Glucocorticoids, cytokines and brain abnormalities in depression

In the paper

“The caregivers’ patterns of cortisol secretion were similar to those of matched control. However, their monocytes showed diminished expression of transcripts bearing response elements for glucocorticoids, and heightened expression of transcripts with response elements for the key pro-inflammatory transcription factor NF-kappaB”

What the sources say

• Supported

  The Methods identify the participants as caregivers of brain-cancer patients and matched controls. The Results state that caregivers had similar cortisol-secretion patterns but diminished expression of monocyte transcripts bearing glucocorticoid response elements and heightened expression of transcripts bearing NF-κB response elements. (LLM, conf=0.95)

  cites Miller et al., 2008 source
• Not checked yetcites Hayden et al., 2006 source

In the paper

“Cytokines can activate the HPA axis, causing an elevation of systemic glucocorticoid levels, and at the same time, they can inhibit GR function at multiple levels, including GR translocation and induction of GR isoforms with reduced capacity to bind ligand”

What the sources say

• Not checked yetcites Pace et al., 2007 source

In the paper

“Actions mediated by both receptors are complementary and operate in different time domains of the stress response: the MR normally prevents stress-induced disturbances, but, if such disturbances occur, the GR can operate and help in the recovery process.”

In the paper

“A reduction in neurogenesis can theoretically contribute to the cognitive symptoms of depression, even though by itself is unlikely to produce the full mood disorder”

What the sources say

• Not checked yetcites Lucassen et al., 2010 source

In the paper

“dexamethasone administration induced an increase in the number of neutrophils and a decrease in the number of lymphocytes in healthy controls, whereas this effect was not observed in non-suppressors”

In the paper

“depressed patients show higher levels of pro-inflammatory cytokines, acute phase proteins, chemokines and cellular adhesion molecules”

What the sources say

• Not checked yetcites Raison et al., 2006 source
• Not checked yetcites Howren et al., 2009 source

In the paper

“The MR binds cortisol with higher affinity, hence it regulates normal HPA fluctuations, being significantly bound even at the circadian trough, and fully bound at the circadian peak and during stressful episodes. The GR, of lower affinity, gets extensively occupied in times of stress.”

What the sources say

• Not checked yetcites de Kloet et al., 2005 source

In the paper

“Depression is highly prevalent in infectious, autoimmune and neurodegenerative diseases, and this co-morbidity cannot be attributed only to the psychological distress of the starting disease”

What the sources say

• Not checked yetcites Pollak and Yirmiya, 2002 source

In the paper

“Although it is possible that an imbalance between MR and GR could increase the vulnerability to stress-related psychiatric disorders in predisposed individuals”

What the sources say

• Not checked yetcites de Kloet et al., 2007 source

In the paper

“severe or chronic stress exposure, both in early life as well as in adulthood, can cause neural cell death and atrophy of neuronal processes, and also affect hippocampal neurogenesis and plasticity”

What the sources say

• Not checked yetcites McEwen and Seeman, 1999 source
• Not checked yetcites Sapolsky, 2000 source

In the paper

“A failure in GR function, as hypothesized to take place in depression, may therefore result from reduced glucocorticoid binding to GR, reduced GR expression, enhanced activation of inflammatory pathways, or lack of co-repressor activity”

What the sources say

• Not checked yetcites De Bosscher and Haegeman, 2009 source

In the paper

“if stress is repetitively experienced in an uncontrollable and unpredictable manner, it can cause alterations in dendrite and spine morphology in specific brain regions, and eventually suppress adult neurogenesis”

What the sources say

• Not checked yetcites Mirescu and Gould, 2006 source
• Not checked yetcites Joels et al., 2007 source

In the paper

“If, during systemic infections, cancer or autoimmune diseases, the activation of the peripheral immune system is prolonged, the immune signalling to the brain could lead to an exacerbation of sickness behaviour and to the development of depressive symptoms in vulnerable individuals”

What the sources say

• Not checked yetcites Dantzer et al., 2008 source

In the paper

“therapeutic administration of the cytokine interferon-alpha (IFN-alpha) leads to a depressive symptomatology in up to 50% of patients, who show similar biological alterations as those found in MD and can be treated with antidepressant medication”

What the sources say

• Not checked yetcites Capuron and Miller, 2004 source
• Not checked yetcites Raison et al., 2005 source
• Not checked yetcites Maddock et al., 2005 source

In the paper

“While dexamethasone administration significantly suppressed the mitogen-induced lymphocyte proliferation and the interleukin-1beta (IL-1beta) production in healthy controls, MD patients exhibited dexamethasone non-suppression”

What the sources say

• Not checked yetcites Maes et al, 1991 source

In the paper

“Glucocorticoids act by binding to the cytosolic GR, which is subsequently activated and is thus able to translocate into the nucleus.”

