N-3 polyunsaturated fatty acids promote astrocyte differentiation and neurotrophin production independent of cAMP in patient-derived neural stem cells

Abstract

30Evidence from epidemiological and laboratory studies, as well as randomized placebo-controlled 31 trials, suggests supplementation with n-3 polyunsaturated fatty acids (PUFAs) may be efficacious 32 for treatment of major depressive disorder (MDD). The mechanisms underlying n-3 PUFAs 33 potential therapeutic properties remain unknown. There are suggestions in the literature that glial 34 hypofunction is associated with depressive symptoms and that antidepressants may normalize 35 glial function. In this study, iPSC-derived neuronal stem cell lines were generated from 36 individuals with MDD. Astrocytes differentiated from patient-derived neuronal stem cells 37 (iNSCs) were verified by GFAP. Cells were treated with eicosapentaenoic acid (EPA), 38 docosahexaenoic acid (DHA) and stearic acid (SA). During astrocyte differentiation, we found 39 that n-3 PUFAs increased GFAP expression and GFAP positive cell formation. BDNF and 40 GDNF production were increased in the astrocytes derived from patients subsequent to n-3 41 PUFA treatment. Stearic Acid (SA) treatment did not have this effect. CREB activity 42 (phosphorylated CREB) was also increased by DHA and EPA but not by SA. Furthermore, when 43 these astrocytes were treated with n-3 PUFAs, the cAMP antagonist, RP-cAMPs did not block n-44 3 PUFA CREB activation. However, the CREB specific inhibitor (666-15) diminished BDNF 45 and GDNF production induced by n-3 PUFA, suggesting CREB dependence. Together, these 46 results suggested that n-3 PUFAs facilitate astrocyte differentiation, and may mimic effects of 47 some antidepressants by increasing production of neurotrophic factors. The CREB-dependence 48 and cAMP independence of this process suggests a manner in which n-3 PUFA could augment 49 antidepressant effects. These data also suggest a role for astrocytes in both MDD and 50 antidepressant action. 51 52 53Major depressive disorder (MDD) is the most common psychiatric disorder, with almost 54 one in six individuals experiencing at least one depressive episode at some point in their lifetime. 55It is currently the leading cause of disability worldwide [1, 2]. While effective treatments exist, 56 about one third of patients treated with antidepressants do not reach symptomatic remission [3, 57 4]. While some of these non-remitters may respond to ketamine or other rescue strategies, 58 additional therapeutic options are needed. 59Brain regions and even cell-types contributing to MDD are not well established [4]. 60Evidence from clinical, preclinical and post-mortem studies suggests that dysfunction and 61 degeneration of astrocytes may be one of potential candidates, and astrocytes may also represent 62 a potential therapeutic target for MDD [5][6][7][8]. Antidepressants, including SSRIs and ketamine, 63 increase brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor 64 (GDNF) expression in primary cultured animal astrocytes [9][10][11]. Substantial evidence suggested 65 that astrocytes might be the main resource of antidepressant...

The role of soluble epoxide hydrolase and its inhibitors in depression

“…Results showed that both the high and the low-dose of ω-3 PUFAs were superior to placebo, and that the efficacy of high-dose ω-3 PUFAs was superior to that of low-dose. In line with these findings, clinical studies within our and other laboratories, again using similar concentrations of ω-3 PUFAs, have showed that diets rich in EPA and DHA provide beneficial anti-inflammatory and anti-depressant effects ( Chang et al., 2019 ; Colombo et al., 1989 ; Luo et al., 2020 ; Rapaport et al., 2016 ; Su et al., 2014 ; Yu et al., 2020 ; Zhou et al., 2019 ). Moreover, we have also previously demonstrated that in vitro treatment of human hippocampal progenitors with EPA and DHA can prevent reduction in neurogenesis caused by IL1β, much like treatment with antidepressants, sertraline and venlafaxine, does ( Borsini et al., 2017 ).…”

Omega-3 polyunsaturated fatty acids protect against inflammation through production of LOX and CYP450 lipid mediators: relevance for major depression and for human hippocampal neurogenesis

“…Nutrition-based therapeutic strategies consisting of the omega-3 polyunsaturated fatty acids (ω-3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are considered promising therapeutic approaches [4,5]. Indeed, clinical studies within our and other laboratories have showed that diets rich in ω-3 PUFAs, such as EPA and DHA provide beneficial anti-inflammatory and antidepressant effects [6][7][8][9][10][11][12]. Moreover, we have also previously demonstrated that in vitro treatment of human hippocampal progenitors with EPA and DHA can prevent reduction in neurogenesis caused by IL1β, much like treatment with antidepressants, sertraline and venlafaxine, does [13].…”

“…This ability of PUFAs to protect neurones from the detrimental effects of inflammation is likely to be relevant for their antidepressant action, at least in the sub-group of patients with major depression characterised by immune dysregulation [6][7][8][9][10][11][12]. In particular, activation of the inflammatory response system in these patients is characterised by an increase in the production of inflammatory cytokines, including interleukin-1beta (IL1β) and IL6 both in the periphery and in the cerebrospinal fluid [1,14].…”

Investigating the Role of G-protein Bias in the Anti-Nociceptive and Side Effect Profiles of Two Novel Mu Opioid Receptor Agonists Kurkinol and Kurkinorin

“…However, with the development of the live-cell CADDi cAMP reporter (Montana Molecular; Bozeman, USA) the level of cAMP inhibition in primary cultures can be assessed via plate reader in a high throughput manner. Recent work has also shown this method of determining real-time cAMP levels is compatible with primary neural stem cells, indicating it may be used successfully in primary striatal cultures (Yu et al, 2020). This experiment can be further strengthened by utilising the recently released β-arrestin2 CADDi (Montana Molecular).…”