Abstract
Chronic neuroinflammation has a major impact on brain structure and function and has recently been implicated as a causative factor in major psychiatric and neurodegenerative disorders.
Of the different types of proinflammatory mediators which have been identified as a consequence of the activation of the immune system, the cytokines play a crucial role.
The multiple effects of chronic low-grade inflammation initiated by chronic stress and major psychiatric disorders such as depression and schizophrenia on the integrity of the brain’s neural network have been attributed to the neurotoxicity of the proinflammatory cytokines, to the modulation of the biogenic amine neurotransmitters and to the activation of the neurotoxic arm of the tryptophan-kynurenine pathway. In major depression the activation of this pathway by proinflammatory cytokines and glucocorticoids results in the synthesis of the glutamatergic agonist quinolinic acid and neurotoxic kynurenines. These compounds affect the integrity of the neural networks which contribute to neurodegeneration. In addition, the intermediary metabolism of brain glucose is adversely affected as a result of the inflammation-induced dysfunction of insulin.
These changes form a basis for neurodegeneration which, in the middle aged and elderly, could be the prelude for dementia.
Parts of the chapter were previously published in Immunology and Psychiatry; Current Topics in Neurotoxicity, volume 8, pp 229–242, Springer, 2015.
Similar content being viewed by others
References
Almeida OP, Marsh K, Alfonso H, et al. B vitamins reduce the long-term risk of depression after stroke: the VITATOPS-DEP trial. Ann Neurol. 2010;68:503–10.
Altamura AC, Pozzoli S, Fiorentin A, Dell’osso B. Neurodevelopmental and inflammatory patterns in schizophrenia in relation to pathophysiology. Prog Neuropsychopharmac Biol Psychiatry. 2013;42:63–70.
Bernstein HG, Ernsy T, Lendeckel U, et al. Reduced neuronal expression of insulin-degrading enzyme in the dorsolateral prefrontal cortex in patients with haloperidol treated chronic schizophrenia. J Psychiatry Res. 2009;43:1095–105.
Gal EM, Sherman AD. L-kynurenine and its synthesis and possible regulating function in the brain. Neurochem Res. 1980;5:223–39.
Geerlings MT, Schoevers RA, Beckman AT. Depression and risk of cognitive decline in Alzheimer’s disease. Br J Psychiatry. 2000;176:568–75.
Green RC, Cupples LA, Kurz A, et al. Depression as a risk factor for Alzheimer’s disease: the MIRAGE study. Arch Neurol. 2003;60:53–9.
Guillemin GT, Brew BT. Implications of the kynurenine pathway and quinlinic acid in Alzheimer’s disease. Redox Rep. 2002;7:199–206.
Han Q, Tao DA, Li J. Structure, expression and function of kynurenine aminotransferase in human and rodent brain. Cell Molec Life Sci. 2010;67:353.
Harrison NA, Doeller CF, Voon V, et al. Peripheral inflammation acutely impairs human spatial memory via actions on medial temporal lobe glucose metabolism. Biol Psychiatry. 2014;76(7):585–93.
Jorm AF. History of depression as a risk factor for dementia: an update. Aust N Z J Psychiatry. 2001;35:776–81.
Lapin IP, Oxenkrug GF. Intensification of the central serotonergic processes as a possible determinant of the thymoleptic effect. Lancet. 1969;1:132–16.
Lapin IP. Kynurenines as a possible participant of depression. Pharmacopsychiat. Neuropharmacol. 1973;6:273–279.
Lapin IP. Neurokynurenines (NEKY) as common neurochemical links of stress and anxiety. Adv ERxp Med Biol. 2003;527:121–125.
Lee S, Tong M, Hang S. CSF and brain indices of insulin resistance, oxidative stress and neurodegeneration in early and late Alzheimer’s disease. J Alzheimers Dis Parkinsonism. 2013;3:128–35.
Leonard BE. Changes in the immune system an depression and dementia. Int J Dev Neurosci. 2001;19:305–21.
Leonard BE. Inflammation and depression: is there a causal connection with dementia? Neurotox Res. 2006;10:149–60.
Leonard BE. The concept of depression as a dysfunction of the immune system. Mod Trends Pharmacopsychiat. 2010;27:52–71.