• Also stated in: § 2.3. Molecular basis of glucocorticoid action · plain

  “Once in the nucleus, the GR either binds to DNA and switches on the expression of anti-inflammatory genes, or acts indirectly by protein–protein interaction to repress the activity of a number of distinct signalling pathways such as nuclear factor-kappaB (NF-kappaB)”

What the sources say

• Not checked yetcites Revollo and Cidlowski, 2009 source

In the paper

“Hyperactivity of the HPA axis in MD can be demonstrated by the altered feedback inhibition, as seen by increased circulating cortisol and non-suppression of cortisol following administration of dexamethasone”

What the sources say

• Not checked yetcites Holsboer et al., 1982 source
• Not checked yetcites Holsboer-Trachsler et al., 1991 source

In the paper

“The development of functional glucocorticoid resistance was accompanied by the accumulation of glucocorticoid-insensitive cells in the spleen that exhibit impaired nuclear translocation of the GR and lack of glucocorticoid-induced suppression of NF-kappaB”

What the sources say

• Not checked yetcites Engler et al., 2008 source

In the paper

“IL-1beta and IL-6, both of which increase during infection, have been described as playing a central role in synaptic plasticity, neurogenesis and neuromodulation”

What the sources say

• Not checked yetcites McAfoose and Baune 2009 source

In the paper

“Whereas an acute or short-term stressful life event can enhance immune responses, chronic or long-term stress can suppress immunity.”

In the paper

“Stockmeier et al. (2004) observed that the packing density of glia, pyramidal neurons and granule cell neurons is significantly increased in all hippocampal subfields and the dentate gyrus, and pyramidal neuron soma size is significantly decreased, suggesting that a significant reduction in neuropil in MD may account for the decreased hippocampal volume detected by neuroimaging.”

What the sources say

• Not checked yetcites Stockmeier et al. (2004) source

In the paper

“chronic administration of corticosterone produced depressive symptoms both in wild type and knockout mice, and the effects of CMS on behavioural depression could be mimicked by exogenous administration of IL-1beta”

What the sources say

• Not checked yetcites Goshen et al., 2008 source

In the paper

“splenocytes of mice stimulated with the bacterial cell wall component lipopolysaccharide (LPS) and also repeatedly subjected to social disruption were less sensitive to the anti-inflammatory actions of glucocorticoids, showing increased levels of pro-inflammatory cytokines”

What the sources say

• Not checked yetcites Engler et al., 2008 source

In the paper

“both inhibiting the IL-1 receptor and using IL-1 receptor null mice prevented the anhedonic behaviour caused by chronic stress exposure”

What the sources say

• Not checked yetcites Koo and Duman, 2008 source

In the paper

“HPA axis hyperactivity and inflammation might be part of the same pathophysiological process: HPA axis hyperactivity is a marker of glucocorticoid resistance, implying ineffective action of glucocorticoid hormones on target tissues, which could lead to immune activation; equally, inflammation could stimulate HPA axis activity via both a direct action of cytokines on the brain and by inducing gluc”

In the paper

“exposure to chronic restraint stress prior to the injury exacerbated a depressive-like behaviour causing also an increase in IL-1beta gene expression, whereas a pre-treatment with a corticosteroid synthesis inhibitor before stress was able to eliminate the damaging effects of chronic stress. In addition, interference with IL-1beta signalling, through administration of an IL-1 receptor antagonist,”

What the sources say

• Not checked yetcites Norman et al., 2010 source

In the paper

“Immunoenhancement is observed when acute stress is experienced at early stages of immune activation, while immunosuppression may be observed at late stages of the immune response”

