Because all types of cells express IGF-1 receptors,
all tissues respond to IGF-1 [40]. However, in contrast
to the periphery, brain IGF-1R mRNA expression
changes during the lifetime and differs between par-
ticular stages of organogenesis in a highly structure-
specific manner. The data show that the amount of
IGF-1R in the fetal brain is four- to ten-fold higher than
in adults, indicating its importance in embryonic devel-
opment. The highest IGF-1R mRNA and protein levels
are observed in the choroid plexus and in circumven-
tricular organs. In brain areas with a laminar structure,
such as the cerebellar cortex, hippocampus or olfactory
bulbs, IGF-1 receptors are present in high density
throughout the lifetime and are located mainly in syn-
aptic areas. Studies have estimated the lowest IGF-1R
mRNA content to be in the white matter, although the
receptor is present in all parts of the brain [40].
The role of the IGF-1 binding protein
family in the action of IGF-1 in the brain
The biological functions of IGF-1 are mainly regu-
lated by a family of six binding proteins (IGFBP-1
through IGFBP-6). In the circulation, over 99% of
IGF-1 is bound to these proteins. In the periphery, the
liver is the main source of IGFBPs, but their presence
has been shown in all cells and tissues with some de-
gree of specificity. The biological activity of the bind-
ing proteins is regulated through post-translational
modifications such as phosphorylation or glycosyla-
tion. Moreover, IGFBP actions are controlled by spe-
cific proteases that cleave the binding proteins into
fragments with reduced or no affinity for the IGFs
[17]. Two family members, IGFBP-3 and IGFBP-5,
are bound with Acid Labile Subunit (ALS) to increase
their effectiveness in prolonging the half-life of
IGF-1:IGFBP-3/5 complexes. Experimental studies
have demonstrated that the binding proteins also pos-
sess activities independent of their interaction with
IGF-1, and some (i.e., IGFBP-6) show a preferential
affinity for IGF-2 [37].
Apart from IGFBP-1, all other IGF-binding pro-
teins are expressed in the CNS [37] with a high degree
of anatomical specificity [40]. Data concerning their
actions in the brain are scarce. Studies suggest contra-
dictory findings for IGFBP actions depending on the
structure, not only in the periphery but also in the
CNS. Thus far, data concerning the probable mecha-
nisms of the regulatory actions of IGFBP in the brain
suggest their diverse functions depend on the type of
the binding protein studied.
In summary, IGFBPs may play a key role in the
regulation of brain IGF-1 levels by the following:
a) controlling IGF-1 transport in the plasma and its
diffusion and efflux from the vascular space; b) in-
creasing the half-life of IGFs and slowing down the
loss of their biological activity; c) providing access to
specific binding sites in extra- and intracellular areas;
d) modulating, inhibiting or facilitating IGF binding
to receptors [37].
The role of the IGF-1 family
in the development of depression
Because IGF-1 has the ability to influence many pro-
cesses such as synaptic plasticity, adult neurogenesis
and differentiation, it has been suggested that distur-
bances in the IGF-1 system are involved in the devel-
opment of affective disorders. Unlike in the case of
BDNF, no genetic polymorphism has been found un-
ambiguously confirming the association between
IGF-1 and the occurrence of depression.
The evidence for disturbances
in the IGF-1 family in depression –
clinical studies
Despite intensive research, there are discrepancies in
the estimates of the peripheral IGF-1 levels in patients
1626 Pharmacological Reports, 2013, 65, 1622�1631
suffering from affective disorders. Studies conducted
in different laboratories showed an elevation in the
blood levels of IGF-1 in depressed patients [42].
However, other data showed a decrease in the periph-
eral levels of IGF-1. The mechanism of these changes
has not been defined yet. However, it was suggested
that hyperactivity of the HPA axis in depressed pa-
tients may be responsible for the changes in the blood
levels of IGF-1. A recent paper by Palomino and col-
leagues [30] reported no changes in peripheral IGF-1
levels in patients suffering from depression. This dis-
crepancy may arise from many different factors, e.g.,
the course of the disease, ongoing therapy or general
health conditions.
