Immunological aspects in the neurobiology of suicide: Elevated microglial density in schizophrenia and depression is associated with suicide

Steiner, Johann; Bielau, Hendrik; Brisch, Ralf; Dános, P.; Ullrich, Oliver; Mawrin, Christian; Bernstein, Hans‐Gert; Bogerts, Bernhard

doi:10.1016/j.jpsychires.2006.10.013

Cited by 682 publications

(466 citation statements)

References 37 publications

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“…IL-1 was shown not only to decrease hippocampal neurogenesis in human hippocampal progenitor cells but also to upregulate the expression of the enzymes, IDO, KMO, and kynureninase and, crucially, treatment with a KMO inhibitor reversed the effects of IL-1 on hippocampal neurogenesis (Zunszain et al, 2012). The reduction in GM volume and the decrease in neuronal density that has been found in some depressed patients post-mortem may be related to higher brain concentrations of microglia-derived QA, as was recently reported in subjects with MDD (Steiner et al, 2008(Steiner et al, , 2011. Conversely, psychiatric medication may increase the synthesis of the potentially neuroprotective compound, KA, and/or decrease the synthesis of 3HK.…”

Section: Discussionsupporting

confidence: 53%

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

Savitz

Drevets

Smith

et al. 2014

Neuropsychopharmacol

201

139

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Inflammation-related changes in the concentrations of kynurenine pathway metabolites occur in depression secondary to medical conditions but are not firmly established in primary mood disorders. Reductions in hippocampal and amygdalar volume that putatively reflect dendritic atrophy are widely reported in major depressive disorder (MDD). Here we tested whether the relative serum concentrations of putatively neuroprotective (kynurenic acid (KA)) and neurotoxic (3-hydroxykynurenine (3HK) and quinolinic acid (QA)) kynurenine pathway metabolites were altered in primary MDD and whether these metabolites were associated with hippocampal and amygdalar volume. A total of 29 moderately to severely depressed unmedicated subjects who met DSM-IV criteria for MDD and 20 healthy controls (HCs) completed a structural MRI scan and provided blood sample for kynurenine metabolite analysis, performed using high-performance liquid chromatography with tandem mass spectrometry. Cytokine concentrations were measured with ELISA and gray matter volumes were measured with the automated segmentation software, FreeSurfer. An a priori defined variable of interest, the KA/ QA ratio, a putative neuroprotective index, trended lower in the MDD versus the HC group and correlated negatively with anhedonia but positively with the total hippocampal and amygdala volume in the MDD subjects. The post hoc data reduction methods yielded three principal components. Component 1 (interleukin-1 receptor antagonist, QA, and kynurenine) was significantly elevated in MDD participants versus the HCs, whereas component 2 (KA, tryptophan, and kynurenine) was positively correlated with hippocampal and amygdala volume within the MDD group. Our results raise the possibility that an immune-related imbalance in the relative metabolism of KA and QA predisposes to depression-associated dendritic atrophy and anhedonia.

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Section: Discussionsupporting

confidence: 53%

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

Savitz

Drevets

Smith

et al. 2014

Neuropsychopharmacol

201

139

View full text Add to dashboard Cite

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“…Steiner et al. (2008) demonstrated that the density of human leukocyte antigen‐DR‐immunoreactive microglia in the prefrontal cortex, anterior cingulate cortex, and mediodorsal thalamus was elevated in patients with major depression who committed suicide, while the microglial density was not increased in depressed patients who did not commit suicide. Steiner et al.…”