What the sources say

• Not checked yetcites Dhabhar, 2009 source

In the paper

“mice lacking IL-1 receptor exhibited adrenal hypertrophy and elevated serum corticosterone levels in response to stressors and failed to develop glucocorticoid resistance”

In the paper

“it is possible that increased levels of pro-inflammatory cytokines, especially IL-1 and IL-6, may contribute to the pathophysiology of depression inducing, as we will discuss below, glucocorticoid resistance, neurodegeneration, or indeed other yet unknown mechanism”

In the paper

“glucocorticoids potentiate both the peripheral and central pro-inflammatory response to a peripheral immune challenge if they are administered prior to the challenge. Contrarily, when glucocorticoids are administered after the peripheral immune challenge, they suppress the pro-inflammatory response measured as IL-1beta and IL-6.”

What the sources say

• Not checked yetcites Frank et al. (2010) source

In the paper

“An interesting recent study supports the idea that chronic stress is accompanied by GR resistance and activation of pro-inflammatory pathways”

What the sources say

• Not checked yetcites Miller et al., 2008 source

In the paper

“Multiple inflammatory cytokines, oxygen radical damage, tryptophan catabolites (see below) and neurodegenerative biomarkers have all been established in patients with MD and corroborated by animal models of depression”

What the sources say

• Not checked yetcites Maes et al., 2009 source

In the paper

“Glucocorticoid resistance can underlie the HPA axis disturbances and this might be caused by cytokines.”

In the paper

“mice subjected to chronic mild stress (CMS) showed increased IL-1beta levels in the hippocampus and in parallel a development of changes in behaviour resembling depressive symptoms, such as decreased sucrose preference and reduced social exploration. In contrast, mice with deletion of the IL-1 receptor did not display such behavioural changes”

What the sources say

• Not checked yetcites Goshen et al., 2008 source

In the paper

“The selective and persistent loss of hippocampal volume could be induced by neurodegeneration, leading to hippocampal neuronal death, and also by decreased neurogenesis”

What the sources say

• Not checked yetcites Sapolsky, 2004 source

In the paper

“an acute injection of IL-1beta increases sickness and levels of plasma corticosterone, while these effects are attenuated after subchronic treatment”

What the sources say

• Not checked yetcites Anisman et al., 2008a

In the paper

“the study of MD patients done by Müller et al. (2001) did not found any proof of patterns of reactive astrogliosis, synaptic density or synaptic reorganization”

What the sources say

• Not checked yetcites Müller et al. (2001) source

In the paper

“neuroimaging studies have consistently shown reduced size of hippocampal volume in MD as reported by meta-analysis studies of patients with recurrent depression”

• Also stated in: § 5. Neurodegeneration · plain

  “and with longer duration of illness”

What the sources say

• Not checked yetcites Videbech and Ravnkilde, 2004 source
• Not checked yetcites Campbell et al., 2004 source
• Not checked yetcites McKinnon et al., 2009

In the paper

“depressed patients with increased inflammatory biomarkers are more likely to be resistant to antidepressant therapy, a response to treatment has been associated with decreased inflammatory responses”

What the sources say

• Not checked yetcites Raison et al., 2006 source
• Not checked yetcites Miller et al., 2009 source

In the paper

“the removal of endogenous glucocorticoids abolished the depressive-like effects of CMS, indicating that the blunting of the adrenocortical activation may play a role in their resistance to develop depression”

What the sources say

• Not checked yetcites Goshen et al., 2008 source

In the paper

“many of the structural changes and the volume reduction appear to be reversible”

In the paper

“Dexamethasone is used in premature infants to prevent and/or treat bronchopulmonary dysplasia that can adversely affect early neurodevelopment and can probably cause a loss of cerebral volume (Grier and Halliday, 2003).”

What the sources say

• Not checked yetcites Grier and Halliday, 2003 source

In the paper

“They showed that peripheral administration of LPS in mice activates IDO to induce a depressive-like behavioural syndrome and to increase the brain serotonin turnover.”

What the sources say

• Not checked yetcites O’Connor et al., 2009

In the paper

“Interestingly, this GR blockade attenuated the hippocampal abnormalities and rescued the diabetic mice from the cognitive deficits (Revsin et al., 2009).”

