Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2018

Open Access 01-12-2018 | Research

Intracellular inflammatory and antioxidant pathways in postmortem frontal cortex of subjects with major depression: effect of antidepressants

Authors: David Martín-Hernández, Javier R. Caso, J. Javier Meana, Luis F. Callado, José L. M. Madrigal, Borja García-Bueno, Juan C. Leza

Published in: Journal of Neuroinflammation | Issue 1/2018

Login to get access

Abstract

Background

Studies show that Toll-like receptors (TLRs), members of the innate immune system, might participate in the pathogenesis of the major depressive disorder (MDD). However, evidence of this participation in the brain of patients with MDD has been elusive.

Methods

This work explores whether the protein expression by immunodetection assays (Western blot) of elements of TLR-4 pathways controlling inflammation and the oxidative/nitrosative stress are altered in postmortem dorsolateral prefrontal cortex of subjects with MDD. The potential modulation induced by the antidepressant treatment on these parameters was also assessed. Thirty MDD subjects (15 antidepressant-free and 15 under antidepressant treatment) were matched for gender and age to 30 controls in a paired design.

Results

No significant changes in TLR-4 expression were detected. An increased expression of the TLR-4 endogenous ligand Hsp70 (+ 33%), but not of Hsp60, and the activated forms of mitogen-activated protein kinases (MAPKs) p38 (+ 47%) and JNK (+ 56%) was observed in MDD. Concomitantly, MDD subjects present a 45% decreased expression of DUSP2 (a regulator of MAPKs) and reduced (− 21%) expression of the antioxidant nuclear factor Nrf2. Antidepressant treatment did not modify the changes detected in the group with MDD and actually increased (+ 25%) the expression of p11, a protein linked with the transport of neurotransmitters and depression.

