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Journal ArticleDOI

Modulation of c-Jun N-terminal kinase signaling and specific glucocorticoid receptor phosphorylation in the treatment of major depression.

01 Sep 2015-Medical Hypotheses (Churchill Livingstone)-Vol. 85, Iss: 3, pp 291-294

TL;DR: It is proposed that modulation of glucocorticoid phosphorylation at serine 226, by targeting JNK signaling pathway, could be a potential strategy for antidepressant treatment.
Abstract: Glucocorticoid resistance is a common finding in major depressive disorder Increased glucocorticoid receptor (GR) phosphorylation at serine 226 is associated with increased glucocorticoid resistance Previously we have demonstrated that depressed patients exhibit higher levels of GR phosphorylated at serine 226 compared to healthy controls The enzyme that is involved in this specific GR phosphorylation is c-Jun N-terminal kinase (JNK) We propose that modulation of glucocorticoid phosphorylation at serine 226, by targeting JNK signaling pathway, could be a potential strategy for antidepressant treatment We base this assumption on the results of previous research that examined GR phosphorylation and JNK signaling in animal models and human studies We also discuss the potential challenges in targeting JNK signaling pathway in depression
Topics: Glucocorticoid receptor (61%), c-jun (58%), Phosphorylation (57%), Glucocorticoid (55%), Kinase (52%)

