Current Medicinal Chemistry, 2011, 18, 245-255 245

Inflammatory and Neurodegenerative Pathways in Depression: A New

Avenue for Antidepressant Development?
M. Catena-Dell’Osso*,1, C. Bellantuono2, G. Consoli1, S. Baroni1, F. Rotella3 and D. Marazziti1
1
Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa, Pisa, Italia
2
Sezione di Psichiatria, Dipartimento di Neuroscienze, Università Politecnica delle Marche, Ancona, Italia
3
Dipartimento di Scienze Neurologiche e Psichiatriche, Università di Firenze, Firenze, Italia
Abstract: The latest advancement in neurobiological research provided an increasing evidence that inflammatory and
neurodegenerative pathways play a relevant role in depression. Preclinical and clinical studies on depression highlighted
an increased production of inflammatory markers, such as interleukin (IL)-1, IL-6, tumor necrosis factor-
and interferon-

and . On the other hand, acute and chronic administration of cytokines or cytokine inducers were found to trigger de-
pressive symptoms. According to the cytokine hypothesis, depression would be due to a stress-related increased produc-
tion of pro-inflammatory cytokines that, in turn, would lead to increased oxidative and nitrosative brain damage and to in-
doleamine 2,3 dioxygenase (IDO) induction, with production of tryptophan (TRP) catabolites along the IDO pathway
(TRYCATs) and consequent reduced availability of TRP and serotonin (5-HT). Cytokines would also play a role in the
onset of the glucocorticoid resistance, underlying the overdrive of the hypothalamic-pituitary-adrenal axis. Therefore, the
activation of the inflammatory and neurodegenerative pathways would lead to the brain damage observed in depression
through both reduced neurogenesis and increased neurodegeneration. Besides the 5-HT system, other targets, possibly
within the I&ND pathways, should be considered for the future treatment of depression: cytokines and their receptors, in-
tracellular inflammatory mediators, IDO, TRYCATs, glucocorticoid receptors, neurotrophic factors may all represent pos-
sible therapeutic targets for novel antidepressants. In addition, it should be also clarified the role of the existing anti-
inflammatory drugs in the treatment of depression, and those compounds with the anti-inflammatory and anti-oxidative
properties should be examined either as monotherapy or adjunctive therapy. In conclusion, the molecular inflammatory
and neurodegenerative pathways might provide new targets for antidepressant development and might be crucial to estab-
lish a rational treatment of depression aimed, hopefully, to its causal factors.
Keywords: Cytokines, depression, inflammation, neurodegeneration, neurogenesis, glucocorticoid-resistance, indolamine, 2,3
dioxygenase.

INTRODUCTION supported by the findings of increased levels of several in-

Depression is a psychiatric disorder characterized by the
presence of affective, cognitive, psychomotor and neuro-
vegetative symptoms, which pervades all aspects of life and
impairs individual’s family and personal relationships, work
adjustment and general health. This disabling condition,
often associated with unemployment and poverty, represents
a major cause of morbidity worldwide and is currently
considered the fourth-leading cause of disease burden [1-3].
The pathophysiology of the disorder remains to be
clarified. For decades, research focused mainly on mono-
amines. Several data, in fact, are available in the literature
regarding alterations of serotonin (5-HT), dopamine and
norepinephrine [4-6]. Despite extensive research on neuro-
transmitter systems, however, data are inconclusive and the
monoamine hypothesis does not seem sufficient to explain
the whole picture of depression. This consideration high-
lighted the need of novel pathophysiological models of de-
pression that, in turn, could lead to the discovery of new
therapeutic targets for antidepressant development. The re-
cent advancement in neurobiological research provided an
increasing evidence that inflammatory and neurodegenera-
tive pathways would play a relevant role in the development
of depression [7-9]. The hypothesis of the involvement of
inflammatory pathways in depression is consistently
*Address correspondence to this author at the Dipartimento di Psichiatria,
Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa, via Roma,
67, I-56100 Pisa, Italy; Tel: +39 050 835412; Fax: +39 050 21581;
E-mail: catena.mario@virgilio.it
flammatory markers, including pro-inflammatory cytokines
as interleukin-1 (IL-1), IL-6, interferon- (IFN) and tu-
mor necrosis factor
(TNF
) [10-14]. In particular, external
and internal stressors would contribute to the onset of de-
pression through the activation in the brain of inflammatory
processes which, in turn, would lead to neurodegeneration
[15-18]. Neurodegenerative processes, in fact, are now
thought to be involved in the development of depression:
magnetic resonance imaging studies indicated that depressed
patients show significant structural alterations in different
brain regions, including hippocampus, prefrontal cortex,
amygdala, anterior cingulated and basal ganglia [19-24].