What the sources say

• Not checked yetcites Revsin et al., 2009 source

In the paper

“Therefore, while dexamethasone can exert neurodegenerative effects in the developing brain, it can also increase VEGF levels, which, in contrast, may play a neuroprotective role (Feng et al., 2009).”

What the sources say

• Not checked yetcites Feng et al., 2009 source

In the paper

“This ‘glucocorticoid cascade hypothesis’ of stress and hippocampal damage was proposed to be involved in age-related accumulation of hippocampal damage in disorders like Alzheimer’s disease and depression (Sapolsky et al., 1986).”

What the sources say

• Not checked yetcites Sapolsky et al., 1986 source

In the paper

“Therefore, we cannot unequivocally accept the simple model that glucocorticoids cause neurodegeneration, but rather that elevated cytokines, in the context of glucocorticoid resistance, are probably the offenders.”

In the paper

“Chronic inflammation is now considered to play a central role in the pathogenesis of cardiovascular disease, multiple sclerosis, diabetes, cancer and MD.”

In the paper

“In response to LPS, cells produce several cytokines, and glucocorticoids control their expression. In the absence of this negative feedback, some cytokines, in particular tumor necrosis factor alpha (TNF-alpha), become highly toxic and cause a nonselective cell death.”

In the paper

“At the same time, dexamethasone causes an increase in mRNA and protein levels of vascular endothelial growth factor A (VEGF), which has neurotrophic and neurogenesis enhancing effects.”

What the sources say

• Not checked yetcites Feng et al., 2009 source

In the paper

“it has been hypothesized that depression is not a true neurodegenerative disorder (Thompson et al., 2008) or at least it does not involve only a deficit in neurogenesis”

What the sources say

• Not checked yetcites Thompson et al., 2008 source

In the paper

“Chronic stressors induce sustained elevations in cortisol, which, over time, cause immune cells to undergo a compensatory downregulation of GR activity.”

In the paper

“Indeed there is clinical evidence that depression is a common antecedent of Alzheimer’s disease and may be an early manifestation of dementia before the cognitive declines become apparent.”

In the paper

“Interestingly, both the anti-inflammatory drug and the IDO antagonist are able to normalize the kynurenine/tryptophan ratio.”

What the sources say

• Not checked yetcites O’Connor et al., 2009

In the paper

“Contrary to the studies shown above where glucocorticoids exert neurodegenerative effects in the developing brain, a few studies have shown that dexamethasone may also play a neurotrophic and neuroprotective role.”

In the paper

“kynurenic acid is an N-methyl d-aspartate (NMDA) receptor antagonist, and is generally considered neuroprotective”

What the sources say

• Not checked yetcites Wichers and Maes 2004
• Not checked yetcites Wichers et al., 2005 source
• Not checked yetcites Müller and Schwarz, 2007 source

In the paper

“This limits the ability of cortisol to further reduce immune responses, even in the presence of high circulating glucocorticoid levels, and as a result there is low-grade inflammation, which is hypothesized to contribute to the infectious, autoimmune, and cardiac diseases, whose risk is linked to stress.”

In the paper

“An additional useful model to assess the effect of glucocorticoids on neurodegeneration is Type 1 diabetes, a common metabolic disorder characterized by an increased secretion of glucocorticoids and cognitive deficits.”

In the paper

“3-hydroxykynurenine and quinolinic acid are NMDA receptor agonists, potentially neurotoxic and thus potentially contributing to depression”

What the sources say

• Not checked yetcites Wichers and Maes 2004
• Not checked yetcites Wichers et al., 2005 source
• Not checked yetcites Hashimoto, 2009 source

In the paper

“The development of depressive symptomatology is a frequent side effect of glucocorticoid treatment and one of the symptoms of Cushing’s syndrome.”

In the paper

“Boldrini et al. (2009) showed increased progenitor cells in MD patients treated with antidepressants. More specifically, patients receiving these drugs had more dividing cells in the hippocampus than untreated patients and controls.”

What the sources say

• Not checked yetcites Boldrini et al. (2009) source

In the paper

“Due to an inhibitory control of the hippocampus on the HPA axis, damage to this structure is expected to disinhibit the HPA axis, causing increased glucocorticoid levels over time.”