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• W2997165255 abstract "Abstract Background Palmitoylethanolamide (PEA) is a pleiotropic endogenous lipid mediator currently used as a “dietary food for special medical purposes” against neuropathic pain and neuro-inflammatory conditions. Several mechanisms underlie PEA actions, among which the “entourage” effect, consisting of PEA potentiation of endocannabinoid signaling at either cannabinoid receptors or transient receptor potential vanilloid type-1 (TRPV1) channels. Here, we report novel molecular mechanisms through which PEA controls mast cell degranulation and substance P (SP)-induced histamine release in rat basophilic leukemia (RBL-2H3) cells, a mast cell model. Methods RBL-2H3 cells stimulated with SP were treated with PEA in the presence and absence of a cannabinoid type-2 (CB2) receptor antagonist (AM630), or a diacylglycerol lipase (DAGL) enzyme inhibitor (OMDM188) to inhibit the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). The release of histamine was measured by ELISA and β-hexosaminidase release and toluidine blue staining were used as indices of degranulation. 2-AG levels were measured by LC-MS. The mRNA expression of proposed PEA targets ( Cnr1, Cnr2 , Trpv1 , Ppara and Gpr55 ), and of PEA and endocannabinoid biosynthetic ( Napepld, Dagla and Daglb ) and catabolic ( Faah , Naaa and Mgl ) enzymes were also measured. The effects of PEA on the activity of DAGL-α or -β enzymes were assessed in COS-7 cells overexpressing the human recombinant enzyme or in RBL-2H3 cells, respectively. Results SP increased the number of degranulated RBL-2H3 cells and triggered the release of histamine. PEA counteracted these effects in a manner antagonized by AM630. PEA concomitantly increased the levels of 2-AG in SP-stimulated RBL-2H3 cells, and this effect was reversed by OMDM188. PEA significantly stimulated DAGL-α and -β activity and, consequently, 2-AG biosynthesis in cell-free systems. Co-treatment with PEA and 2-AG at per se ineffective concentrations downmodulated SP-induced release of histamine and degranulation, and this effect was reversed by OMDM188. Conclusions Activation of CB2 underlies the inhibitory effects on SP-induced RBL-2H3 cell degranulation by PEA alone. We demonstrate for the first time that the effects in RBL-2H3 cells of PEA are due to the stimulation of 2-AG biosynthesis by DAGLs." @default.
• W2997165255 created "2020-01-10" @default.
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• W2997165255 date "2019-12-01" @default.
• W2997165255 modified "2023-10-18" @default.
• W2997165255 title "Palmitoylethanolamide counteracts substance P-induced mast cell activation in vitro by stimulating diacylglycerol lipase activity" @default.
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• W2997165255 doi "https://doi.org/10.1186/s12974-019-1671-5" @default.
• W2997165255 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6933707" @default.
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