In this paper, the most relevant findings on the presence
of inflammatory and neurodegenerative processes in depres-
sion will be reviewed with a particular focus on the possible
impact on future antidepressant development.
NEUROINFLAMMATION
Inflammation is generally considered one of the final
mechanisms through which external and internal stressors
may lead to a disease. This concept, universally accepted for
a large part of somatic illnesses, has been extended to neuro-
psychiatric disorders, including depression. In fact, several
inflammatory markers have been found in depressed pa-
tients, in particular increased levels of acute phase proteins,
pro-inflammatory cytokines and their receptors in peripheral
blood and cerebrospinal fluid (CSF), lowered serum zinc, as
well as elevated peripheral blood concentrations of chemoki-

0929-8673/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.

246 Current Medicinal Chemistry, 2011 Vol. 18, No. 2
nes, adhesion molecules and inflammatory mediators, in
particular prostaglandins [10-12, 25].
The inflammation of the central nervous system (CNS),
which has been labeled neuroinflammation, is characterized
by activation of glial cells (microglia and astrocytes) and
expression of pro-inflammatory mediators, as well as of neu-
rotoxic factors, such as superoxid, nitric oxide (NO) and
TNF
(Fig. 1). Neuroinflamation is typical of neurodegen-
erative diseases, like Alzheimer's disease and Parkinson's
disease [26], but also other stimuli, like acute brain injury or
infection, can trigger an inflammatory response that includes
activation of microglia and astrocytes with increased produc-
tion of cytokines, chemokines, acute phase proteins, com-
plement factors, antibodies and T lymphocytes [27]. While
microglial activation is necessary and critical for host de-
fense, as in the case of brain injury and infection, over-
activation of microglia is neurotoxic [28]. In neurodegenera-
tive diseases, the inflammatory response is continuous and
prolonged and is likely to have detrimental effects [29]. In-
flammatory processes, in fact, may attempt to clear dying
cells and initiate repair processes, but also contribute to cell
death and degeneration. The mechanisms initiating deleteri-
ous neuroinflammation are poorly understood. It is possible
that, after immunological perturbation during critical periods
of development [30], microglia can become primed so that
additional stimuli would result in an exaggerated and pro-
longed pro-inflammatory response that enhances neuron
damage.
Systemic inflammation seems to provoke a similar proc-
ess within the CNS through the activation of brain microglia
[26] (Fig. 1). It has been demonstrated that following a sin-
gle intraperitoneal lipopolysaccharide (LPS) injection there
is TNF
production in the periphery which, in turn, initiates
TNF
production (mRNA and protein) in the brain. In fact,
pro-inflammatory cytokines have been found to pass the
blood-brain barrier and reach the brain [31, 32]. At this level
they can activate both (a) endothelial and immune cells, in-
cluding perivascular macrophages that, in turn, can produce
further inflammatory mediators, and (b) peripheral afferent
nerves, including the vagus nerve, so that the cytokine signal
may reach distant brain areas, including nucleus of the soli-
tary tract and hypothalamus [31, 32]. The activation of neu-
roinflammatory processes may explain the high comorbidity
rates of depression with inflammatory diseases, including
coronary heart disorder, human immunodeficiency virus
(HIV) infection, inflammatory bowel disease, multiple scle-
rosis and rheumatoid arthritis [33-35]. In addition, the high
incidence of depression in the post-partum period might be
related to the significant inflammatory activity which charac-
terizes this phase, including increases in IL-6 and lower
plasma tryptophan (TRP) with indoleamine 2,3 dioxygenase
(IDO) activation [36].
THE CYTOKINE HYPOTHESIS OF DEPRESSION
The cytokine hypothesis suggests that external and inter-
nal stressors might lead to depression through inflammatory
processes that, subsequently, would provoke alterations of
the 5-HT system and the hypothalamic-pituitary-adrenal
(HPA) axis [15-18]. These latter, according to this notion,
Catena-Dell’Osso et al.
should, thus, be considered consequences rather than etio-
logic factors of depression [37].
After the first evidence of T-cell activation in depressed
patients [38], consistent findings of increased levels of pro-
inflammatory cytokines, in particular IL-1, IL-6, IFN- and
TNF
, have been widely reported in depression [10-14].
