A systematic, integrative review of the effects of the endocannabinoid system on inflammation and neurogenesis in animal models of affective disorders

Giacobbe, Juliette; Marrocu, Alessia; Benedetto, Maria Grazia Di; Pariante, Carmine M.; Borsini, Alessandra

doi:10.1016/j.bbi.2020.12.024

Cited by 19 publications

(16 citation statements)

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“…However, all our previous results with this model have been replicated in animal and clinical studies, including changes in neurogenesis by cytokines, cortisol, and antidepressants, and changes in stress-and inflammation-regulated genes both in the whole blood mRNA of depressed patients and in the hippocampal mRNA of animal models of depression [13,20,29,30,[34][35][36]46]. We also acknowledge the relatively small sample size of depressed patients used to measure ω-3 PUFAsderived lipid mediators and the fact that the study was not a randomised placebo control trial; in future studies, it would be important to replicate these findings in a much larger cohort of depressed patients, and to extend our investigations also to other classes of ω-3 PUFAs metabolites, including endocannabinoids [58]. Finally, it is important to highlight the fact that, concentrations of EPA and DHA (both 10 µM), used in this study and in our previous in vitro studies [13,37,41], are concentrations that likely cannot be achieved with consumption of food rich in ω-3 PUFAs [59], but rather require therapeutic PUFAs supplements.…”

Section: Discussionmentioning

confidence: 88%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 88%

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

et al. 2021

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“…The endocannabinoid system (ECS) is a modulator of multiple physiological activities, including in the nervous, endocrine, immune, blood circulation, gastrointestinal tract and reproductive systems ( Di Marzo et al, 1998 ). Accordingly, dysregulation of the ECS is involved with various pathological conditions, including inflammation among others ( Di Marzo and Piscitelli, 2015 ; Hillard, 2018 ), whereas therapeutic modulation of ECS activity has beneficial effects on various medical conditions, including those associated with inflammation ( Ambrose and Simmons, 2019 ; Giacobbe et al, 2021 ). ECS is involved in both innate and adaptive immunity and in several chronic inflammatory diseases ( Chiurchiù et al, 2015 ).…”

Section: The Endocannabinoid System and Inflammationmentioning

confidence: 99%

Medical Cannabis Activity Against Inflammation: Active Compounds and Modes of Action

2022

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Inflammation often develops from acute, chronic, or auto-inflammatory disorders that can lead to compromised organ function. Cannabis (Cannabis sativa) has been used to treat inflammation for millennia, but its use in modern medicine is hampered by a lack of scientific knowledge. Previous studies report that cannabis extracts and inflorescence inhibit inflammatory responses in vitro and in pre-clinical and clinical trials. The endocannabinoid system (ECS) is a modulator of immune system activity, and dysregulation of this system is involved in various chronic inflammations. This system includes cannabinoid receptor types 1 and 2 (CB1 and CB2), arachidonic acid-derived endocannabinoids, and enzymes involved in endocannabinoid metabolism. Cannabis produces a large number of phytocannabinoids and numerous other biomolecules such as terpenes and flavonoids. In multiple experimental models, both in vitro and in vivo, several phytocannabinoids, including Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabigerol (CBG), exhibit activity against inflammation. These phytocannabinoids may bind to ECS and/or other receptors and ameliorate various inflammatory-related diseases by activating several signaling pathways. Synergy between phytocannabinoids, as well as between phytocannabinoids and terpenes, has been demonstrated. Cannabis activity can be improved by selecting the most active plant ingredients (API) while eliminating parts of the whole extract. Moreover, in the future cannabis components might be combined with pharmaceutical drugs to reduce inflammation.

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“…Cannabinoids are well established as anti-inflammatory agents with a significant and wide range of immunosuppressive properties that have been meticulously reviewed before (20)(21)(22)(23)(24)(25). CBD, the nonpsychotic cannabinoid, was shown to induce myeloid-derived suppressor cells (MDSCs) which suppressed T cell proliferation in vitro and in vivo (26).…”

Section: Mechanisms and Nature Of Immunomodulation Caused By Cannabin...mentioning

confidence: 99%

Role of Gut Microbiota in Cannabinoid-Mediated Suppression of Inflammation

Varsha¹,

Nagarkatti²,

Nagarkatti³

2022

Adv. Drug Alcohol Res.

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Cannabinoids and the endocannabinoid system have been well established to play a crucial role in the regulation of the immune response. Also, emerging data from numerous investigations unravel the imperative role of gut microbiota and their metabolites in the maintenance of immune homeostasis and gut barrier integrity. In this review, we concisely report the immunosuppressive mechanisms triggered by cannabinoids, and how they are closely associated with the alterations in the gut microbiome and metabolome following exposure to endogenous or exogenous cannabinoids. We discuss how cannabinoid-mediated induction of microbial secondary bile acids, short chain fatty acids, and indole metabolites, produced in the gut, can suppress inflammation even in distal organs. While clearly, more clinical studies are necessary to establish the cross talk between exo- or endocannabinoid system with the gut microbiome and the immune system, the current evidence opens a new avenue of cannabinoid-gut-microbiota-based therapeutics to regulate immunological disorders.

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A systematic, integrative review of the effects of the endocannabinoid system on inflammation and neurogenesis in animal models of affective disorders

Cited by 19 publications

References 103 publications

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

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

Medical Cannabis Activity Against Inflammation: Active Compounds and Modes of Action

Role of Gut Microbiota in Cannabinoid-Mediated Suppression of Inflammation

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