Section: Discussionmentioning

confidence: 99%

Gunn rats with glial activation in the hippocampus show prolonged immobility time in the forced swimming test and tail suspension test

et al. 2018

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IntroductionRecent studies imply that glial activation plays a role in the pathogenesis of psychiatric disorders, such as schizophrenia and major depression. We previously demonstrated that Gunn rats with hyperbilirubinemia show congenital gliosis and schizophrenia‐like behavior.MethodsAs it has been suggested that major depression involves glial activation associated with neuroinflammation, we examined whether Gunn rats show depression‐like behavior using the forced swimming test (FST) and the tail suspension test (TST). In addition, we quantitatively evaluated both microgliosis and astrogliosis in the hippocampus of Gunn rats using immunohistochemistry analysis of the microglial marker ionized calcium‐binding adaptor molecule (Iba) 1 and the astrocytic marker S100B.ResultsBoth the FST and TST showed that immobility time of Gunn rats was significantly longer than that of normal control Wistar rats, indicating that Gunn rats are somewhat helpless, a sign of depression‐like behavior. In the quantification of immunohistochemical analysis, Iba1immunoreactivity in the dentate gyrus (DG), cornu ammonis (CA) 1, and CA3 and the number of Iba1‐positive cells in the CA1 and CA3 were significantly increased in Gunn rats compared to Wistar rats. S100B immunoreactivity in the DG, CA1, and CA3 and the number of S100B‐positive cells in the DG and CA3 were significantly increased in Gunn rats compared to Wistar rats.ConclusionOur findings suggest that both microglia and astrocyte are activated in Gunn rats and their learned helplessness could be related to glial activation.

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“…Activated M1 microglia produce prostaglandins, chemokines, cytokines, complement proteins, proteinases, reactive oxygen species, and reactive nitrogen species, the sustained production of which can have a deleterious effect on susceptible cell populations by enhancing oxidative stress and activating cell death pathways through stimulation of kinases and caspase cascades [43]. Postmortem evidence is growing: brain microglial activation has been suggested in postmortem and positron emission tomography studies using (R)-[11C]PK11195, a ligand that recognizes the translocator protein [44][45][46][47]. Other postmortem studies have found increased numbers and structural degenerative impairments of human leukocyte antigen-antigen D related+ microglia in schizophrenia [48][49][50].…”

Section: Discussionmentioning

confidence: 99%

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

et al. 2016

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Alterations in the innate inflammatory response may underlie the pathophysiology of psychiatric diseases. Current antipsychotics modulate pro-/anti-inflammatory pathways, but their specific actions on these pathways remain only partly explored. This study was conducted to elucidate the regulatory role of paliperidone (1 mg/kg i.p.) on acute (6 h) and chronic (6 h/day for 21 consecutive days) restraint stressinduced alterations in 2 emerging endogenous anti-inflammatory/antioxidant mechanisms: nuclear factor erythroid-related factor 2 (NRF2)/antioxidant enzymes pathway, and the cytokine milieu regulating M1/M2 polarization in microglia, analyzed at the mRNA and protein levels in prefrontal cortex samples. In acute stress conditions, paliperidone enhanced NRF2 levels, possibly related to phosphoinositide 3-kinase upregulation and reduced kelch-Like ECH-associated protein 1 expression. In chronic conditions, paliperidone tended to normalize NRF2 levels through a phosphoinositide 3-kinase related-mechanism, with no effects on kelch-Like ECH-associated protein 1. Antioxidant response element-dependent antioxidant enzymes were upregulated by paliperidone in acute stress, while in chronic stress, paliperidone tended to prevent stress-induced downregulation of the endogenous antioxidant machinery. However, paliperidone increased transforming growth factor-β and interleukin-10 in favor of an M2 microglia profile in acute stress conditions, which was also corroborated by paliperidone-induced increased levels of the M2 cellular markers arginase I and folate receptor 2. This latter effect was also produced in chronic conditions. Immunofluorescence studies suggested an increase in the number of microglial cells expressing arginase I and folate receptor 2 in the stressed animals pretreated with paliperidone. In conclusion, the enhancement of endogenous antioxidant/anti-inflammatory pathways by current and new antipsychotics could represent an interesting therapeutic strategy for the future.

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Immunological aspects in the neurobiology of suicide: Elevated microglial density in schizophrenia and depression is associated with suicide

Cited by 682 publications

References 37 publications

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

Gunn rats with glial activation in the hippocampus show prolonged immobility time in the forced swimming test and tail suspension test

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

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