Further, evidence from animal models supports the hypothe-
sis of the involvement of inflammatory pathways in depres-
sion. For example, an increased production of IL-1 and 2 has
been reported in condition of chronic mild stress [39]. In
addition, the latest animal models of depression are based on
induced inflammation through the administration of cytoki-
nes or cytokine inducers, such as LPS [40-43]. The admini-
stration of LPS or IL-6 may cause a behavioral syndrome
that resembles depression and has been called sickness syn-
drome. In fact, following the exposure to inflammatory chal-
lenges, animals develop the sickness behavioral syndrome,
which shows strong similarity with depression, including
anhedonia, anorexia, asthenia, sedation, behavioral distur-
bances, decreased locomotor activity and exploration [43].
In humans, the administration of LPS to healthy volun-
teers was found to cause an acute increase of depressive and
anxious symptoms [44], whereas the administration of Sal-
monella typhi vaccine, a cytokine inducer, provoked mood
depression, fatigue, psychomotor retardation and cognitive
disturbances [45, 46]. Following these evidences, it has been
proposed that depression may be characterized by an in-
creased translocation of LPS from intestinal gram-negative
bacteria, a condition called leaky gut which might induce
peripheral inflammation [47, 48]. It would be an intestinal
barrier damage to permit the translocation of LPS from the
gut into the blood. The evidence of a higher prevalence of
serum IgM and IgA against six enterobacteria in depressed
patients, as compared with healthy volunteers, support this
hypothesis [48]. The increased blood LPS levels would in-
duce both peripheral and central inflammation, with the con-
sequent onset of the sickness syndrome-related symptoms
[49-52]. Further, it is well known that long-term exposure to
cytokines may precipitate the onset of depression. In fact, up
to 70% of subjects who underwent immune-therapy with
IFN-
for infection or cancer develop a full blown depres-
sion, and the rates were even higher when subthreshold syn-
dromes were considered [53-57].
In humans, the effectiveness of antidepressants was
shown to be increased by adding anti-inflammatory drugs. In
a open label study, acetylsalicylic acid augmentation was
shown to accelerate antidepressant efficacy of fluoxetine in
depressed patients who had not responded to fluoxetine
alone [58]. In another study, depressed patients treated with
celecoxib, a cyclooxygenase-2 inhibitor, in combination with
reboxetine showed a greater clinical improvement, as com-
pared with those taking reboxetine plus placebo [59]. More
recently, in a double-blind and placebo-controlled trial, 40
depressed patients were randomized to fluoxetine plus cele-
coxib and to fluoxetine plus placebo. The first combination
led to a significant greater improvement of depressive symp-
toms, as compared with the second, with no differences in
the side effect profile between the 2 groups [60]. Anti-
inflammatory drugs showed antidepressant properties, even
when used in the treatment of autoimmune and inflammatory
Inflammation and Neurodegeneration in Depression Current Medicinal Chemistry, 2011 Vol. 18, No. 2 247

Fig. (1). Effects of the inflammatory cascade within the CNS. Once activated, microglia initiate an inflammatory cascade where the release of
pro-inflammatory mediators, including IL-1, IL-6, TNF-
, IFN-
and , and reactive nitrogen and oxygen radicals activates astroglia with a
consequent amplification of inflammatory signals within the CNS. At the level of microglia, pro-inflammatory cytokines activate the enzyme
IDO which induce the degradation of TRP into QA, a potent NMDA agonist and stimulator of GLU release. The overexposure to cytokines
and QA compromises a number of astrocytic functions leading to downregulation of GLU transporters, impaired GLU reuptake, and in-
creased GLU release, as well as decreased production of neurotrophic factors. The excessive astrocytic GLU release coupled to several fac-
tors including its inadequate reuptake by astrocytes and oligodendrocytes, activation of NMDA receptors by QA, decline in neurotrophic
support and oxidative stress, ultimately impair neural plasticity through excitotoxicity and apoptosis. The overexposure of oligodendrocytes
to cytokines, in particular TNF-
which has a direct toxic effect on them, also contributes to neuronal death and demyelination.
5-HT, serotonin; BDNF, brain-derived neurotrophic factor; CNS, central nervous system; GLU, glutamate; IDO, indolamine 2,3 dioxygenase;
IFN, interferon; IL, interleukin; NMDA, N-methyl-D-aspartate; KYN, kynurenine; QA, quinolinic acid; TNF, tumor necrosis factor; TRP,
tryptophan.

disorders. In a double-blind placebo-controlled trial for the
treatment of psoriasis, the administration of etanercept, a
TNF
antagonist, led to a significant improvement of de-
pression [61]. There exists a preliminary observation that 3
poly-unsatured fatty acids (PUFAs), which have relevant
anti-inflammatory effects, were successfully used in the
treatment of depressed patients either as monotherapy or as
adjunctive therapy [62]. On the other hand, antidepressants
might have anti-inflammatory effects, since they were dem-
onstrated to reduce IFN- and increase IL-10, a negative
immunoregolatory cytokine [63], and to revert immunologi-
cal dysfunctions described in depression and anxiety disor-
ders [64].