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Modulation of c-Jun N-terminal kinase signaling and specific
glucocorticoid receptor phosphorylation in the treatment of major
depression
q
Milica J. Jovicic
a
, Iva Lukic
b
, Marija Radojcic
b
, Miroslav Adzic
b
, Nadja P. Maric
a,c,
a
School of Medicine, University of Belgrade, Serbia
b
Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, Serbia
c
Clinic for Psychiatry, Clinical Center of Serbia, Belgrade, Serbia
article info
Article history:
Received 19 April 2015
Accepted 27 May 2015
abstract
Glucocorticoid resistance is a common finding in major depressive disorder. Increased glucocorticoid
receptor (GR) phosphorylation at serine 226 is associated with increased glucocorticoid resistance.
Previously we have demonstrated that depressed patients exhibit higher levels of GR phosphorylated
at serine 226 compared to healthy controls. The enzyme that is involved in this specific GR phosphory-
lation is c-Jun N-terminal kinase (JNK). We propose that modulation of glucocorticoid phosphorylation at
serine 226, by targeting JNK signaling pathway, could be a potential strategy for antidepressant treat-
ment. We base this assumption on the results of previous research that examined GR phosphorylation
and JNK signaling in animal models and human studies. We also discuss the potential challenges in tar-
geting JNK signaling pathway in depression.
Ó 2015 Elsevier Ltd. All rights reserved.
Introduction
The etiology of depression is still poorly understood, and pre-
sent treatment strategies fail to alleviate the symptoms of 10–
40% of depressed individuals [1]. Current trends in mood disorders
research highlight the need of distinguishing between the specific
syndromes that fall under the wide ‘‘umbrella’’ of major depres-
sion, in order to personalize treatment and achieve better thera-
peutic response. This notion found support in basic research,
which demonstrated significantly different gene expression pro-
files between stress-related depression models and endogenous
depression models [2].
Dysregulation of the hypothalamic–pituitary–adrenal (HPA)
axis has long been associated with stress-related depression [3].
Namely, a significant percentage of depressed patients exhibit
increased blood cortisol levels, and this effect is higher in those
with comorbid anxiety [4,5]. Effects of cortisol are mediated
through the glucocorticoid receptor (GR), including the feedback
regulation of the HPA axis. Therefore, the impairment of GR
signaling is suggested to play a pivotal role in the HPA axis dysreg-
ulation in stress-related depression [6,7].
The GR regulates the expression of a variety of genes, including
ones that are involved in metabolism and immunity, neuronal sur-
vival, neurogenesis and regulation of HPA axis [8]. Therefore, in
addition to its role in the neuroendocrine system, GR signaling is
strongly involved in immune system response. Cortisol is one of
the most potent anti-inflammatory hormones in the body, and
pathways coupled with glucocorticoid resistance may conspire
during chronic stress to contribute to chronic activation of inflam-
matory responses [9]. Namely, a large body of research supports
the notion of inflammatory disturbance in depression [10,11].
Chronic stress, through glucocorticoid resistance (i.e. decreased
sensitivity to anti-inflammatory effects of glucocorticoids), may
contribute to chronic activation of immune system in major
depressive disorder [12].
Considering the complex interplay between glucocorticoid and
inflammatory signaling (in both physiological and pathological
conditions), as well as evidence of dysfunction of both these sys-
tems in major depression, targeting one or both systems could be
a potential therapeutic strategy for this disorder [13].
The glucocorticoid receptor signaling
GR is a ligand-dependent transcriptional factor that resides in
the cell cytoplasm in its inactive form. After ligand binding it
http://dx.doi.org/10.1016/j.mehy.2015.05.015
0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.
q
Sources of support: Researchers received Grant support from the Ministry of
Education, Science and Technological Development, Republic of Serbia (Project
III41029).
Corresponding author at: Clinic for Psychiatry, Clinical Center of Serbia,
Pasterova 2, 11000 Belgrade, Serbia. Tel./fax: +381 11 3065637.
E-mail address: nadjamaric@yahoo.com (N.P. Maric).
Medical Hypotheses 85 (2015) 291–294
Contents lists available at ScienceDirect
Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy
Citations
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TL;DR: The published data on proposed molecular mechanisms that contribute to the development of glucocorticoid resistance in brain are reviewed, including changes in the expression of the GR gene, biosynthesis of GR isoforms, and GR posttranslational modifications.
Abstract: Exposure to stress activates the hypothalamic–pituitary–adrenal axis and leads to increased levels of glucocorticoid (GC) hormones. Prolonged elevation of GC levels causes neuronal dysfunction, decreases the density of synapses, and impairs neuronal plasticity. Decreased sensitivity to glucocorticoids (glucocorticoid resistance) that develops as a result of chronic stress is one of the characteristic features of stress-induced psychopathologies. In this article, we reviewed the published data on proposed molecular mechanisms that contribute to the development of glucocorticoid resistance in brain, including changes in the expression of the glucocorticoid receptor (GR) gene, biosynthesis of GR isoforms, and GR posttranslational modifications. We also present data on alterations in the expression of the FKBP5 gene encoding the main component of cell ultra-short negative feedback loop of GC signaling regulation. Recent discoveries on stressand GRinduced changes in epigenetic modification patterns as well as normalizing action of antidepressants are discussed. GR and FKBP5 gene polymorphisms associated with stress-induced psychopathologies are described, and their role in glucocorticoid resistance is discussed.

32 citations


Cites background from "Modulation of c-Jun N-terminal kina..."

  • ...3 2017 Development of GC resistance in psychiatric disorders is now commonly believed to be related to increased GR phosphorylation at the serine S226 residue [63]....

    [...]


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TL;DR: Results from this uncontrolled study suggest icariin may decrease depressive symptoms and reduce alcohol consumption in persons with bipolar disorder and alcohol use.
Abstract: Objectives: Bipolar disorder is associated with a very high prevalence of alcohol-related disorders. However, few studies have examined treatment in this population. Preclinical research suggests a role for the flavonoid icariin in mood and addictive disorders. In this open-label pilot study, we investigated the feasibility and safety of using icariin for persons with bipolar disorder and alcohol abuse or dependence. Methods: Ten participants with bipolar I or bipolar II disorders, currently depressed, and with active alcohol abuse or dependence were given open-label icariin of up to 300 mg/day for 8 weeks using a flexible dosing strategy. Participants were assessed using the Hamilton Rating Scale for Depression (HAMD), Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR), Hamilton Rating Scale for Anxiety (HAMA), and Young Mania Rating Scale (YMRS). Standard drinks, heavy drinking days, and drinking days were also quantified. Baseline and exit data were analyzed using the Wilcoxon S...

