Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways

Abstract

Running title: EPA, but not DHA induces proliferation in NSCs Abbreviations: AA, Arachidonic acid, AEA, anandamide, DHA. Docosahexaenoic acid; EPA, eicosapentaenoic acid, 2-AG, 2-arachidonylglycerol 2 Title: Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways 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-1 deficient mice, EPA significantly decreased proliferation and p-p38 MAPK levels compared to controls, suggesting a key role for IL-1 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-1 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.

A moderate diet restriction during pregnancy alters the levels of endocannabinoids and endocannabinoid-related lipids in the hypothalamus, hippocampus and olfactory bulb of rat offspring in a sex-specific manner

“…On the other hand, it is possible that some brain structures were protected from the effects of a moderate caloric restriction implemented only during pregnancy by the preferential uptake of the fetal tissues of specific LC-PUFAs, such as AA or n-3 PUFAs. It is interesting to note here that the n-3 PUFAs can affect the levels of endocannabinoids by decreasing their levels by competing for the metabolic enzymes [70, 84], or by increasing their levels depending on different circumstances [78, 85]. Additionally, the presence of sexual dimorphism mainly associated to the alterations found in olfactory bulb and the PEA levels in all the brain regions of females, suggest that the maternal calorie-restriction might have affected the male and female offspring through different mechanisms.…”

Interplay Between n‐3 and n‐6 Long‐Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair

“…These alterations suggest competition for shared biosynthetic pathways as DHA and EPA displace ARA from membrane phospholipids. Interestingly, recent work in our laboratory found that acute administration of DHA or EPA significantly increased 2-AG, although not AEA levels in neural stem cells [73]. This increase may be driven by competition for the inactivating enzymes, such as COX-2, although further work is needed to fully elucidate the underlying mechanisms.…”

“…DHA and EPA treatment has consistently been shown to increase adult hippocampal neurogenesis across a range of animal models [134], also in neural stem cells, where DHA appears to promote neuronal differentiation [73]. Similarly, the endocannabinoid system is essential for adult neurogenesis in both the hippocampus [135, 136] and SVZ [137], although studies into the pro-neurogeneic effects of endocannabinoids in the dentate gyrus have produced conflicting results.…”

“…Work in our laboratory is the first to explore the role of the endocannabinoid system in the pro-neurogeneic effects of DHA and EPA [73]. In this study, addition of DHA or EPA to neural stem cells induces opposing effects on cell fate, which are directed by different signalling pathways.…”

Clearing the fog: a review of the effects of dietary omega-3 fatty acids and added sugars on chemotherapy-induced cognitive deficits

“…Researchers reported that activation of nuclear receptors for which n-3 FAs are ligands (e.g., peroxisome proliferator-activated receptor alpha [PPARα]) protected mice from a reduction in AHN induced by whole-brain irradiation [48]. Additionally, evidence from cell culture studies suggests that EPA and DHA have distinct effects on neural stem cells; EPA seems to induce neural stem cell proliferation via direct effects on endocannabinoid pathways [49]. …”