The relationship between depression and inflammation is
further supported by the evidence that decreased levels of 3
PUFAs or higher 6/3 ratio may facilitate the onset of de-
pression [65-67]. In fact, the reduction of 3 PUFAs, which
shows anti-inflammatory properties by decreasing the pro-
duction of IL-1 and TNF
, as well as the (relative) increase
of 6 PUFAs, which have pro-inflammatory effects, would
enhance the propensity to inflammatory reactions and, thus,
to depression. It has been demonstrated that individuals with
lower serum 3 PUFA or higher 6/3 ratio showed signifi-
cantly higher stress-induced TNF
and IFN responses,
which, in turn, were related to anxiety and perceived-stress
levels [68, 69]. Moreover, as mentioned before, 3 PUFAs
seem to be effective in the treatment of mood disorders [66,
70].
CYTOKINE EFFECTS ON NEUROTRANSMITTERS
METABOLISM: IMPLICATIONS FOR THE 5-HT
HYPOTHESIS OF DEPRESSION
It is well known that depression is characterized by de-
creased plasma levels of L-TRP, the precursor of 5-HT, and
248 Current Medicinal Chemistry, 2011 Vol. 18, No. 2
that experimental TRP depletion may induce depressive
symptoms in healthy subjects. The low TRP plasma concen-
trations observed in depression might be related to the in-
creased levels of IL-1, TNF-
and IFN [71, 72]. In fact,
pro-inflammatory cytokines, through the stimulation of in-
flammatory signaling pathways, such as the nuclear factor
(NF) B, p38 mitogen-activated protein kinase (MAPK),
signal transducer and activator of transcription (STAT) 1a,
can activate the enzyme indoleamine 2,3 dioxygenase (IDO)
that, in turn, induces the degradation of TRP into TRP
catabolites along the IDO pathway (TRYCATs), such as
kynurenine (KYN) and quinolinic acid (QA) [73, 74]. The
relevance of IDO activation in the cytokine-induced depres-
sion is supported by several data: the presence of decreased
TRP and increased KYN blood levels was associated to the
development of depression in hepatitis C patients treated
with IFN-
[54, 75]. During the post-partum period, IDO
activation was significantly related to both inflammatory
markers and depression severity [76]. It is interesting to
mention that, in mice, the blockade of IDO inhibited the de-
velopment of the LPS-induced sickness syndrome [77].
In addition, it is hypothesized that the activation of the
molecular signaling inflammatory pathways by the pro-
inflammatory cytokines, with IDO activation and decreased
TRP plasma levels, might be responsible for the lowered
central 5-HT concentrations found in depression. TRYCATs
seem to produce relevant behavioral effects on their own,
independently from the low 5-HT levels. The administration
of KYN alone, in fact, was found to induce depressive be-
haviors in mice [77] and to produce anxiogenic effects [78].
Further, TRYCATs seem to display neurotoxic effects. In
particular, at the level of microglia, KYN is converted into
QA, a potent N-methyl-D-aspartate (NMDA) agonist and
stimulator of glutamate (GLU) release, that exerts its neuro-
toxicity by inducing oxidative stress resulting in lipid per-
oxidation (Fig. 1) [79-82].
Accordingly to the above findings, a modification of the
5-HT hypothesis of depression has been proposed focusing
on inflammation-induced TRP degradation and TRYCATs
production rather than on TRP and 5-HT depletion. Indeed,
after IDO activation, more TRP would be converted into
TRYCATs, with a decrease of both 5-HT and TRP and in-
creased neurotoxicity.
CYTOKINE EFFECTS ON HPA AXIS
The HPA axis is the key system regulating the biological
response to stress. Its hyperactivity, together with impair-
ment of the negative feed-back mechanisms, reflecting a
decreased responsiveness to glucocorticoids or glucocorti-
coid resistance, represents one of the most replicated bio-
logical correlates of depression [83]. It is believed that be-
tween 40 and 60% of depressed patients, especially those
presenting melancholic and/or psychotic symptoms, do not
show the physiological suppression of cortisol following the
administration of dexamethasone (Dex), a synthetic gluco-
corticoid [83-88].