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Journal ArticleDOI
Juntao Zhang1, Wenjuan Lin1, Ming-ming Tang1, Ya-wei Zhao1  +3 moreInstitutions (1)
TL;DR: It is shown, for the first time, that JNK activities in the Hb, Amyg, and mPFC are involved in the modulation of neuroinflammation-induced depression and participate in the regulation of the expression of proinflammatory cytokines and GR phosphorylation, which are pathological factors associated with depression.
Abstract: Depression is associated with immune dysregulation and the aberrant activity of the hypothalamic-pituitary-adrenal (HPA) axis. However, the neurobiological molecular mechanisms underlying these associations remain unclear. c-Jun amino-terminal kinase (JNK), an important modulator in inflammation and stress responses, is often critically implicated in the development of central nervous system diseases. However, whether and how JNK mediates neuroinflammation-induced depression remains largely unknown. In this study, we investigated the role of JNK in depressive-like behaviors induced by central lipopolysaccharide (LPS) infusion. The results showed that LPS infusion led to depressive-like behaviors, accompanied by increased proinflammatory cytokine expression, increased JNK activation, and upregulated glucocorticoid receptor (GR) phosphorylation at serine 246 (pGR-Ser246) in the habenula (Hb), amygdala (Amyg) and medial prefrontal cortex (mPFC). Treatment with SP600125, a known JNK inhibitor, prevented the LPS-induced hyper-activation of JNK and alleviated depressive-like behaviors. Moreover, LPS-induced increases in the expression levels of TNF-α, IL-1β and pGR-Ser246 in these brain regions were reduced when the rats were treated with SP600125. Our results show, for the first time, that JNK activities in the Hb, Amyg, and mPFC are involved in the modulation of neuroinflammation-induced depression and participate in the regulation of the expression of proinflammatory cytokines and GR phosphorylation, which are pathological factors associated with depression. Our findings provide new insights into the mechanism of neuroinflammation-associated depression and suggest that the JNK pathway may be a potential target for treating inflammation-related depression.

9 citations


Journal ArticleDOI
Abstract: The classification and treatment of breast cancer is largely defined by the expression of steroid hormone receptors (HRs), namely estrogen receptor (ER) and progesterone receptor (PR), and gene amplification/overexpression of human epidermal growth factor receptor 2 (HER2). More recently, studies of androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR) have revealed that targeting these related HRs may be a promising strategy for a more personalized approach to the treatment of specific subtypes of HR+ breast cancer. For example, GR expression is associated with a good prognosis in ER+ breast cancer, but predicts poor prognosis in triple-negative breast cancer (TNBC). GR, like ER, PRs, and AR, is a ligand-activated transcription factor, but also has significant ligand-independent signaling activities. GR transcriptional activity is classically regulated by circulating glucocorticoids (GCs; ligand-dependent). Recent studies demonstrate that GR transcriptional activity is also regulated by a variety of cellular stress stimuli that input to GR Ser134 phosphorylation via rapid activation of the p38 mitogen activated protein kinase (MAPK) signaling pathway (ligand-independent). Furthermore, ligand-independent GR activation promotes feedforward signaling loops that mediate sustained activation of stress signaling pathways to drive advanced cancer biology (i.e. migration, invasion, chemoresistance, survival, and cellular growth). In this review, we will focus on the role of GR as a key sensor and mediator of physiologic and tumor microenvironment (TME)-derived cellular stress signaling in TNBC and discuss how targeting GR and/or associated signaling pathways may provide a strategy to inhibit deadly TNBC progression.

