title: Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways.
abstract: Emerging evidence suggests a complex interplay between the endocannabinoid system, omega-3 fatty acids and the immune system in the promotion of brain self-repair. However, it is unknown if all omega-3 fatty acids elicit similar effects on adult neurogenesis and if such effects are mediated or regulated by interactions with the endocannabinoid system. This study investigated the effects of DHA and EPA on neural stem cell (NSC) fate and the role of the endocannabinoid signalling pathways in these effects. EPA, but not DHA, significantly increased proliferation of NSCs compared to controls, an effect associated with enhanced levels of the endocannabinoid 2-arachidonylglycerol (2-AG) and p-p38 MAPK, effects attenuated by pre-treatment with CB1 (AM251) or CB2 (AM630) receptor antagonists. Furthermore, in NSCs derived from IL-1β deficient mice, EPA significantly decreased proliferation and p-p38 MAPK levels compared to controls, suggesting a key role for IL-1β signalling in the effects observed. Although DHA similarly increased 2-AG levels in wild-type NSCs, there was no concomitant increase in proliferation or p-p38 MAPK activity. In addition, in NSCs from IL-1β deficient mice, DHA significantly increased proliferation without effects on p-P38 MAPK, suggesting effects of DHA are mediated via alternative signalling pathways. These results provide crucial new insights into the divergent effects of EPA and DHA in regulating NSC proliferation and the pathways involved, and highlight the therapeutic potential of their interplay with endocannabinoid signalling in brain repair.
authors.affiliation: Department of Life Sciences, University of Roehampton, Whitelands College, London, UK; Faculty of Health and Social Sciences, Bournemouth University, Dorset, UK. Electronic address: sdyall@bournemouth.ac.uk.
authors.forename: S C
authors.initials: SC
authors.lastname: Dyall
authors.affiliation: Department of Life Sciences, University of Roehampton, Whitelands College, London, UK.
authors.forename: H K
authors.initials: HK
authors.lastname: Mandhair
authors.affiliation: Department of Life Sciences, University of Roehampton, Whitelands College, London, UK.
authors.forename: R E A
authors.initials: REA
authors.lastname: Fincham
authors.affiliation: Physiology, School of Medicine, National University of Ireland, Galway, Ireland; Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland; NCBES Centre for Pain Research and Neuroscience Centre, National University of Ireland, Galway, Ireland.
authors.forename: D M
authors.initials: DM
authors.lastname: Kerr
authors.affiliation: Physiology, School of Medicine, National University of Ireland, Galway, Ireland; NCBES Centre for Pain Research and Neuroscience Centre, National University of Ireland, Galway, Ireland.
authors.forename: M
authors.initials: M
authors.lastname: Roche
authors.affiliation: Department of Life Sciences, University of Roehampton, Whitelands College, London, UK.
authors.forename: F
authors.initials: F
authors.lastname: Molina-Holgado
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D063388:Endocannabinoids / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D063388:Endocannabinoids; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid
keywords: CB1 cannabinoid receptor; CB2 cannabinoid receptor; Docosahexaenoic acid; Eicosapentaenoic acid; Endocannabinoids; Neurogenesis