Only one study investigating changes in the IGF-
binding protein family has been published thus far.
Bezchlibnyk et al. [5] reported that subjects with de-
pression exhibited decreased IGFBP-2 mRNA expres-
sion in the prefrontal cortex (post mortem) and that
this effect was observed predominantly in patients re-
motely treated with lithium or not treated at all. In the
CNS, IGFBP-2 is the predominant IGFBP, and the
authors postulated that in the light of the morphologi-
cal changes observed in depressed patients, it is possi-
ble that decreased expression of this protein may lead
to abnormal neuronal connectivity or remodeling and
contribute to depression. Furthermore, the decreased
IGFBP-2 possibly plays a role in the pathogenesis of
depression because it may indicate abnormalities in
IGF transport from the site of its production or ineffi-
cient targeting to specific cell types resulting in a loss
of IGF sensitivity.
The evidence of IGF-1 family disturbances
in depression – experimental studies
Data concerning the actions of the IGF family in ani-
mal models of depression are not unequivocal, which
may be attributed to the specificity of the models used
or the animal age and gender, which may influence
IGF-1 levels. For example, chronic deficiency of
IGF-1 in the periphery and in the hippocampus was
observed in mice showing depressive-like behavioral
disturbances [28]. Research performed in our labora-
tory using the prenatal stress model of depression
showed that there were no changes in peripheral
IGF-1 levels between control and stressed rats. How-
ever, a significant decrease was observed in the hip-
pocampus and frontal cortex (unpublished data). This
finding suggests that fluctuations in the blood IGF-1
level are not a sine qua non condition of its changes in
the brain, although IGF-1 crosses the blood-brain bar-
rier. Moreover, changes in IGF-1 levels observed in
experimental models may be affected by other factors,
e.g., the condition of the immune system of the tested
animals. This was confirmed by studies in LPS-
challenged mice (model of inflammation-induced
acute stress) in which IGF-1 mRNA was decreased in
some areas of the brain [32, 33]. Maternal separation
was yet another model tested for changes in the levels
of neurotrophic factors. Lee et al. [20] examined its
effects in the prefrontal cortex and found that the lev-
els of IGF-1 and IGF-1R mRNAs differed between
control and stressed animals and that these changes
were time dependent. Another group of researchers
discovered that maternal separation (alone or com-
bined with a single restraint stress) decreased the ex-
pression of IGF-1R and IGFBP-2 mRNAs in adult
animals [10].
The antidepressant-like actions of IGF-1
In the light of the discovery of alterations in IGF-1
levels in depression-like states, the question arises
whether IGF-1 exerts antidepressant-like activity and
whether antidepressants may influence the IGF-1
family of factors. To explore the putative antidepres-
sant activity of IGF-1, many research groups adminis-
tered IGF-1 (subcutaneously or intracerebroventricu-
larly) to animals and then subjected them to behav-
ioral testing. Different behavioral tests were used,
e.g., the forced swimming test and/or the tail suspen-
sion test, which have a high predictive validity for an-
tidepressant activity. Most data are very consistent
and show that IGF-1 treatment exerts antidepressant
like-activity by normalization of behavioral distur-
bances in various animal models of depression [14,
15, 22, 32, 33]. Furthermore, some studies indicated
that IGF-1 treatment is also effective in reducing sick-
ness behavior caused by icv injection of LPS or
TNF-a [6, 8]. Because the IGF-1R antagonist JB1
abolishes IGF-1 antidepressant activity, this activity is
clearly mediated by the IGF-1 receptor (our unpub-
lished data). Furthermore, the antidepressant-like ef-
fects of IGF-1 were often associated with an increase
in cell proliferation in the hippocampus [14].
