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Is an Innovative Drug Delivery System and a Potential Bioregulator cells Article A Glucuronic Acid-Palmitoylethanolamide Conjugate (GLUPEA) Is an Innovative Drug Delivery System and a Potential Bioregulator Emiliano Manzo 1,† , Aniello Schiano Moriello 1,2,3, Francesco Tinto 1, Roberta Verde 1,2, Marco Allarà 1,2,3, Luciano De Petrocellis 1,2 , Ester Pagano 2,4, Angelo A. Izzo 2,4, Vincenzo Di Marzo 1,2,5,* and Stefania Petrosino 1,2,3,*,† 1 Istituto di Chimica Biomolecolare, CNR, 80078 Pozzuoli, Napoli, Italy; [email protected] (E.M.); [email protected] (A.S.M.); [email protected] (F.T.); [email protected] (R.V.); [email protected] (M.A.); [email protected] (L.D.P.) 2 Endocannabinoid Research Group, 80078 Pozzuoli, Napoli, Italy; [email protected] (E.P.); [email protected] (A.A.I.) 3 Epitech Group S.p.A., 35030 Saccolongo, Padova, Italy 4 Dipartimento di Farmacia, Università di Napoli Federico II, 80138 Naples, Napoli, Italy 5 Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, CRIUCPQ and INAF-Centre NUTRISS, Faculties of Medicine and Agriculture and Food Sciences, Université Laval, Quebéc, QC G1V 0A6, Canada * Correspondence: [email protected] (V.D.M.); [email protected] (S.P.) † These authors contributed equally to this work. Citation: Manzo, E.; Schiano Moriello, Abstract: Palmitoylethanolamide (PEA) is an endogenous anti-inflammatory lipid mediator and a A.; Tinto, F.; Verde, R.; Allarà, M.; De widely used nutraceutical. In this study, we designed, realized, and tested a drug-carrier conjugate Petrocellis, L.; Pagano, E.; Izzo, A.A.; Di between PEA (the active drug) and glucuronic acid (the carrier). The conjugate, named GLUPEA, Marzo, V.; Petrosino, S. A Glucuronic was characterized for its capability of increasing PEA levels and exerting anti-inflammatory activity Acid-Palmitoylethanolamide both in vitro and in vivo. GLUPEA treatment, compared to the same concentration of PEA, resulted Conjugate (GLUPEA) Is an in higher cellular amounts of PEA and the endocannabinoid 2-arachidonoyl glycerol (2-AG), and Innovative Drug Delivery System and increased 2-AG-induced transient receptor potential vanilloid type 1 (TRPV1) channel desensitization a Potential Bioregulator. Cells 2021, 10, to capsaicin. GLUPEA inhibited pro-inflammatory monocyte chemoattractant protein 2 (MCP-2) 450. https://doi.org/10.3390/ release from stimulated keratinocytes, and it was almost as efficacious as ultra-micronized PEA at cells10020450 reducing colitis in dinitrobenzene sulfonic acid (DNBS)-injected mice when using the same dose. Academic Editor: Cord Brakebusch GLUPEA is a novel pro-drug able to efficiently mimic the anti-inflammatory and endocannabinoid enhancing actions of PEA. Received: 21 January 2021 Accepted: 18 February 2021 Keywords: allergic contact dermatitis; chemokine; colitis; drug-carrier; endocannabinoid system; Published: 20 February 2021 inflammation; keratinocytes; palmitoylethanolamide; pro-drug; TRPV1 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. Palmitoylethanolamide (PEA) is a substance of natural origin produced not only in many plant and animal food sources [1–7], but also in a broad variety of mammalian cells and tissues [8–19]. Chemically, PEA is the amide of a fatty acid—palmitic acid— with ethanolamine. One of the main enzymes responsible for its biosynthesis is N- Copyright: © 2021 by the authors. acyl-phosphatidyl-ethanolamine-selective phospholipase D (NAPE-PLD), which catalyzes Licensee MDPI, Basel, Switzerland. the hydrolysis of direct PEA phospholipid precursors, i.e., N-palmitoyl-phosphatidyl- This article is an open access article ethanolamines [20]. The hydrolysis of PEA to palmitic acid and ethanolamine depends on distributed under the terms and the catalytic action of both fatty acid amide hydrolase (FAAH) [21] and, more specifically, conditions of the Creative Commons N-acylethanolamine-hydrolyzing acid amidase (NAAA) [22]. Attribution (CC BY) license (https:// The mechanism of action of PEA is still under investigation. It seems that PEA does not creativecommons.org/licenses/by/ act through just one main mechanism, but conversely, via synergistic interactions among 4.0/). Cells 2021, 10, 450. https://doi.org/10.3390/cells10020450 https://www.mdpi.com/journal/cells Cells 2021, 10, 450 2 of 18 Cells 2021, 10, 450 3 of 19 different signaling pathways, thus explaining its pleiotropic therapeutic effects [7,19]. In fact, both direct and indirect (via “entourage” effects) receptor-mediated mechanisms polysaccharide,have been demonstrated has emerged for as this an mediator. excellent carrier In particular, due to itits has high been hydrophilicity proved that and PEA bi- is ocompatibility,able to directly and activate lack of the toxicity