Conclusion

Data indicate an altered TLR-4 immune response in the brain of subjects with MDD. Additional research focused on the mechanisms contributing to the antidepressant-induced TLR-4 pathway modulation is warranted and could help to develop new treatment strategies for MDD.
Appendix
Available only for authorised users
Literature
1.
Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56.CrossRefPubMedPubMedCentral
2.
Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology. 2012;37:137–62.CrossRefPubMed
3.
Morris AA, Zhao L, Ahmed Y, Stoyanova N, De Staercke C, Hooper WC, Gibbons G, Din-Dzietham R, Quyyumi A, Vaccarino V. Association between depression and inflammation--differences by race and sex: the META-Health study. Psychosom Med. 2011;73:462–8.CrossRefPubMedPubMedCentral
4.
Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67:446–57.CrossRefPubMed
5.
Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimaki M. Cumulative meta-analysis of interleukins 6 and 1beta, tumour necrosis factor alpha and C-reactive protein in patients with major depressive disorder. Brain Behav Immun. 2015;49:206–15.CrossRefPubMedPubMedCentral
6.
Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24–31.CrossRefPubMed
7.
Udina M, Hidalgo D, Navines R, Forns X, Sola R, Farre M, Capuron L, Vieta E, Martin-Santos R. Prophylactic antidepressant treatment of interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis. J Clin Psychiatry. 2014;75:e1113–21.CrossRefPubMed
8.
Engler H, Brendt P, Wischermann J, Wegner A, Rohling R, Schoemberg T, Meyer U, Gold R, Peters J, Benson S, Schedlowski M. Selective increase of cerebrospinal fluid IL-6 during experimental systemic inflammation in humans: association with depressive symptoms. Mol Psychiatry. 2017;22:1448–54.CrossRefPubMed
9.
Strawbridge R, Arnone D, Danese A, Papadopoulos A, Herane Vives A, Cleare AJ. Inflammation and clinical response to treatment in depression: a meta-analysis. Eur Neuropsychopharmacol. 2015;25:1532–43.CrossRefPubMed
10.
Garcia-Bueno B, Caso JR, Madrigal JL, Leza JC. Innate immune receptor Toll-like receptor 4 signalling in neuropsychiatric diseases. Neurosci Biobehav Rev. 2016;64:134–47.CrossRefPubMed
11.
12.
Crack PJ, Bray PJ. Toll-like receptors in the brain and their potential roles in neuropathology. Immunol Cell Biol. 2007;85:476–80.CrossRefPubMed
13.
Garate I, Garcia-Bueno B, Madrigal JL, Caso JR, Alou L, Gomez-Lus ML, Mico JA, Leza JC. Stress-induced neuroinflammation: role of the Toll-like receptor-4 pathway. Biol Psychiatry. 2013;73:32–43.CrossRefPubMed
14.
Hanke ML, Kielian T. Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci (Lond). 2011;121:367–87.CrossRef
15.
16.
17.
Guha M, Mackman N. LPS induction of gene expression in human monocytes. Cell Signal. 2001;13:85–94.CrossRefPubMed
18.
Dean B, Tawadros N, Scarr E, Gibbons AS. Regionally-specific changes in levels of tumour necrosis factor in the dorsolateral prefrontal cortex obtained postmortem from subjects with major depressive disorder. J Affect Disord. 2010;120:245–8.CrossRefPubMed
19.
Shelton RC, Claiborne J, Sidoryk-Wegrzynowicz M, Reddy R, Aschner M, Lewis DA, Mirnics K. Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Mol Psychiatry. 2011;16:751–62.CrossRefPubMed
20.
Thomas AJ, Ferrier IN, Kalaria RN, Woodward SA, Ballard C, Oakley A, Perry RH, O'Brien JT. Elevation in late-life depression of intercellular adhesion molecule-1 expression in the dorsolateral prefrontal cortex. Am J Psychiatry. 2000;157:1682–4.CrossRefPubMed
21.
Torres-Platas SG, Cruceanu C, Chen GG, Turecki G, Mechawar N. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav Immun. 2014;42:50–9.CrossRefPubMed
22.
Steiner J, Walter M, Gos T, Guillemin GJ, Bernstein HG, Sarnyai Z, Mawrin C, Brisch R, Bielau H, Meyer zu Schwabedissen L, et al. Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J Neuroinflammation. 2011;8:94.CrossRefPubMedPubMedCentral
23.
Busse M, Busse S, Myint AM, Gos T, Dobrowolny H, Muller UJ, Bogerts B, Bernstein HG, Steiner J. Decreased quinolinic acid in the hippocampus of depressive patients: evidence for local anti-inflammatory and neuroprotective responses? Eur Arch Psychiatry Clin Neurosci. 2015;265:321–9.CrossRefPubMed
24.
Torres-Platas SG, Hercher C, Davoli MA, Maussion G, Labonte B, Turecki G, Mechawar N. Astrocytic hypertrophy in anterior cingulate white matter of depressed suicides. Neuropsychopharmacology. 2011;36:2650–8.CrossRefPubMedPubMedCentral
25.
Mahajan GJ, Vallender EJ, Garrett MR, Challagundla L, Overholser JC, Jurjus G, Dieter L, Syed M, Romero DG, Benghuzzi H, Stockmeier CA. Altered neuro-inflammatory gene expression in hippocampus in major depressive disorder. Prog Neuro-Psychopharmacol Biol Psychiatry. 2018;82:177–86.CrossRef
26.