Cytokines have been demonstrated to produce several ef-
fects at the level of the HPA axis. The acute administration
of pro-inflammatory cytokines have been shown to activate
Catena-Dell’Osso et al.
the HPA axis, through the expression and release of cortico-
trophin-releasing hormone (CRH) [15, 89]. The increased
cortisol levels after HPA axis activation play the physiologi-
cal function of limiting the extension of the inflammatory
processes. In fact, cortisol would inhibit the further release of
pro-inflammatory agents through its action on the glucocor-
ticoid receptors (GRs) located on immune cells [18]. For
example, in healthy volunteers, IFN-
administration leads
to significant increases of cortisol concentrations [90]. How-
ever, in depression, glucocorticoids seem to lose their ability
to work upon the immune cells, while inhibiting a further
release of pro-inflammatory cytokines, adhesion molecules
and acute phase proteins [18]. Accordingly, in depressed
patients, significant and positive correlations between IL-6
activity and post-Dex cortisol values were found [15]. Breast
cancer patients with depression showed higher plasma levels
of IL-6 coupled to altered Dex suppression test, as compared
with those without depression [91]. After LPS exposure,
individuals with glucocorticoid resistance, as revealed by the
higher cortisol response after Dex administration, also
showed increased cytokine (IL-6 and TNF
) responses,
even if they were not depressed [92]. On the other hand, the
acute activation of the HPA axis after IFN
was considered a
predictor of the subsequent development of depression [93].
In fact, ACTH and cortisol responses to the administration of
IFN
were found to be significantly higher in those patients
who subsequently developed depression than in those who
did not. The HPA axis response to the acute IFN
admini-
stration may reveal a vulnerability to IFN
-induced depres-
sion [93].
It has been proposed that the alteration of GRs expression
and functioning, which may account for the glucocorticoid
resistance, should underlie both the inability of glucocorti-
coids to limit inflammation and the impairment of the nega-
tive feed-back mechanisms observed in depression [18, 94,
95]. The cytokines-mediated activation of the inflammatory
signaling molecules, such as NF-B, p38 MAPK and STAT,
was found to limit GRs function through the impairment of
the translocation from cytoplasm to nucleus and the inhibi-
tion of GRs binding to DNA [96]. Moreover, cytokines seem
to alter GR expression by increasing the production of GR,
a less active GR isoform, and by reducing the
isoform ex-
pression, which is the active form of GR [96]. In a recent
experimental study evaluating the impact of mouse IFN-
on
the functioning of the GR, a significant inhibition of Dex-
induced GR-mediated MMTV-luciferase activity and a sig-
nificant decrease of DEX-induced GR-binding to its DNA
response element were detected [97]. Therefore, the cytoki-
nes may be involved in the genesis of the glucocorticoid re-
sistance which seems to characterized depressed patients [18,
98].
STRESS-INDUCED ACTIVATION OF THE INFLAM-
MATORY RESPONSE IN DEPRESSION
If inflammation is involved in the pathophysiology of
depression, which are the triggering factors of the inflamma-
tory responses in those healthy subjects who will become
depressed? When depression occurs in the context of a medi-
cal illness, such as autoimmune or inflammatory diseases,
infectious or tissue damage or destruction, the activation of
Inflammation and Neurodegeneration in Depression
peripheral and, then, central inflammatory responses can be
easily attributed to the same factors leading to the somatic
illness. However, when depression occurs in healthy sub-
jects, the triggering factors of inflammation are less clear.
Since the report of Karl Abraham (1911), the role of
stress has been considered critical for the onset of psychopa-
thology. In his work on manic-depressive illness, Abraham
proposed that the occurrence of negative events during early
childhood was essential to the development of depression
and that recent events of loss would provoke the onset of
melancholia [99]. After the acceptance of this theory by
Freud [100], the model according to which early life events,
i.e. those occurring during childhood/adolescence, are pre-
disposing factors to the onset of psychopathology, while
recent life events, i.e. those occurring shortly before the on-
set of a disorder, are precipitating factors, is one of the most
widely accepted to explain the aetiology of mental illness.
This is the basis of Bowlby’s work [101-103] and of cogni-
tive and behavioral theories of psychopathology, and data
coming from epidemiological studies, carried out in clinical
and community samples, showed a consistent association
between the occurrence of stressful events and the onset of
depression [104-111].
Psychosocial stressors have been found to activate pe-
ripheral and central inflammatory responses [112-115]. In
animal paradigms of stress, increased IL-1 and IL-6 were
observed in the blood and brain [116, 117]. In humans, Maes
et al. [68, 118] first demonstrated that psychological stress
may induce an inflammatory response with increased levels
of IFN and TNF
. In healthy volunteers exposed to public
speaking and mental arithmetic stressors, a significant in-
crease of NFB DNA binding was detected in peripheral
blood mononuclear cells [112]. Chronic stress, including
familiar conflicts and perceived stress, was associated with
increases of PCR and IL-6 [113-115]. Increased inflamma-
tion was also found in the presence of early life events, such
as childhood abuse, as revealed by the increased levels of
CRP [119]. Further, exaggerated NF-B and IL-6 responses
to psychosocial stressors, as well as amplified IL-6 response
to antigenic challenge, were detected in depressed patients
[120, 121].