Pharmacological Reports, 2013, 65, 1622�1631 1627
The IGF system and depressionEwa Szczêsny et al.
Depression is often accompanied by an increase in
anxiety. Acute and chronic administration of IGF-1
(both central and peripheral) decreases anxiety levels
in animals. Concomitant administration of a nonspe-
cific IGFBP inhibitor also has anxiolytic and
antidepressant-like effects [22]. The mechanism of
action of IGF in behavioral disturbances has not yet
been clearly identified. However, it was proposed that
IGF-1 influences neuronal plasticity and learning by
affecting other neurotrophic factors such as BDNF
[26]. This was confirmed by reports of the positive
impact of IGF-1 on the synthesis of BDNF and the
synergy of these trophic factors in antidepressant ac-
tion. The joint action of these factors also increases
hippocampal cell proliferation and neurogenesis in
the adult rat [1]. Most of the data show that the antide-
pressant effect of IGF-1 is comparable to the effect of
antidepressants.
The influence of antidepressant drugs on IGF-1 ex-
pression has also been examined. Grunbaum-Novak et
al. [11] showed that acute and chronic administration
of fluoxetine affects IGF-1 mRNA expression in differ-
ent ways, varying between specific brain structures
(hippocampus and cortex). The authors suggested an
additional role of IGF-1R activation in the therapeutic
effects of fluoxetine. However, upregulation of the ex-
pression of IGF-1 and its receptor was observed in the
frontal cortex after repeated fluoxetine administration,
and its downregulation was observed in the hippocam-
pus. These data suggest that, thus far, it is not clear if
changes induced in the IGF-1 system contribute to cog-
nitive improvement in animals treated with antidepres-
sant drugs. Nevertheless, chronic administration of an-
other drug, venlafaxine, increases IGF-1 levels but
solely in the hippocampus [18].
Basing on experimental data, the authors presented
the hypothesis that another mechanism of the antide-
pressant action of IGF-1 may be related to the regula-
tion of serotonin levels. Hoshaw et al. [14] found that
depletion of serotonin by the tryptophan hydroxylase
inhibitor p-chlorophenylalanine blocked the ability of
IGF-1 to decrease immobility and increase swimming
behavior in the forced swimming test in mice. How-
ever, IGF-1 increased the basal level of serotonin in
the ventral hippocampus 3 days after icv administra-
tion. Therefore, it may be concluded that IGF-1 pro-
duces antidepressant-like effects by upregulating se-
rotonin levels, at least in the hippocampus. In line
with this theory, the Aguado group [2] found that
IGF-1 receptors were present on serotonergic neuron
cell bodies in the raphe and co-localized in the hippo-
campus with projections from the raphe, thus possibly
leading to the direct activation of serotonin release.
The anti-inflammatory effect of IGF-1
The uniqueness of IGF-1 manifests itself in the ability
to antagonize the immune response. In in vitro studies,
IGF-1 was shown to inhibit inflammatory processes,
mainly through inhibiting the expression of proin-
flammatory cytokines, i.e., IFN-g, IL-1b and TNF-a
[34]. In contrast, IGF-1 can also enhance the produc-
tion of anti-inflammatory cytokines, namely, IL-4 and
IL-10. However, an increase in proinflammatory cyto-
kines may cause a decrease in IGF-1, but this process
is organ- and tissue-specific [29]. In the brain, micro-
glial cells are an important source of IGF-1 during de-
velopment both during inflammation and after injury.
Recent data published by Suh et al. [38] suggest that
chronic neuroinflammation and upregulation of proin-
flammatory cytokines may lead to neurodegeneration
by suppressing the production of microglia-derived
neuronal growth factors such as IGF-1, which indi-
cates a relationship between IGF-1 and proinflamma-
tory cytokines. In the LPS-induced depression-like
state, Park et al. [32] showed for the first time in vivo
that IGF-1 tempers the innate immune response
within the brain and reduces the expression of inflam-
matory markers such as IL-1b, TNF-a or iNOS, and
increases the expression of BDNF.