Garate I, Garcia-Bueno B, Madrigal JL, Bravo L, Berrocoso E, Caso JR, Mico JA, Leza JC. Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression. J Neuroinflammation. 2011;8:151.CrossRefPubMedPubMedCentral
27.
García-Bueno B, Gassó P, MacDowell KS, Callado LF, Mas S, Bernardo M, Lafuente A, Meana JJ, Leza JC. Evidence of activation of Toll-like receptor-4 proinflammatory pathway in schizophrenia. J Psychiatry Neurosci. 2016;41:E46–55.CrossRefPubMedPubMedCentral
28.
Garcia-Fuster MJ, Diez-Alarcia R, Ferrer-Alcon M, La Harpe R, Meana JJ, Garcia-Sevilla JA. FADD adaptor and PEA-15/ERK1/2 partners in major depression and schizophrenia postmortem brains: basal contents and effects of psychotropic treatments. Neuroscience. 2014;277:541–51.CrossRefPubMed
29.
Mitchell S, Vargas J, Hoffmann A. Signaling via the NFkappaB system. Wiley Interdiscip Rev Syst Biol Med. 2016;8:227–41.CrossRefPubMed
30.
Lauridsen JK, Olesen RH, Vendelbo J, Hyde TM, Kleinman JE, Bibby BM, Brock B, Rungby J, Larsen A. High BMI levels associate with reduced mRNA expression of IL10 and increased mRNA expression of iNOS (NOS2) in human frontal cortex. Transl Psychiatry. 2017;7:e1044.CrossRefPubMedPubMedCentral
31.
Chou CT, He S, Jan CR. Paroxetine-induced apoptosis in human osteosarcoma cells: activation of p38 MAP kinase and caspase-3 pathways without involvement of [Ca2+]i elevation. Toxicol Appl Pharmacol. 2007;218:265–73.CrossRefPubMed
32.
Cui J, Yang K, Yu X, Wang JL, Li J, Zhang Y, Li H. Chronic fluoxetine treatment upregulates the activity of the ERK1/2-NF-kappaB signaling pathway in the hippocampus and prefrontal cortex of rats exposed to forced-swimming stress. Med Princ Pract. 2016;25:539–47.CrossRefPubMedPubMedCentral
33.
Lopez JP, Fiori LM, Cruceanu C, Lin R, Labonte B, Cates HM, Heller EA, Vialou V, Ku SM, Gerald C, et al. MicroRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes. Nat Commun. 2017;8:15497.CrossRefPubMedPubMedCentral
34.
Mercier G, Lennon AM, Renouf B, Dessouroux A, Ramauge M, Courtin F, Pierre M. MAP kinase activation by fluoxetine and its relation to gene expression in cultured rat astrocytes. J Mol Neurosci. 2004;24:207–16.CrossRefPubMed
35.
Vargas-Caraveo A, Sayd A, Maus SR, Caso JR, Madrigal JLM, García-Bueno B, Leza JC. Lipopolysaccharide enters the rat brain by a lipoprotein-mediated transport mechanism in physiological conditions. Sci Rep. 2017;7:13113.CrossRefPubMedPubMedCentral
36.
MacDowell KS, Pinacho R, Leza JC, Costa J, Ramos B, Garcia-Bueno B. Differential regulation of the TLR4 signalling pathway in post-mortem prefrontal cortex and cerebellum in chronic schizophrenia: relationship with SP transcription factors. Prog Neuro-Psychopharmacol Biol Psychiatry. 2017;79:481–92.CrossRef
37.
Zheng P, Zeng B, Zhou C, Liu M, Fang Z, Xu X, Zeng L, Chen J, Fan S, Du X, et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry. 2016;21:786–96.CrossRefPubMed
38.
Berk M, Williams LJ, Jacka FN, O'Neil A, Pasco JA, Moylan S, Allen NB, Stuart AL, Hayley AC, Byrne ML, Maes M. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013;11:200.CrossRefPubMedPubMedCentral
39.
Maes M, Kubera M, Leunis JC, Berk M. Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut. J Affect Disord. 2012;141:55–62.CrossRefPubMed
40.
41.
Hung YY, Huang KW, Kang HY, Huang GY, Huang TL. Antidepressants normalize elevated Toll-like receptor profile in major depressive disorder. Psychopharmacology. 2016;233:1707–14.CrossRefPubMed
42.
43.
Bown C, Wang JF, MacQueen G, Young LT. Increased temporal cortex ER stress proteins in depressed subjects who died by suicide. Neuropsychopharmacology. 2000;22:327–32.CrossRefPubMed
44.
45.
Schmitz ML, Bacher S, Kracht M. I kappa B-independent control of NF-kappa B activity by modulatory phosphorylations. Trends Biochem Sci. 2001;26:186–90.CrossRefPubMed
46.
Moron JA, Zakharova I, Ferrer JV, Merrill GA, Hope B, Lafer EM, Lin ZC, Wang JB, Javitch JA, Galli A, Shippenberg TS. Mitogen-activated protein kinase regulates dopamine transporter surface expression and dopamine transport capacity. J Neurosci. 2003;23:8480–8.CrossRefPubMed
47.
Zhu CB, Blakely RD, Hewlett WA. The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology. 2006;31:2121–31.PubMed
48.
Einat H, Manji HK. Cellular plasticity cascades: genes-to-behavior pathways in animal models of bipolar disorder. Biol Psychiatry. 2006;59:1160–71.CrossRefPubMed
49.
Shiflett MW, Balleine BW. Contributions of ERK signaling in the striatum to instrumental learning and performance. Behav Brain Res. 2011;218:240–7.CrossRefPubMed
50.
Gourley SL, Wu FJ, Kiraly DD, Ploski JE, Kedves AT, Duman RS, Taylor JR. Regionally specific regulation of ERK MAP kinase in a model of antidepressant-sensitive chronic depression. Biol Psychiatry. 2008;63:353–9.CrossRefPubMed
51.