Leonard BE. Inflammation as a cause of the metabolic syndrome in depression. Mod Trends Pharmacopsychiatry. 2013;28:117–26.
Leonard BE. Inflammation and depression: a causal or coincidental link to pathophysiology? Acta Neuropsychiatr. 2017;23:1–16.
Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry. 1995;19:305–12.
McIntyre RS, Rosenbluth M, Ramasulbu R, et al. Managing medical and psychiatric morbidity in individuals with major depression and bipolar disorder. Ann Clin Psychiatry. 2012;24:163–9.
Merete C, Falcon LM, Tucker KL. Vitamin B6 is associated with depressive symptomatology in Massachusetts elders. J Am Coll Nutr. 2008;27:421–7.
Myint A-M, Kim Y-K. Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Med. Hypotheses. 2003;61:519–25.
Myint A-M, Kim Y-K. Network beyond IDO in psychiatric disorders: revisiting the neurodegeneration hypothesis. Prog Neuropsyhopharmac Biol Psychiatry. 2014;48:304–13.
Nanri A, Pham WM, Kurotani K, et al. Serum pyridoxal concentrations in depressive symptoms among Japanese adults: results of a prospective study. Eur JClin Nutr. 2013;67:1060–5.
Norbert M, Aye-Mu M, Markus JS. Immunology and psychiatry: from basic research to therapeutic interventions. Curr Top Neurotox. 2015;8:229–42.
Oxenkrug GF. Interferon gamma inducible kynurenine/pteridine in inflammation cascade: implication for ageing associated psychiatric and medical disorders. J Neural Transm. 2011;118:75–85.
Oxenkrug GF. Insulin resistance and dysregulation of the tryptophan-kynurenine –NAD pathway. Mol Neurobiol. 2013;48:294–301.
Peters A, Schweiger U, Pelleren L, et al. The selfish brain: competitor for energy. Neurosci Biobehav Rev. 2004;48:143–80.
Rapp MA, Schneider-Beeri M, Grossman HT, et al. Increased hippocampal plaques and tangles in patients with Alzheimer’s disease with a life-long history of major depression. Arch Gen Psychiatry. 2006;63:161–7.
Sanchez-Villegas A, Poreste J, Schlatter J, et al. Association between folate, vitamin B6 and vitamin B12 intake in depressives in the SUN cohort study. J Hum Nutr Diet. 2009;22:122–33.
Sas K, Robotka H, Toldie J, Veccei L. Mitochondrial metabolic disturbances, oxidative stress and the kynurenine system with a focus on neurodegenerative disorders. J Neurol Sci. 2009;257:221–39.
Schwarz M, Schechter R. Systemic inflammatory cells fight of neurodegenerative diseases. Nat Rev Neurobiol. 2010;6:405–10.
Seline YI. Neuroimaging studies of mood disorder: effects on the brain. Biol Psychiatry. 2002;54:338–52.
Smith RS. The macrophage theory of depression. Med Hypotheses. 1991;35:298–306.
Stone TW. Neuropharmacology of quinolinic acid and kynurenic acid. Pharmacol Rev. 1993;45:310–06.
Sun K, Steffens DC, Au R, et al. Amyloid associated depression: a prodromal depression of Alzheimer’s disease? Arch Gen Psychiatry. 2008;65:542–50.
Xanthos DN, Sandkuehler J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci. 2014;15:43–53.
Yirmiya R, Goshen I. Immune modulation of learning, memory, neuroplasticity and neurogenesis. Brain Behav Immun. 2011;25:181–213.
Zhao Z. Insulin receptor deficits in schizophrenia and in cellular and animal models of the insulin receptor dysfunction. Schizophr Res. 2006;84:1–14.
Conflict of Interest
None.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Leonard, B.E. (2018). Chronic Inflammation and Resulting Neuroprogression in Major Depression. In: Kim, YK. (eds) Understanding Depression . Springer, Singapore. https://doi.org/10.1007/978-981-10-6580-4_16
Download citation
DOI: https://doi.org/10.1007/978-981-10-6580-4_16
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-10-6579-8
Online ISBN: 978-981-10-6580-4
eBook Packages: MedicineMedicine (R0)