These findings are interesting in the context of the
inflammatory theory of depression, which states that
1628 Pharmacological Reports, 2013, 65, 1622�1631
Fig. 2. IGF-Binding protein family
disturbances in the levels of cytokines are responsible
for the development of depressive behavior.
The neuroprotective role of IGF-1
Studies of the neuroprotective effects of IGF-1 have
been conducted in different models of injury and in-
sult to the brain. Regardless of the route of admini-
stration, IGF-1 shows a protective effect. Moreover,
IGF-1 exerts neuroprotective actions both in vitro and
in vivo in pathologies involving an overproduction of
proinflammatory cytokines, e.g., stroke, brain trauma
and multiple sclerosis [12]. In vitro studies have
shown that IGF-1 suppresses neurotoxicity caused by
TNF-a or LPS [31].
The signaling pathway of the survival-promoting
effects of IGF-1 involves the activation of the
PI3K/AKT or MAPK/ERK (mitogen-activated pro-
tein kinases/extracellular signal-regulated kinases)
pathways. As mentioned before, binding of IGF-1 to
the receptor causes phosphorylation of IRS-1. When
tyrosine-phosphorylated IRS-1 interacts with the cy-
toplasmic protein PI3K through its Src Homology-2
domains, its activation leads to the inhibition of apop-
tosis by activating downstream proteins and mole-
cules such as AKT or phospholipase C (PLC). Activa-
tion of downstream elements of the intracellular sig-
naling network (mTOR, BAD) promotes cell survival
(Fig. 3).
Among the many agents capable of regulating the
activity of AKT/GSK, serotonin is worth special at-
tention. GSK-3b also plays a role in the regulation of
serotonin receptor cell surface trafficking [19]. Clini-
cal data suggest that intracellular signaling in the
brain and its regulation is altered in psychiatric condi-
tions. Moreover, Barreto and co-workers [4] found
that in rats that underwent a subchronic restraint stress
procedure, genes encoding components of the PI3K/
AKT and MAPK/ERK signaling pathways are down-
regulated in the infralimbic medial prefrontal cortex
(a structure impaired in patients suffering from major
depression). Thus, it is very likely that disturbances in
neurotrophic factor signaling are of a dual origin.
Both changes in the level of growth factors as well as
alterations in intracellular signaling pathways and
their modulation may contribute to the behavioral and
physiological disorders observed in depression.
Conclusions
The studies cited above provide evidence that neu-
rotrophic factors in general and IGF-1 in particular
play an important role in the regulation of the CNS
function. In light of the wide variety of IGF-1 actions,
including its involvement in neuronal growth, differ-
entiation and maturation, its modulation of behavioral
disturbances, its antidepressant and anti-inflammatory
action and its role in neuroprotection and the control
of intracellular signal transduction, it may be a perfect
subject for research aiming to elucidate the role of
growth factors in CNS function and their potential in-
volvement in the development of mental disorders.
Acknowledgment:This study was supported by the grant POIG.01.01.02-12-004/09-00 �Depression-Mechanisms-Therapy�financed by European Regional Development Fund.
Pharmacological Reports, 2013, 65, 1622�1631 1629
The IGF system and depressionEwa Szczêsny et al.