The mechanisms through which stress may lead to the ac-
tivation of the inflammatory response involve catechola-
mines and the HPA axis systems [18]. In particular, psycho-
social stressors, including early adversities, interpersonal
conflicts, social isolation, may provoke the release of CRH
and cathecolamines by the hypothalamus. The interaction of
catecholamines with
and  adreno-receptors at the level of
the immune system would lead to increased NFB DNA
binding, while resulting in the release of inflammatory me-
diators [122, 123]. Pro-inflammatory cytokines, in turn,
would enter the brain and, once reached the microglia, acti-
vate the inflammatory signaling pathways, such as NFB,
while causing a central neuroinflammation (Fig. 1) [26]. On
the other hand, the activation of CRH and, then, of HPA
axis, that normally inhibits the inflammatory signaling path-
ways (including NFB), in pathological conditions would
lose its inhibitory action. In fact, during depression or in
condition of chronic stress, glucocorticoids seemed to lose
their anti-inflammatory properties and cannot suppress the
Current Medicinal Chemistry, 2011 Vol. 18, No. 2 249
further release of cortisol. This condition, known as gluco-
corticoid resistance, seems to be, at least in part, related to
the action of cytokine on GRs [18]. The perpetuation of the
central inflammation and the continuous activation of the
HPA axis seem to provoke disrupting effects in the brain,
while leading to increased excitotoxicity, decreased neu-
rotrophism and alteration of monoamines metabolism, all
factors which seem to contribute to the brain damage which
is now thought to underlie, or at least accompany, depression
[19].
INFLAMMATION AND ENHANCED NEURODE-
GENERATION IN DEPRESSION
Recent neuroimaging studies, including structural mag-
netic resonance imaging (MRI), have opened new avenues in
the understanding of depression. In fact, significant structural
alterations in several brain regions, including hippocampus,
prefrontal cortex, amygdala, anterior cingulated and basal
ganglia, have been reported in depressed patients [19-24].
Further, neurophysiological abnormalities in multiple areas
of orbital and medial prefrontal cortex, hippocampus,
amygdala, and related parts of striatum and thalamus, the
so-called limbic-cortical-striatal-pallidal-thalamic tract
(LCSPT), have been reported in depressed patients. Since the
structures in the LCSPT circuit are all involved in the regula-
tion of mood, anxiety and cognition, damage to any of its
portion could potentially produce depression, either directly
by neuronal damage, or indirectly by changes in neurotrans-
mitter balance [124-126]. The loss of the volume of the
above-mentioned brain areas seems to be related to both in-
creased neurodegeneration and decreased neurogenesis
[127].
There is now evidence that the activation of inflamma-
tory processes, including increased oxidative and nitrosative
stress, production of pro-inflammatory cytokines and TRI-
CATs, can trigger the neurodegenerative processes observed
in depression [18] (Fig. 1). Inflammation, in fact, can in-
crease the production of oxygen radicals, while leading to
brain oxidative damage [128]. For example, increased levels
of malondialdehyde (MDA) and 8-hydroxy-2-deoxy-
guanosine, suggestive of DNA oxidative damage, have been
reported in depression [129-131]. The increased generation
of oxygen radicals, overwhelming the antioxidant defences
of the brain, leads to mitochondrial dysfunction and accumu-
lation of oxidized proteins, while causing programmed cell
death, apoptosis, DNA damage, alteration of proteolysis and
of membrane fatty acid with enhanced lipidic peroxidation
[128, 132-134].
Further, depression was found to be characterized by in-
creased serum IgM levels against both nitro-bovine serum
albumin (BSA) and phosphatidyl inositol. A nitrosative
damage of BSAs with production of NO-BSA would explain
the activation of such IgM response [131, 135]. The imbal-
ance of NO metabolism was found to produce detrimental
effects within the neurons. In fact, an overproduction of NO
can lead to the S-nitrosylation of cysteines in proteins and
the inhibition of cell respiration with release of superoxide
anions, which may interact with NO superoxide anions,
while leading to the formation of the peroxynitrite, that is
highly oxidant and neurotoxic [136, 137].
