The ω-3 endocannabinoid docosahexaenoyl ethanolamide reduces seizure susceptibility in mice by activating cannabinoid type 1 receptors

Ghanbari, Mohammad-Mahdi; Loron, Ali Gharibi; Sayyah, Mohammad

doi:10.1016/j.brainresbull.2021.02.011

Cited by 8 publications

(7 citation statements)

References 58 publications

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“…However, additional endogenous lipids have been shown to also have robust activity at CB1 including the anandamide congeners, ( N -acyl ethanolamines; NAEs), docosahexaenoyl ethanolamine and linoleoyl ethanolamine 33 , 34 . Importantly, oxygenated metabolites of polyunsaturated NAEs have been shown to have activity at CB1 receptors that was more efficacious than CP55940 33 and that blunted seizure activity in a CB1-dependent manner 34 . Each of these endogenous lipids are tonically present throughout the body, though their levels are regulated by enzymatic activity.…”

Section: Resultsmentioning

confidence: 99%

“…There are two canonical endogenous CB1 receptor ligands, anandamide and 2-arachidonoyl glycerol (2-AG). However, additional endogenous lipids have been shown to also have robust activity at CB1 including the anandamide congeners, ( N -acyl ethanolamines; NAEs), docosahexaenoyl ethanolamine and linoleoyl ethanolamine 33 , 34 . Importantly, oxygenated metabolites of polyunsaturated NAEs have been shown to have activity at CB1 receptors that was more efficacious than CP55940 33 and that blunted seizure activity in a CB1-dependent manner 34 .…”

Section: Resultsmentioning

confidence: 99%

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Cannabinoid CB1 receptors regulate salivation

Andreis

Billingsley

Shirazi

et al. 2022

Sci Rep

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Saliva serves multiple important functions within the body that we typically take for granted, such as helping prepare food for swallowing and defense against oral pathogens. Dry mouth is a primary symptom of Sjӧgren’s syndrome and is a side effect of many drug treatments. Cannabis users frequently report dry mouth, but the basis for this is still unknown. If the effects occur via the endogenous cannabinoid signaling system, then this may represent a novel mechanism for the regulation of salivation. We examined expression of cannabinoid CB1 receptors in submandibular salivary gland using immunohistochemistry and tested regulation of salivation by THC and cannabinoid-related ligands. We now report that CB1 receptors are expressed in the axons of cholinergic neurons innervating the submandibular gland. No staining is seen in submandibular gland epithelial cells (acinar and ductal), or myoepithelial cells (MECs). Treatment with THC (4 mg/kg, IP) or the cannabinoid receptor agonist CP55940 (0.5 mg/kg) reduced salivation in both male and female mice 1 h after treatment. CBD had no effect on its own but reversed the effect of THC in a concentration-dependent manner. Neither the CB1 receptor antagonist SR141716 (4 mg/kg) nor the CB2-selective agonist JWH133 (4 mg/kg) had an effect on salivation. We also found that fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide and related lipids, regulates salivation. Salivation was reduced in FAAH knockout mice as well as mice treated with the FAAH blocker URB597 (4 mg/kg). URB597 had no effect in CB1 knockout mice. FAAH protein is detected intracellularly in acinar but not ductal epithelial cells. In lipidomics experiments, we found that FAAH knockout mice chiefly had elevated levels of acylethanolamines, including anandamide, and reduced levels of acyglycines. Our results are consistent with a model wherein endocannabinoids activate CB1 receptors on cholinergic axons innervating the submandibular gland. THC likely acts by plugging into this system, activating CB1 receptors to reduce salivation, thus offering a mechanism underlying the dry mouth reported by cannabis users.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Cannabinoid CB1 receptors regulate salivation

Andreis

Billingsley

Shirazi

et al. 2022

Sci Rep

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“…Both the CNR1 and CNR2 receptors have important functions in reproductive organs, including the placenta [ 67 , 68 ], since activation of the ECS receptors can affect both pregnancy progression and labor [ 29 , 67 ] by controlling the action of endocannabinoids, cytokine release, and by modulating the mitochondrial activity [ 69 , 70 ]. Within the cells, n-3 FA DHA and EPA can be converted to the endocannabinoids DHEA and eicosapentaenoyl ethanolamide (EPEA), which have a chemical structure similar to the endocannabinoid AEA; it was reported that DHEA and EPEA exhibit binding affinity and agonist activity on both CNR1 and CNR2 [ 71 , 72 ]. Thus, the effects of FO on the ECS can be mediated by these n-3 FA-derived endocannabinoids.…”