Dwivedi Y, Rizavi HS, Roberts RC, Conley RC, Tamminga CA, Pandey GN. Reduced activation and expression of ERK1/2 MAP kinase in the post-mortem brain of depressed suicide subjects. J Neurochem. 2001;77:916–28.CrossRefPubMed
52.
Galeotti N, Ghelardini C. Regionally selective activation and differential regulation of ERK, JNK and p38 MAP kinase signalling pathway by protein kinase C in mood modulation. Int J Neuropsychopharmacol. 2012;15:781–93.CrossRefPubMed
53.
54.
Morioka N, Suekama K, Zhang FF, Kajitani N, Hisaoka-Nakashima K, Takebayashi M, Nakata Y. Amitriptyline up-regulates connexin43-gap junction in rat cultured cortical astrocytes via activation of the p38 and c-Fos/AP-1 signalling pathway. Br J Pharmacol. 2014;171:2854–67.CrossRefPubMedPubMedCentral
55.
Patterson KI, Brummer T, O'Brien PM, Daly RJ. Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem J. 2009;418:475–89.CrossRefPubMed
56.
Jeffrey KL, Brummer T, Rolph MS, Liu SM, Callejas NA, Grumont RJ, Gillieron C, Mackay F, Grey S, Camps M, et al. Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nat Immunol. 2006;7:274–83.CrossRefPubMed
57.
Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 2009;284:13291–5.CrossRefPubMedPubMedCentral
58.
Martin-de-Saavedra MD, Budni J, Cunha MP, Gomez-Rangel V, Lorrio S, Del Barrio L, Lastres-Becker I, Parada E, Tordera RM, Rodrigues AL, et al. Nrf2 participates in depressive disorders through an anti-inflammatory mechanism. Psychoneuroendocrinology. 2013;38:2010–22.CrossRefPubMed
59.
Martin-Hernandez D, Bris AG, MacDowell KS, Garcia-Bueno B, Madrigal JL, Leza JC, Caso JR. Modulation of the antioxidant nuclear factor (erythroid 2-derived)-like 2 pathway by antidepressants in rats. Neuropharmacology. 2016;103:79–91.CrossRefPubMed
60.
Bouvier E, Brouillard F, Molet J, Claverie D, Cabungcal JH, Cresto N, Doligez N, Rivat C, Do KQ, Bernard C, et al. Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression. Mol Psychiatry. 2017;22:1701–13.CrossRefPubMed
61.
Maes M, Fisar Z, Medina M, Scapagnini G, Nowak G, Berk M. New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates--Nrf2 activators and GSK-3 inhibitors. Inflammopharmacology. 2012;20:127–50.CrossRefPubMed
62.
Leonard B, Maes M. Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev. 2012;36:764–85.CrossRefPubMed
63.
Schmidt AJ, Heiser P, Hemmeter UM, Krieg JC, Vedder H. Effects of antidepressants on mRNA levels of antioxidant enzymes in human monocytic U-937 cells. Prog Neuro-Psychopharmacol Biol Psychiatry. 2008;32:1567–73.CrossRef
64.
Swisher JF, Burton N, Bacot SM, Vogel SN, Feldman GM. Annexin A2 tetramer activates human and murine macrophages through TLR4. Blood. 2010;115:549–58.CrossRefPubMedPubMedCentral
65.
Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P. Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc Natl Acad Sci U S A. 2011;108:9262–7.CrossRefPubMedPubMedCentral
66.
Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, Vaugeois JM, Nomikos GG, Greengard P. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science. 2006;311:77–80.CrossRefPubMed
67.
Svenningsson P, Kim Y, Warner-Schmidt J, Oh YS, Greengard P. p11 and its role in depression and therapeutic responses to antidepressants. Nat Rev Neurosci. 2013;14:673–80.CrossRefPubMedPubMedCentral
68.
69.
Steiner J, Bielau H, Brisch R, Danos P, Ullrich O, Mawrin C, Bernstein HG, Bogerts B. Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J Psychiatr Res. 2008;42:151–7.CrossRefPubMed
70.
71.
Deep-Soboslay A, Akil M, Martin CE, Bigelow LB, Herman MM, Hyde TM, Kleinman JE. Reliability of psychiatric diagnosis in postmortem research. Biol Psychiatry. 2005;57:96–101.CrossRefPubMed
Metadata
Title
Intracellular inflammatory and antioxidant pathways in postmortem frontal cortex of subjects with major depression: effect of antidepressants
Authors
David Martín-Hernández
Javier R. Caso
J. Javier Meana
Luis F. Callado
José L. M. Madrigal
Borja García-Bueno
Juan C. Leza
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-018-1294-2

Other articles of this Issue 1/2018

Journal of Neuroinflammation 1/2018 Go to the issue

Research

Activation of melanocortin receptor 4 with RO27-3225 attenuates neuroinflammation through AMPK/JNK/p38 MAPK pathway after intracerebral hemorrhage in mice

Research

Reduced gut microbiome protects from alcohol-induced neuroinflammation and alters intestinal and brain inflammasome expression

Research

Impact of nutrition on inflammation, tauopathy, and behavioral outcomes from chronic traumatic encephalopathy

Case report

Systemic autoinflammation with intractable epilepsy managed with interleukin-1 blockade

Research

Characterization of a Listeria monocytogenes meningitis mouse model

Research

Effects of umbilical cord blood cells, and subtypes, to reduce neuroinflammation following perinatal hypoxic-ischemic brain injury