Fig. 3. Schematic illustration of the intracellular pathways activatedby IGF-1. Binding of IGF-1 to the extracellular subunits of the IGF-1receptor causes phosphorylation of IRS-1, which interacts withcytoplasmic PI3K (phosphatidylinositide 3-kinase). PI3K activatesPLC and protein kinase B (AKT). Through AKT, it influences mTOR(mammalian target for rapamycin) and caspase 9, causes phospho-rylation of BAD (Bcl-2-associated death promoter protein) and thuspromotes cell survival and protein synthesis and inhibits glycogensynthesis via GSK-3b (glycogen synthase kinase-3b). Autophospho-rylation of IGF-1R also leads to the recruitment of SHC (SH2-contain-ing protein), the binding of the adaptor protein GRB2 (growth factorreceptor-bound protein-2), the recruitment of SOS (son of sevenless)and the activation of Ras, serine/threonine kinase Raf and MEK1/2(MAP kinase kinases) and ERK1/2 (extracellular signal regulatedkinases), which also promotes cell survival
References:
1. Aberg MA, Aberg ND, Hedbäcker H, Oscarsson J,
Eriksson PS: Peripheral infusion of IGF-I selectively in-
duces neurogenesis in the adult rat hippocampus. J Neu-
rosci, 2000, 20, 2896–2903.
2. Aguado F, Carmona MA, Pozas E, Aguiló A, Martínez-
Guijarro FJ, Alcantara S, Borrell V et al.: BDNF regu-
lates spontaneous correlated activity at early develop-
mental stages by increasing synaptogenesis and expres-
sion of the K+/Cl� co-transporter KCC2. Development,
2003, 130, 1267–1280.
3. Annuziata M, Granata R, Ghigo E: The IGF system.
Acta Diabetol, 2011, 48, 1–9.
4. Barreto RA, Walker FR, Dunkley PR, Day TA, Smith
DW: Fluoxetine prevents development of an early
stress-related molecular signature in the rat infralimbic
medial prefrontal cortex. Implications for depression?
BMC Neurosci, 2012, 13, 125–142.
5. Bezchlibnyk YB, Xu L, Wang JF, Young LT: Decreased
expression of insulin-like growth factor binding protein 2
in the prefrontal cortex of subjects with bipolar disorder
and its regulation by lithium treatment. Brain Res, 2007,
1147, 213–217.
6. Bluthé RM, Kelley KW, Dantzer R: Effects of insulin-
like growth factor-I on cytokine-induced sickness behav-
ior in mice. Brain Behav Immun, 2006, 20, 57–63.
7. Cieœlik K, Sowa-Kuæma M, Ossowska G, Legutko B,
Wolak M, Opoka W, Nowak G: Chronic unpredictable
stress-induced reduction in the hippocampal brain-
derived neurotrophic factor (BDNF) gene expression is
antagonized by zinc treatment. Pharmacol Rep, 2011, 63,
537–543.
8. Dantzer R, Gheusi G, Johnson RW, Kelley KW: Central
administration of insulin-like growth factor-1 inhibits
lipopolysaccharide-induced sickness behavior in mice.
Neuroreport, 1999, 10, 289–292.
9. Duman R: Role of neurotrophic factors in the etiology
and treatment of mood disorders. Neuromolecular Med,
2004, 5, 11–25.
10. Erabi K, Morinobu S, Kawano K, Tsuji S, Yamawaki S:
Neonatal isolation changes the expression of IGF-IR and
IGFBP-2 in the hippocampus in response to adulthood
restraint stress. Int J Neuropsychopharmacol, 2007, 10,
369–381.
11. Grunbaum-Novak N, Taler M, Gil-Ad I, Weizman A,
Cohen H, Weizman R: Relationship between antidepres-
sants and IGF-1 system in the brain: possible role in cog-
nition. Eur Neuropsychopharmacol, 2008, 18, 431–438.
12. Guan J, Bennet L, Gluckman PD, Gunn AJ.: Insulin-like
growth factor-1 and post-ischemic brain injury. Prog
Neurobiol, 2003, 70, 443–462.
13. Hellweg R, Lang UE, Nagel M, Baumgartner A: Sub-
chronic treatment with lithium increases nerve growth
factor content in distinct brain regions of adult rats. Mol
Psychiatry, 2002, 7, 604–608.
