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Chronic Inflammation and Resulting Neuroprogression in Major Depression

  • Brian E. LeonardEmail author
Chapter

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.

Keywords

Neuroinflammation Cytokines Depression Tryptophan-kynurenine pathway Neurodegeneration Dementia 

Notes

Conflict of Interest

None.

References

  1. 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.CrossRefGoogle Scholar
  2. 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.CrossRefGoogle Scholar
  3. 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.CrossRefGoogle Scholar
  4. Gal EM, Sherman AD. L-kynurenine and its synthesis and possible regulating function in the brain. Neurochem Res. 1980;5:223–39.CrossRefGoogle Scholar
  5. Geerlings MT, Schoevers RA, Beckman AT. Depression and risk of cognitive decline in Alzheimer’s disease. Br J Psychiatry. 2000;176:568–75.CrossRefGoogle Scholar
  6. 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.CrossRefGoogle Scholar
  7. Guillemin GT, Brew BT. Implications of the kynurenine pathway and quinlinic acid in Alzheimer’s disease. Redox Rep. 2002;7:199–206.CrossRefGoogle Scholar
  8. 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.CrossRefGoogle Scholar
  9. 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.CrossRefGoogle Scholar
  10. Jorm AF. History of depression as a risk factor for dementia: an update. Aust N Z J Psychiatry. 2001;35:776–81.CrossRefGoogle Scholar
  11. Lapin IP, Oxenkrug GF. Intensification of the central serotonergic processes as a possible determinant of the thymoleptic effect. Lancet. 1969;1:132–16.CrossRefGoogle Scholar
  12. Lapin IP. Kynurenines as a possible participant of depression. Pharmacopsychiat. Neuropharmacol. 1973;6:273–279.Google Scholar
  13. Lapin IP. Neurokynurenines (NEKY) as common neurochemical links of stress and anxiety. Adv ERxp Med Biol. 2003;527:121–125.Google Scholar
  14. 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.PubMedPubMedCentralGoogle Scholar
  15. Leonard BE. Changes in the immune system an depression and dementia. Int J Dev Neurosci. 2001;19:305–21.CrossRefGoogle Scholar
  16. Leonard BE. Inflammation and depression: is there a causal connection with dementia? Neurotox Res. 2006;10:149–60.CrossRefGoogle Scholar
  17. Leonard BE. The concept of depression as a dysfunction of the immune system. Mod Trends Pharmacopsychiat. 2010;27:52–71.Google Scholar
  18. Leonard BE. Inflammation as a cause of the metabolic syndrome in depression. Mod Trends Pharmacopsychiatry. 2013;28:117–26.CrossRefGoogle Scholar
  19. Leonard BE. Inflammation and depression: a causal or coincidental link to pathophysiology? Acta Neuropsychiatr. 2017;23:1–16.Google Scholar
  20. Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry. 1995;19:305–12.CrossRefGoogle Scholar
  21. 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.PubMedGoogle Scholar
  22. Merete C, Falcon LM, Tucker KL. Vitamin B6 is associated with depressive symptomatology in Massachusetts elders. J Am Coll Nutr. 2008;27:421–7.CrossRefGoogle Scholar
  23. Myint A-M, Kim Y-K. Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Med. Hypotheses. 2003;61:519–25.CrossRefGoogle Scholar
  24. Myint A-M, Kim Y-K. Network beyond IDO in psychiatric disorders: revisiting the neurodegeneration hypothesis. Prog Neuropsyhopharmac Biol Psychiatry. 2014;48:304–13.CrossRefGoogle Scholar
  25. 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.CrossRefGoogle Scholar
  26. Norbert M, Aye-Mu M, Markus JS. Immunology and psychiatry: from basic research to therapeutic interventions. Curr Top Neurotox. 2015;8:229–42.CrossRefGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. Oxenkrug GF. Insulin resistance and dysregulation of the tryptophan-kynurenine –NAD pathway. Mol Neurobiol. 2013;48:294–301.CrossRefGoogle Scholar
  29. Peters A, Schweiger U, Pelleren L, et al. The selfish brain: competitor for energy. Neurosci Biobehav Rev. 2004;48:143–80.CrossRefGoogle Scholar
  30. 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.CrossRefGoogle Scholar
  31. 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.CrossRefGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. Schwarz M, Schechter R. Systemic inflammatory cells fight of neurodegenerative diseases. Nat Rev Neurobiol. 2010;6:405–10.CrossRefGoogle Scholar
  34. Seline YI. Neuroimaging studies of mood disorder: effects on the brain. Biol Psychiatry. 2002;54:338–52.CrossRefGoogle Scholar
  35. Smith RS. The macrophage theory of depression. Med Hypotheses. 1991;35:298–306.CrossRefGoogle Scholar
  36. Stone TW. Neuropharmacology of quinolinic acid and kynurenic acid. Pharmacol Rev. 1993;45:310–06.Google Scholar
  37. 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.CrossRefGoogle Scholar
  38. Xanthos DN, Sandkuehler J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci. 2014;15:43–53.CrossRefGoogle Scholar
  39. Yirmiya R, Goshen I. Immune modulation of learning, memory, neuroplasticity and neurogenesis. Brain Behav Immun. 2011;25:181–213.CrossRefGoogle Scholar
  40. Zhao Z. Insulin receptor deficits in schizophrenia and in cellular and animal models of the insulin receptor dysfunction. Schizophr Res. 2006;84:1–14.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.National University of IrelandGalwayIreland

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