Possible contribution of IGF-1 to depressive disorder · suffering from affective disorders exhibit...

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: [email protected]

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


(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-



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


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].



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


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.



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

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Received: July 31, 2013; in the revised form: September 11, 2013;accepted: September 13, 2013.



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