250 Current Medicinal Chemistry, 2011 Vol. 18, No. 2
Another mechanism through which inflammation may
activate neurodegenerative processes is, as already men-
tioned, IDO activation with production of TRICATs, includ-
ing KYN, KIN acid (KA) and QA [55, 75, 138] (Fig. 1). KIN
is preferentially converted in KA in astrocytes and in QA in
microglia [80, 139]. The QA was found to provoke acute
destruction of postsynaptic neurons, especially at the level of
striatum, pallidal formation and hippocampus [140], and to
impair the metabolism of several neurotransmitters, such as
dopamine, choline, gamma-amino-butyric acid and
enkephalines [141-144]. The agonism to NMDA glutamate
receptors [145] and the pro-oxidant effects explain the high
neurotoxicity of QA [79-82, 146].
Finally, pro-inflammatory cytokines themselves seems to
produce neurotoxic effect [6]. TNF
was reported to inhibit
cell survival signals and caspase-dependent cascade and to
potentiate glutamate neurotoxicity by increasing its release
and reducing its reuptake [147]. Interleukin-1 can directly
lead to neuronal death through increased seizure activity and
the activation of tyrosine kinases which increase NMDA
receptor function [148, 149].
DECREASED NEUROGENESIS: THE NEURO-
TROPHIC HYPOTHESIS OF DEPRESSION
It is currently known that neurogenesis occurs also in
adults and is fundamental for the integrity of the brain. Adult
neurogenesis is localized in the subventricular zone, where
cells migrate via the rostral migratory pathway to the olfac-
tory bulb, and in the subgranular zone, which gives rise to
cells in the granule cell layer of the hippocampus [150].
Stressful experiences were found to inhibit adult neurogene-
sis in the dentate gyrus of hippocampus [151-152]. Early
stressors, that have been associated with developmental ab-
normalities of hippocampus, amygdala, anterior cingulated
cortex and corpus callosum, seem to provoke long-lasting
decreases of neurogenesis. It has been demonstrated that the
separation of rat pups from their mothers during the postnatal
period leads to a decreased proliferation of hippocampal
granule cell precursors during development and adulthood
[153]. On the contrary, environmental enrichment, such as
access to running-wheels and antidepressants administration,
seems to have a positive impact on neurogenesis [147, 154,
155].
Neurotrophins, and in particular brain-derived neurotro-
phic factor (BDNF), are the main responsible for the adult
neurogenesis. BDNF can activate transcription factors that,
in turn, act on gene controlling neuronal survival/death, neu-
ronal differentiation/growth and plasticity [156]. Brain-
derived neurotrophic factor is the most widely distributed
trophic factor in the brain and has been shown to increase the
length and complexity of the dendritic trees in cortical neu-
rons, while contributing to the remodelling of the distribu-
tion of synapses along neuronal processes and dendritic
growth [157].
It has been hypothesized that decreased levels of neu-
rotrophic factors, in particular BDNF, may account for the
volume loss of the brain structures observed in depression. In
eterozygous BDNF knock-out (BDNF+/-) mice, neurogenesis
in the dentate gyrus of the hippocampus was significantly
Catena-Dell’Osso et al.
reduced, and this result was associated with a marked reduc-
tion of the volume of the dentate gyrus [158]. In human brain
tissues obtained post-mortem from drug-free suicide victims
(half of them diagnosed retrospectively as depressed), the
expression of BDNF was found to be decreased in hippo-
campus, as well as in the ventral prefrontal cortex, as com-
pared with non-suicidal subjects or drug-treated suicide vic-
tims [159]. Other studies evaluated blood peripheral BDNF
levels in depressed patients and found lowered serum and
plasma BDNF concentrations [160-166] that increased after
antidepressant treatments [161-165, 167]. In a study per-
formed in our department, decreased serum and plasma
BDNF levels were found in 15 depressed patients, as com-
pared with matched healthy control subjects [168]. Along 1
year of antidepressant treatment, the plasma BDNF levels
increased up to normal levels within the first month in paral-
lel with mood improvement [167].