14. Hoshaw BA, Hill TI, Crowley JJ, Malberg JE, Khawaja
X, Rosenzweig- Lipson S, Schechter LE, Lucki I:
Antidepressant-like behavioral effects of IGF-1 produced
by enhanced serotonin transmission. Eur J Pharmacol,
2008, 594, 109–116.
15. Hoshaw BA, Malberg JE, Lucki I: Central administration
of IGF-I and BDNF leads to long-lasting antidepressant-
like activity. Brain Res, 2005, 1037, 204–208.
16. Jiang C, Salton SR: The role of neurotrophins in major
depressive disorder. Transl Neurosci, 2013, 4, 46–58.
17. Jones JI, Clemmons DR: Insulin-like growth factors and
their binding proteins: biological actions. Endocr Rev,
1995, 16, 3–34.
18. Khawaja X, Xu J, Liang JJ, Barrett JE: Proteomic analy-
sis of protein changes developing in rat hippocampus af-
ter chronic antidepressant treatment: Implications for de-
pressive disorders and future therapies. J Neurosci Res,
2004, 75, 451–460.
19. Kitagishi Y, Kobayashi M, Kikuta K, Matsuda S: Roles
of PI3K/AKT/GSK3/mTOR pathway in cell signaling of
mental illnesses. Depress Res Treat, 2012, 752563, 1–8.
20. Lee KY, Miki T, Yokoyama T, Ueki M, Warita K, Suzuki
S, Ohta K et al.: Neonatal repetitive maternal separation
causes long-lasting alterations in various neurotrophic
factor expression in the cerebral cortex of rats. Life Sci,
2012, 90, 578–584.
21. Li YJ, Xu M, Gao ZH, Wang YQ, Yue Z, Zhang YX,
Li XX et al.: Alterations of serum levels of BDNF-
related miRNAs in patients with depression. PLoS One,
2013, 8, e63648, 1–7.
22. Malberg JE, Platt B, Rizzo SJ, Ring RH, Lucki I,
Schechter LE, Rosenzweig-Lipson S: Increasing the lev-
els of insulin-like growth factor-I by an IGF binding pro-
tein inhibitor produces anxiolytic and antidepressant-like
effects. Neuropsychopharmacology, 2007, 32,
2360–2368.
23. Martino M, Rocchi G, Escelsior A, Contini P, Colicchio
S, de Berardis D, Amore M et al.: NGF serum levels
variations in major depressed patients receiving duloxet-
ine. Psychoneuroendocrinology, 2013, 38, 1824–1828.
24. Masi G, Brovedani P: The hippocampus, neurotrophic
factors and depression: possible implications for the
pharmacotherapy of depression. CNS Drugs, 2011, 25,
913–931.
25. Matheny RW, Nindl BC, Adamo ML: Minireview:
mechano-growth factor: a putative product of the IGF-I
gene expression involved in tissue repair and regenera-
tion. Endocrinology, 2010, 151, 865–875.
26. McCusker RH, McCrea K, Zunich S, Dantzer R, Brous-
sard SR, Johnson RW, Kelley KW: Insulin-like growth
factor-I enhances the biological activity of brain-derived
neurotrophic factor on cerebrocortical neurons. J Neuro-
immunol, 2006, 9,186–190.
27. Miguel-Hidalgo JJ, Rajkowska G: Morphological brain
changes in depression: can antidepressants reverse them?
CNS Drugs, 2002, 16, 361–372.
28. Mitschelen M, Yan H, Farley JA, Warrington JP, Han S,
Hereñú CB, Csiszar A et al.: Long-term deficiency of
circulating and hippocampal insulin-like growth factor I
induces depressive behavior in adult mice: a potential
model of geriatric depression. Neuroscience, 2011, 185,
50–60.
29. O’Connor JC, McCusker RH, Strle K, Johnson RW,
Dantzer R, Kelley KW: Regulation of IGF-I function by
1630 Pharmacological Reports, 2013, 65, 1622�1631
proinflammatory cytokines: at the interface of immunol-
ogy and endocrinology. Cell Immunol, 2008, 252,
91–110.