1 citations


Journal ArticleDOI
TL;DR: The upregulation of CB1 receptor density, but not that of CB2 receptor, as well as the increased mTOR activity in PFC/BA9 of subjects with MDD (AD-free/treated) support their contributions in the complex pathophysiology of MDD and in the molecular mechanisms of antidepressant drugs.
Abstract: Background Dysregulations of endocannabinoids and/or cannabinoid (CB) receptors have been implicated in the pathophysiology and treatment of major depressive disorder (MDD). Methods CB1 and CB2 receptors, neuroprotective mTOR (mechanistic target of rapamycin) and pro-apoptotic JNK1/2 (c-Jun-N-terminal kinases) were quantified by immunoblotting in postmortem prefrontal cortex of MDD and controls, and further compared in antidepressant (AD)-free and AD-treated subjects. Neuroplastic proteins (PSD-95, Arc, spinophilin) were quantified in MDD brains. Results Total cortical CB1 glycosylated (≈54/64 kDa) receptor was increased in MDD (+20%, n=23, p=0.02) when compared with controls (100%, n=19). This CB1 receptor upregulation was quantified in AD-treated (+23%, n=14, p=0.02) but not in AD-free (+14%, n=9, p=0.34) MDD subjects. In the same MDD cortical samples, CB2 glycosylated (≈45 kDa) receptor was unaltered (all MDD: +11%, n=23, p=0.10; AD-free: +12%, n=9, p=0.31; AD-treated: +10%, n=14, p=0.23). In MDD, mTOR activity (p-Ser2448 TOR/t-TOR) was increased (all MDD: +29%, n=18, p=0.002; AD-free: +33%, n=8, p=0.03; AD-treated: +25%, n=10, p=0.04). In contrast, JNK1/2 activity (p-Thr183/Tyr185/t-JNK) was unaltered in MDD subjects. Cortical PSD-95, Arc, and spinophilin contents were unchanged in MDD. Limitations A relative limited sample size. Some MDD subjects had been treated with a variety of ADs. The results must be understood in the context of suicide victims with MDD. Conclusions The upregulation of CB1 receptor density, but not that of CB2 receptor, as well as the increased mTOR activity in PFC/BA9 of subjects with MDD (AD-free/treated) support their contributions in the complex pathophysiology of MDD and in the molecular mechanisms of antidepressant drugs.

1 citations


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TL;DR: In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour, which can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals.
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4,937 citations


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TL;DR: The acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial are described and compared.
Abstract: Objective: This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Method: A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N=3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of ≤5 on the Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR 16 ) (equivalent to ≤7 on the 17-item Hamilton Rating Scale for Depression [HRSD 17 ]) defined remission; a QIDS-SR 16 total score of ≥11 (HRSD 17 ≥14) defined relapse. Results: The QIDS-SR 16 remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, t...

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TL;DR: Preliminary data from patients with inflammatory disorders, as well as medically healthy depressed patients, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication.
Abstract: Recognition that inflammation may represent a common mechanism of disease has been extended to include neuropsychiatric disorders including major depression. Patients with major depression have been found to exhibit increased peripheral blood inflammatory biomarkers, including inflammatory cytokines, which have been shown to access the brain and interact with virtually every pathophysiologic domain known to be involved in depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity. Indeed, activation of inflammatory pathways within the brain is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements, consistent with neuropathologic findings that characterize depressive disorders. Further instantiating the link between inflammation and depression are data demonstrating that psychosocial stress, a well-known precipitant of mood disorders, is capable of stimulating inflammatory signaling molecules, including nuclear factor kappa B, in part, through activation of sympathetic nervous system outflow pathways. Interestingly, depressed patients with increased inflammatory biomarkers have been found to be more likely to exhibit treatment resistance, and in several studies, antidepressant therapy has been associated with decreased inflammatory responses. Finally, preliminary data from patients with inflammatory disorders, as well as medically healthy depressed patients, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication. Translational implications of these findings include the unique opportunity to identify relevant patient populations, apply immune-targeted therapies, and monitor therapeutic efficacy at the level of the immune system in addition to behavior.

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  • ...decreased sensitivity to anti-inflammatory effects of glucocorticoids), may contribute to chronic activation of immune system in major depressive disorder [12]....

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Journal ArticleDOI
TL;DR: It is shown that hyperactivity of the hypothalamic-pituitary-adrenal axis is one of the most consistent biological findings in major depression psychiatry, but the mechanisms underlying this abnormality are still unclear.
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