The impairment of the physiological neurogenetic proc-
esses observed in depression, possibly due to reduced ex-
pression and functioning of BDNF, have been related to the
activation of inflammatory processes. Animal studies dem-
onstrated that, in physiological conditions, cytokines, includ-
ing IL-1, IL-6, TNF
, play a relevant role in providing tro-
phic support to neurons and enhancing neurogenesis [169,
170]. However, excessive and/or prolonged pathological
activation of the immune system, like in the case of the
stress-induced activation of the inflammatory pathways ob-
served in depression, leads to increased brain cytokines lev-
els, which, in turn, would provoke diminished neurotrophic
support and neurogenesis in brain areas relevant to behav-
iours and cognitions [171-175]. Accordingly, the peripheral
administration of LPS, that, as mentioned above, can trigger
both the sickness syndrome and increased hippocampal con-
centrations of IL-1 and TNF
, was also reported to provoke
decreased hippocampal expression of BDNF, as well as re-
duced hippocampal neurogenesis [175]. Acute or chronic IL-
1 administration was found to impair hippocampal cytogene-
sis and neurogenesis [169, 172]. Further, experimental stud-
ies showed that the effects of acute and chronic stress on
behaviours and neuroplasticity may be prevented by the
blockade of cytokine activity through the administration of
IL-1 receptor antagonist, or by the use of IL-1 receptor KO
mice or by transplantation of IL-1 receptor antagonists se-
creting neural precursor cells in the hippocampus [169, 172-
174].
Moreover, the stress-related overdrive of the HPA axis,
which represents one of the most robust biological correlates
of depression, seems to have a role in decreasing the neuro-
genetic processes [176-179]. The hypothesis that inhibition
of neurogenesis following stressful experience may be due to
a higher exposure of the brain to glucocorticoids was sup-
ported by the evidence that, after adrenalectomy, adult rats
did not show any reduction in hippocampal cell proliferation
when separated from their mother during the post-natal pe-
riod [153]. Other reports seem to confirm the negative ef-
fects of stress and glucocorticoids exposure on the structural
plasticity of the hippocampus: the in-vitro administration of
corticosterone, as well as the exposure to chronic variable
stress, can reduce the synaptic plasticity in the CA1 and den-
tate gyrus of the hippocampus of rats, while explaining, per-
haps, the cognitive deficits in hippocampus-dependent learn-
Inflammation and Neurodegeneration in Depression
ing tasks seen after prolonged exposure to stressful events
[180].
Further, the presence of lowered 3 PUFAs, which
seems to represent a vulnerability factor for depression
through their effects on pro-inflammatory cytokines produc-
tion [181], has been shown to have a positive impact on neu-
rogenesis [150]. In adult rats, 3 PUFAs increase neuro-
genesis and the differentiation of neural stem cells [182],
whereas, in the lobster brain, the increase of dietary 3 was
found to be related to increases in the number of S phase
cells [181]. On the contrary, in embryonic rat brain, de-
creased 3 PUFAs levels induced a delay of the normal neu-
ronal development with reduced neurogenesis [183].
CONCLUSIONS
The recent development of neurobiological research has
led to intriguing interpretation of the mechanisms through
which stress and inflammation may influence negatively the
brain and, perhaps, provoke depression. The stress-related
activation of the central inflammatory signalling pathways
seem to underlie the disruption of brain areas relevant for the
regulation of mood and emotions [124]. In this model, the
stress-related increased production of pro-inflammatory cy-
tokines would contribute to the brain damage observed in
depression through both a reduced neurogenesis and an in-
creased neurodegeneration. Further, pro-inflammatory cyto-
kines seem to be also involved in the reduced availability of
TRP and 5-HT and in the onset of the glucocorticoid resis-
tance, two of the most replicated data on the pathophysiol-
ogy of depression [8-56]. This model is not only supported
by biological data, but also by some clinical evidences of a
certain improvement of depressive symptoms after the aug-
mentation of antidepressants with anti-inflammatory drugs
[58-60]. On the other hand, antidepressants were found to
elicit anti-inflammatory effects, through reducing IFN- and
increasing IL-10 levels [63].
Besides the 5-HT system, other targets, possibly within
the inflammatory and neurodegenerative pathways, could be
considered for the implementation of new antidepressants;
cytokines and their receptors, intracellular inflammatory
mediators, IDO, TRYCATs, GRs, neurotrophic factors may
all represent possible novel therapeutic targets for depres-
sion. In addition, it should also be clarified the role of the
existing anti-inflammatory drugs in the treatment of depres-
sion. For example, curcumin, a natural anti-inflammatory
and anti-oxidative substance, was able to reverse depressive
behaviors in experimental models of depression through its
action on NF
and consequent increased hippocampal
BDNF expression and neurogenesis and disruption of the
inhibitory effects of cytokines on GR-mediated gene expres-
sion [184, 185]. Anti-inflammatory compounds with anti-
inflammatory and anti-oxidative properties should be exam-
ined for the treatment of depression, either as monotherapy
or adjunctive therapy. In conclusion, the molecular inflam-
matory and neurodegenerative pathways might provide new
targets for the treatment of depression and appear crucial in
the attempt to move towards therapeutic strategies of depres-
sion based more on causal factors rather than on serendipity.
Current Medicinal Chemistry, 2011 Vol. 18, No. 2 251
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