30. Palomino A, González-Pinto A, Martinez-Cengotita-
bengoa M, Ruiz de Azua S, Alberich S, Mosquera F,
Matute C: Relationship between negative symptoms and
plasma levels of insulin-like growth factor 1 in first-
episode schizophrenia and bipolar disorder patients. Prog
Neuropsychopharmacol Biol Psychiatry, 2013, 44,
29–33.
31. Pang Y, Campbell L, Zheng B, Fan L, Cai Z, Rhodes P:
Lipopolysaccharide-activated microglia induce death of
oligodendrocyte progenitor cells and impede their devel-
opment. Neuroscience, 2010, 166, 464–475.
32. Park SE, Dantzer R, Kelley KW, McCusker RH: Central
administration of insulin-like growth factor-I decreases
depressive-like behavior and brain cytokine expression
in mice. J Neuroinflamm, 2011, 8, 1–14.
33. Park SE, Lawson M, Dantzer R, Kelley KW, McCusker
RH: Insulin-like growth factor-I pepides act centrally to
decrease depression-like behavior of mice treated
intraperitoneally with lipopolisaccharide. J Neuroin-
flamm, 2011, 8, 1–16.
34. Puzik A, Rupp J, Tröger B, Göpel W, Herting E, Härtel
C: Insulin-like growth factor-I regulates the neonatal im-
mune response in infection and maturation by suppres-
sion of IFN-g. Cytokine, 2012, 60, 369–376.
35. Randle PJ: Plasma-insulin activity in hypopituitarism as-
sayed by the rat diaphragm method. Lancet, 1954, 266,
809–810.
36. Réus GZ, Stringari RB, Ribeiro KF, Cipriano AL,
Panizzutti BS, Stertz L, Lersch C et al.: Maternal depri-
vation induces depressive-like behaviour and alters neu-
rotrophin levels in the rat brain. Neurochem Res, 2011,
36, 460–466.
37. Russo VC, Gluckman PD, Feldman EL, Werther GA:
The insulin-like growth factor system and its pleiotropic
functions in brain. Endocr Rev, 2005, 6, 916–943.
38. Suh HS, Zhao ML, Derico L, Choi N, Lee SC.: Insulin-
like growth factor 1 and 2 (IGF1, IGF2) expression in
human microglia: differential regulation by inflamma-
tory mediators. J Neuroinflammation, 2013, 10, 37–53.
39. Supeno NE, Pati S, Hadi RA, Ghani AR, Mustafa Z,
Abdullah JM, Idris FM et al.: IGF-1 acts as controlling
switch for long-term proliferation and maintenance of
EGF/FGF-responsive striatal neural stem cells. Int J Med
Sci, 2013, 10, 522–531.
40. Torres-Aleman I:Toward a comprehensive neurobiology
of IGF-I. Dev Neurobiol, 2010, 70, 384–396.
41. Tsankova NM, Berton O, Renthal W, Kumar A, Neve
RL, Nestler EJ: Sustained hippocampal chromatin regu-
lation in a mouse model of depression and antidepressant
action. Nat Neurosci, 2006, 9, 519–525.
42. Weber- Haman B, Blum WF, Kratzsch J, Gilles M,
Heuser I, Deuschle M: Insulin-like growth factor-I
(IGF-I) serum concentrations in depressed patients: rela-
tionship to saliva cortisol and changes during antidepres-
sant treatment. Pharmacopsychiatry, 2009, 42, 23–28.
43. Wysokiñski A, Gruszczyñski W: Neurotrophins – actual
knowledge (Polish). Post Psychiat Neurol, 2008, 17,
385–390.
Received: July 31, 2013; in the revised form: September 11, 2013;accepted: September 13, 2013.
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The IGF system and depressionEwa Szczêsny et al.
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