Section: Discussionmentioning

confidence: 99%

Maternal supplementation with n-3 fatty acids affects placental lipid metabolism, inflammation, oxidative stress, the endocannabinoid system, and the neonate cytokine concentrations in dairy cows

dos Santos Silva,

Kra,

Butenko

et al. 2024

J Animal Sci Biotechnol

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Background The placenta plays a crucial role in supporting and influencing fetal development. We compared the effects of prepartum supplementation with omega-3 (n-3) fatty acid (FA) sources, flaxseed oil (FLX) and fish oil (FO), on the expression of genes and proteins related to lipid metabolism, inflammation, oxidative stress, and the endocannabinoid system (ECS) in the expelled placenta, as well as on FA profile and inflammatory response of neonates. Late-pregnant Holstein dairy cows were supplemented with saturated fat (CTL), FLX, or FO. Placental cotyledons (n = 5) were collected immediately after expulsion, and extracted RNA and proteins were analyzed by RT-PCR and proteomic analysis. Neonatal blood was assessed for FA composition and concentrations of inflammatory markers. Results FO increased the gene expression of fatty acid binding protein 4 (FABP4), interleukin 10 (IL-10), catalase (CAT), cannabinoid receptor 1 (CNR1), and cannabinoid receptor 2 (CNR2) compared with CTL placenta. Gene expression of ECS-enzyme FA-amide hydrolase (FAAH) was lower in FLX and FO than in CTL. Proteomic analysis identified 3,974 proteins; of these, 51–59 were differentially abundant between treatments (P ≤ 0.05, |fold change| ≥ 1.5). Top canonical pathways enriched in FLX vs. CTL and in FO vs. CTL were triglyceride metabolism and inflammatory processes. Both n-3 FA increased the placental abundance of FA binding proteins (FABPs) 3 and 7. The abundance of CNR1 cannabinoid-receptor-interacting-protein-1 (CNRIP1) was reduced in FO vs. FLX. In silico modeling affirmed that bovine FABPs bind to endocannabinoids. The FLX increased the abundance of inflammatory CD44-antigen and secreted-phosphoprotein-1, whereas prostaglandin-endoperoxide synthase 2 was decreased in FO vs. CTL placenta. Maternal FO enriched neonatal plasma with n-3 FAs, and both FLX and FO reduced interleukin-6 concentrations compared with CTL. Conclusion Maternal n-3 FA from FLX and FO differentially affected the bovine placenta; both enhanced lipid metabolism and modulated oxidative stress, however, FO increased some transcriptional ECS components, possibly related to the increased FABPs. Maternal FO induced a unique balance of pro- and anti-inflammatory components in the placenta. Taken together, different sources of n-3 FA during late pregnancy enhanced placental immune and metabolic processes, which may affect the neonatal immune system.

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“…EPEA and DHEA have however demonstrated anti-proliferative effects on cancer cells via their activation of both CB 1 and CB 2 receptors, and the potencies of both could be enhanced by inhibiting the AEA metabolizing enzyme 44 . In addition, it was found that DHEA exerts an anti-seizure action through its activation of the CB 1 receptor 45 . Finally, DHEA and EPEA were shown to decrease LPS- induced adipocyte IL-6 and MCP-1 levels and that those effects were produced through their liaison to the CB 2 receptor 46 .…”

Section: Discussionmentioning

confidence: 99%

N-eicosapentaenoyl-ethanolamine decreases the proliferation of psoriatic keratinocytes in a reconstructed psoriatic skin model

Simard

Tremblay

Morin

et al. 2023

Sci Rep

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Psoriasis is an inflammatory skin disease that is characterized by keratinocyte hyperproliferation, abnormal epidermal differentiation and dysregulated lipid metabolism. Some lipid mediators of the N-acylethanolamines (NAEs) and monoacylglycerols (MAGs) can bind to cannabinoid (CB) receptors and are referred to as part of the endocannabinoidome. Their implication in psoriasis remains unknown. The aim of the present study was to characterize the endocannabinoid system and evaluate the effects of n-3-derived NAEs, namely N-eicosapentaenoyl-ethanolamine (EPEA), in psoriatic keratinocytes using a psoriatic skin model produced by tissue engineering, following the self-assembly method. Psoriatic skin substitutes had lower FAAH2 expression and higher MAGL, ABHD6 and ABHD12 expression compared with healthy skin substitutes. Treatments with alpha-linolenic acid (ALA) increased the levels of EPEA and 1/2-docosapentaenoyl-glycerol, showing that levels of n-3 polyunsaturated fatty acids modulate related NAE and MAG levels. Treatments of the psoriatic substitutes with 10 μM of EPEA for 7 days resulted in decreased epidermal thickness and number of Ki67 positive keratinocytes, both indicating decreased proliferation of psoriatic keratinocytes. EPEA effects on keratinocyte proliferation were inhibited by the CB1 receptor antagonist rimonabant. Exogenous EPEA also diminished some inflammatory features of psoriasis. In summary, n-3-derived NAEs can reduce the psoriatic phenotype of a reconstructed psoriatic skin model.

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The ω-3 endocannabinoid docosahexaenoyl ethanolamide reduces seizure susceptibility in mice by activating cannabinoid type 1 receptors

Cited by 8 publications

References 58 publications

Cannabinoid CB1 receptors regulate salivation

Cannabinoid CB1 receptors regulate salivation

Maternal supplementation with n-3 fatty acids affects placental lipid metabolism, inflammation, oxidative stress, the endocannabinoid system, and the neonate cytokine concentrations in dairy cows

N-eicosapentaenoyl-ethanolamine decreases the proliferation of psoriatic keratinocytes in a reconstructed psoriatic skin model

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