Inflammation has been identified as one of the main pathophysiological mechanisms underlying neuropsychiatric and neurodegenerative disorders. Despite the role of inflammation in those conditions, there is still a lack of effective anti-inflammatory therapeutic strategies. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) can reduce depressive symptoms and exert anti-inflammatory action putatively by the production of distinct n-3 PUFA-derived metabolites, such as resolvins D (RvD) and E (RvE) series, maresins (MaR) and protectins (PD), which are collectively named specialized pro-resolving mediators (SPMs) and act as strong anti-inflammatory agents. In this review we summarize evidence showing the effects of treatment with those metabolites in pre-clinical models of psychiatric, neurodegenerative and neurological disorders. A total of 25 pre-clinical studies were identified using the PubMed database. Overall, RvD and RvE treatment improved depressive-like behaviors, whereas protectins and maresins ameliorated neurological function. On a cellular level, RvDs increased serotonin levels in a model of depression, and decreased gliosis in neurodegenerative disorders. Protectins prevented neurite and dendrite retraction and apoptosis in models of neurodegeneration, while maresins reduced cell death across all studies. In terms of mechanisms, all SPMs down-regulated pro-inflammatory cytokines. Resolvins activated mTOR and MAP/ERK signaling in models of depression, while resolvins and maresins activated the NF-κB pathway in models of neurodegeneration and neurological disorders. Our review indicates a potential promising approach for tailored therapy with n-3 PUFAs-derived metabolites in the treatment of psychiatric, neurodegenerative, and neurological conditions.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can exert antidepressant, anti-inflammatory and neuroprotective properties, but the exact molecular mechanism underlying their effects is still not fully understood. We conducted both in vitro and clinical investigations to test which EPA or DHA metabolites are involved in these anti-inflammatory, neuroprotective and antidepressant effects. In vitro, we used the human hippocampal progenitor cell line HPC0A07/03C, and pre-treated cells with either EPA or DHA, followed by interleukin 1beta (IL1β), IL6 and interferon-alpha (IFN-α). Both EPA and DHA prevented the reduction in neurogenesis and the increase in apoptosis induced by these cytokines; moreover, these effects were mediated by the lipoxygenase (LOX) and cytochrome P450 (CYP450) EPA/DHA metabolites, 5-hydroxyeicosapentaenoic acid (HEPE), 4-hydroxydocosahexaenoic acid (HDHA), 18-HEPE, 20-HDHA, 17(18)-epoxyeicosatetraenoic acid (EpETE) and 19(20)-epoxydocosapentaenoic acid (EpDPA), detected here for the first time in human hippocampal neurones using mass spectrometry lipidomics of the supernatant. In fact, like EPA/DHA, co-treatment with these metabolites prevented cytokines-induced reduction in neurogenesis and apoptosis. Moreover, co-treatment with 17(18)-EpETE and 19(20)-EpDPA and the soluble epoxide hydroxylase (sEH) inhibitor, TPPU (which prevents their conversion into dihydroxyeicosatetraenoic acid (DiHETE)/ dihydroxydocosapentaenoic acid (DiHDPA) metabolites) further enhanced their neurogenic and anti-apoptotic effects. Interestingly, these findings were replicated in a sample of n = 22 patients with a DSM-IV Major Depressive Disorder, randomly assigned to treatment with either EPA (3.0 g/day) or DHA (1.4 g/day) for 12 weeks, with exactly the same LOX and CYP450 lipid metabolites increased in the plasma of these patients following treatment with their precursor, EPA or DHA, and some evidence that higher levels of these metabolites were correlated with less severe depressive symptoms. Overall, our study provides the first evidence for the relevance of LOX- and CYP450-derived EPA/DHA bioactive lipid metabolites as neuroprotective molecular targets for human hippocampal neurogenesis and depression, and highlights the importance of sEH inhibitors as potential therapeutic strategy for patients suffering from depressive symptoms.

Background Although the pro-inflammatory cytokine, interleukin (IL)6, has been generally regarded as “depressogenic”, recent research has started to question this assumption, in light of the fact that this cytokine can also have anti-inflammatory properties. This bimodal action seems to be dependent on its concentration levels, and on the concomitant presence of other pro-inflammatory cytokines. Methods We exposed a human hippocampal progenitor cell line HPC0A07/03C to cytokine levels described in depressed patients (IL6 5pg/ml with IL1β 10pg/ml or Macrophage Migration Inhibitory Factor (MIF) 300pg/ml), in healthy subjects (IL6 with IL1β, 1pg/ml or MIF 10pg/ml), as well as to the potentially anti-inflammatory, much higher concentrations of IL6 (50000pg/ml). Results Treatment with high concentrations of IL6 with IL1β or MIF (resembling depressed patients) decreases neurogenesis when compared with low concentrations of the same cytokines (healthy subjects), and that this is mediated via production of, respectively, IL8 and IL1β in cell supernatant. Instead, treatment with the very high, anti-inflammatory concentration of IL6 (50000pg/ml) together with high IL1β or MIF prevents the decrease in neurogenesis and reduces both IL8 and IL1β. When the high concentrations of both IL1β and MIF were used in co-treatment, as a model of treatment resistant depression, we also demonstrate a reduction in neurogenesis, and that this is mediated via a decrease in IL4; moreover, co-treatment with high IL1β and MIF and the very high concentration of IL6 prevents the reduction in neurogenesis, and increases IL4. Conclusions Our results demonstrate that IL6 can exert both pro- and anti-inflammatory (potentially antidepressant) properties, depending on its concentrations and combinations with other inflammatory cytokines.

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Background: Electroconvulsive therapy (ECT) is a powerful and fast-acting anti-depressant strategy, often used in treatment-resistant patients. In turn, patients with treatment-resistant depression often present an increased inflammatory response. The impact of ECT on several pathophysiological mechanisms of depression has been investigated, with a focus which has largely been on cellular and synaptic plasticity. Although changes in the immune system are known to influence neurogenesis, these processes have principally been explored independently from each other in the context of ECT. Objective: The aim of this review was to compare the time-dependent consequences of acute and chronic ECT on concomitant innate immune system and neurogenesis-related outcomes measured in the central nervous system in pre-clinical studies. Results: During the few hours following acute electroconvulsive shock (ECS), the expression of the astrocytic reactivity marker glial fibrillary acidic protein (GFAP) and inflammatory genes, such as cyclooxygenase-2 (COX2), were significantly increased together with the neurogenic brain-derived neurotrophic factor (BDNF) and cell proliferation. Similarly, chronic ECS caused an initial upregulation of the same astrocytic marker, immune genes, and neurogenic factors. Interestingly, over time, inflammation appeared to be dampened, while glial activation and neurogenesis were maintained, after either acute or chronic ECS. Conclusion: Regardless of treatment duration ECS would seemingly trigger a rapid increase in inflammatory molecules, dampened over time, as well as a long-lasting activation of astrocytes and production of growth and neurotrophic factors, leading to cell proliferation. This suggests that both innate immune system response and neurogenesis might contribute to the efficacy of ECT.