Rescue of IL-1β-induced Reduction of Human Neurogenesis by omega-3 Fatty Acids and Antidepressants

Brain Behav Immun. 2017 Oct;65:230-238. doi: 10.1016/j.bbi.2017.05.006. Epub 2017 May 18.

Abstract

Both increased inflammation and reduced neurogenesis have been associated with the pathophysiology of major depression. We have previously described how interleukin-1 (IL-1) β, a pro-inflammatory cytokine increased in depressed patients, decreases neurogenesis in human hippocampal progenitor cells. Here, using the same human in vitro model, we show how omega-3 (ω-3) polyunsaturated fatty acids and conventional antidepressants reverse this reduction in neurogenesis, while differentially affecting the kynurenine pathway. We allowed neural cells to proliferate for 3days and further differentiate for 7days in the presence of IL-1β (10ng/ml) and either the selective serotonin reuptake inhibitor sertraline (1µM), the serotonin and norepinephrine reuptake inhibitor venlafaxine (1µM), or the ω-3 fatty acids eicosapentaenoic acid (EPA, 10µM) or docosahexaenoic acid (DHA, 10µM). Co-incubation with each of these compounds reversed the IL-1β-induced reduction in neurogenesis (DCX- and MAP2-positive neurons), indicative of a protective effect. Moreover, EPA and DHA also reversed the IL-1β-induced increase in kynurenine, as well as mRNA levels of indolamine-2,3-dioxygenase (IDO); while DHA and sertraline reverted the IL-1β-induced increase in quinolinic acid and mRNA levels of kynurenine 3-monooxygenase (KMO). Our results show common effects of monoaminergic antidepressants and ω-3 fatty acids on the reduction of neurogenesis caused by IL-1β, but acting through both common and different kynurenine pathway-related mechanisms. Further characterization of their individual properties will be of benefit towards improving a future personalized medicine approach.

Keywords: Cytokines; Fish oil; IL-1 beta; Immune; Kynurenine-pathway; Neurogenic; PUFA; Sertraline; Venlafaxine.

MeSH terms

  • Antidepressive Agents / metabolism
  • Antidepressive Agents / pharmacology*
  • Cell Culture Techniques / methods
  • Cytokines / metabolism
  • Depression / drug therapy
  • Depression / metabolism
  • Depressive Disorder, Major / drug therapy
  • Depressive Disorder, Major / metabolism
  • Docosahexaenoic Acids / pharmacology
  • Eicosapentaenoic Acid / pharmacology
  • Fatty Acids, Omega-3 / metabolism
  • Fatty Acids, Omega-3 / pharmacology*
  • Hippocampus / metabolism
  • Humans
  • Inflammation / metabolism
  • Interleukin-1beta / metabolism
  • Kynurenine / drug effects
  • Kynurenine / metabolism
  • Neurogenesis / drug effects*
  • Neurogenesis / physiology
  • Stem Cells / metabolism

Substances

  • Antidepressive Agents
  • Cytokines
  • Fatty Acids, Omega-3
  • IL1B protein, human
  • Interleukin-1beta
  • Docosahexaenoic Acids
  • Kynurenine
  • Eicosapentaenoic Acid