peroxisome [50–52]. proliferator-activated receptor-α (PPAR-α)[23], or theConsidering orphan receptor this background, G-protein coupledthe aim of GPR55 the present [24], and, study through was to the use activation glucuronic of acid,PPAR- whichα, activate is one transientof the main receptor hyaluronic potential acid vanilloid constituents type 1along (TRPV1) with channels N-glucosamine, or increase as thethe starting expression point of to the develop cannabinoid a new drug-carrier receptor type conjugate 2 (CB2) [characterized25–27]. Additionally, by a homogene- PEA, by ousinhibiting chemical the composition. expression of Therefore, FAAH [28 we] or de bysigned, stimulating realized, the and activity tested of a diacylglycerol drug-carrier conjugate,lipase (DAGL- namedα and GLUPEA, -β, the biosyntheticbetween PEA enzymes (the active for 2-arachidonoyl-glyceroldrug) and glucuronic acid (2-AG)) (the car- [29], rier).may GLUPEA indirectly was activate first cannabinoidcharacterized receptors in in vitro of cell type-1 systems (CB1) to and evaluate type-2 the (CB2), release or TRPV1 of the activechannels, drug—PEA—and which are alternative then tested targets in foran ex theperimental endocannabinoids, model of anandamideallergic contact (AEA) derma- and titis2-AG (ACD) (Scheme in human1 )[30– 34keratinocytes,]. Finally, PEA, and probably against colitis through in anmice, allosteric to evaluate interaction, its potential is also anti-inflammatorycapable of enhancing activity. AEA- Importantly, or 2-AG-induced the mechanism TRPV1 channel of action activation and molecular and desensitiza- targets oftion GLUPEA [28,35– 37were]. also investigated in in vitro cell systems. SchemeScheme 1. 1. PalmitoylethanolamidePalmitoylethanolamide (PEA) (PEA) mechanism mechanism of of ac action.tion. PEA PEA has has been been suggested suggested to to directly directly activateactivate GPR55 GPR55 [24], [24], or or peroxisome peroxisome proliferator-activated receptor-receptor-αα(PPAR- (PPAR-αα)[) 23[23],], and, and, through through the theactivation activation of PPAR-of PPAR-α, toα, sensitizeto sensitize transient transient receptor receptor potential potential vanilloid vanilloid type type 1 (TRPV1) 1 (TRPV1) channels chan- or nelsincrease or increase the expression the expression of cannabinoid of cannabinoid receptor re typeceptor 2 (CB2) type [225 (CB2)–27]. PEA,[25–27]. by PEA, stimulating by stimulating the activity theof diacylglycerolactivity of diacylgl lipaseycerol (DAGL)- lipaseα (DAGL)-and -β [29α and], or - byβ [29], inhibiting or by inhibiting the expression the expression of fatty acid of fatty amide acidhydrolase amide (FAAH)hydrolase [28 (FAAH)], indirectly [28], activatesindirectly cannabinoid activates cannabinoid receptor type receptor 1 (CB1) type and 1 (CB1) CB2, orand TRPV1 CB2,channels. or TRPV1 PEA, channels. possibly throughPEA, possibly an allosteric through interaction, an allosteric may interaction, also enhance may anandamide also enhance (AEA)- anan- or damide (AEA)- or 2-arachidonoyl glycerol (2-AG)-induced TRPV1 channel activation and desensi- 2-arachidonoyl glycerol (2-AG)-induced TRPV1 channel activation and desensitization [28,35–37]. tization [28,35–37]. Although there is an extensive body of literature on the anti-neuro-inflammatory 2.and Materials analgesic and actions Methods of PEA [18,19,37], there are only a few papers reporting data on the 2.1.pharmacokinetics Reagents of this compound [7,38]. Early findings suggest a low bioavailability for this compound,All reagents due were to itspurchased low solubility from inSigma-Aldrich water, which limits(Milano, its absorption Italy) unless following otherwise oral specified.administration TLC plates [39,40 ].(Kieselgel Accordingly, 60 F254) Artamonov and silica and gel colleagues powder (Kieselgel (2005) demonstrated 60, 0.063–0.200 that 3 mm)even were though purchasedN-[9,10- fromH]-PEA Merck accumulates (Darmstadt, in Germany). the hypothalamus, All reagents pituitary, for synthesis and adrenal were usedglands without of rats any 20 minfurther following purification. oral administration, Synthetic intermediates its levels and were GLUPEA very low were [39]. char- Like- −1 acterizedwise, Vacondio by NMR and analysis. colleagues 1D- and (2005) 2D-NMR showed spectra that when were PEA recorded (at a doseon a Bruker of 100 mgAvance- kg ) 400was (400.13 suspended MHz) in and corn on oil a andBruker orally DRX-600 administered equipped to rats,with thea TXI highest CryoProbe concentration in CDCl was3 (δ achieved in the plasma after 15 min and then decreased 2 h following administration [40]. values refer to CHCl3 at 7.26 ppm). HRESIMS was conducted on a Micromass Q-TOF mi- cro.Accordingly,
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