Inhibitory effect of palmitoylethanolamide on gastrointestinal motility in mice

Capasso, Raffaele; Izzo, Angelo A.; Fezza, Filomena; Pinto, Aldo; Capasso, Francesco; Mascolo, Nicola; Marzo, Vincenzo Di

doi:10.1038/sj.bjp.0704339

Cited by 103 publications

(87 citation statements)

References 25 publications

(41 reference statements)

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“…In the present study, we investigated the contribution of NAAA to CFAinduced joint inflammation and the effects of the b-lactambased NAAA inhibitor ARN726 in this model. We found that administration of CFA into the paw of rats causes a substantial decrement in the tissue content of PEA and OEA, as previously shown in other animal models of inflammation (Capasso et al, 2001;De Filippis et al, 2009;Solorzano et al, 2009) and in patients suffering from rheumatoid arthritis (Richardson et al, 2008). Along with changes in PEA and OEA, we found that CFA produces a marked local elevation in the catalytically active form of NAAA, which is produced by self-cleavage of the inactive holoenzyme (Tsuboi et al, 2005).…”

Section: Discussionsupporting

confidence: 60%

“…For example, the PEA content in exudates from mice exposed to carrageenan is substantially lower than that of exudates obtained from naive mice (Solorzano et al, 2009). Similarly, tissue PEA levels are reduced in carrageenan-induced granuloma (De Filippis et al, 2009) and in the intestine of mice treated with croton oil (Capasso et al, 2001;Izzo et al, 2012). Experiments in the macrophage-like RAW264.7 cell line, suggest that the decrease in PEA and OEA accumulation results from transcriptional suppression of N-acyl-PEphospholipase D expression, which is negatively controlled by activators of Toll-like receptor 4 (Zhu et al, 2011).…”

Section: Discussionmentioning

confidence: 85%

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An Important Role for N-Acylethanolamine Acid Amidase in the Complete Freunds Adjuvant Rat Model of Arthritis

Bonezzi

Sasso

Pontis

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The endogenous lipid amides, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), exert marked antinociceptive and anti-inflammatory effects in animal models by engaging nuclear peroxisome proliferator-activated receptor-a. PEA and OEA are produced by macrophages and other host-defense cells and are deactivated by the cysteine amidase, N-acylethanolamine acid amidase (NAAA), which is highly expressed in macrophages and B-lymphocytes. In the present study, we examined whether a) NAAA might be involved in the inflammatory reaction triggered by injection of complete Freund's adjuvant (CFA) into the rat paw and b) administration of 4-cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]-carbamate (ARN726), a novel systemically active NAAA inhibitor, attenuates such reaction. Injection of CFA into the paw produced local edema and heat hyperalgesia, which were accompanied by decreased PEA and OEA content (assessed by liquid chromatography/mass spectrometry) and increased NAAA levels (assessed by Western blot and ex vivo enzyme activity measurements) in paw tissue. Administration of undec-10-ynyl-N-[(3S)-2-oxoazetidin-3-yl] carbamate (ARN14686), a NAAA-preferring activity-based probe, revealed that NAAA was catalytically active in CFA-treated paws. Administration of ARN726 reduced NAAA activity and restored PEA and OEA levels in inflamed tissues, and significantly decreased CFAinduced inflammatory symptoms, including pus production and myeloperoxidase activity. The results confirm the usefulness of ARN726 as a probe to investigate the functions of NAAA in health and disease and suggest that this enzyme may provide a new molecular target for the treatment of arthritis.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 85%

An Important Role for N-Acylethanolamine Acid Amidase in the Complete Freunds Adjuvant Rat Model of Arthritis

Bonezzi

Sasso

Pontis

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…Stimulation with proinflammatory agents such as LPS or carrageenan decreases PEA content in various cells and tissues of rodents, including intestine (Capasso et al, 2001), skin (LoVerme et al, 2005), and leukocytes (Endocannabinoid Research Group et al, 2010;Solorzano et al, 2009). Adding clinical relevance to these findings, it was shown that synovial fluid from patients with rheumatoid arthritis and osteoarthritis contains lower amounts of PEA compared with control subjects (Richardson et al, 2008).…”

Section: Introductionmentioning

confidence: 91%

Proinflammatory Stimuli ControlN-Acylphosphatidylethanolamine-Specific Phospholipase D Expression in Macrophages

Zhu¹,

Solórzano²,

Sahar³

et al. 2011

Mol Pharmacol

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Palmitoylethanolamide (PEA) is an endogenous lipid amide that modulates pain and inflammation by engaging peroxisome proliferator-activated receptor type-␣. Here, we show that the proinflammatory bacterial endotoxin lipopolysaccharide (LPS) decreases PEA biosynthesis in RAW264.7 macrophages by suppressing the transcription of N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD), which catalyzes the production of PEA and other lipid amides. Using a luciferase reporter construct and chromatin immunoprecipitation, we further show that LPS treatment reduces acetylation of histone proteins bound to the NAPE-PLD promoter, an effect that is blocked by the histone deacetylase inhibitor trichostatin A. The transcription factor Sp1 is involved in regulating baseline NAPE-PLD expression but not in the transcriptional suppression induced by LPS. The ability of LPS to down-regulate PEA biosynthesis is impaired in peritoneal macrophages from mutant NAPE-PLD-deficient mice, in which PEA is produced through a compensatory mechanism distinct from NAPE-PLD. Moreover, NAPE-PLD-deficient mice fail to mount a normal inflammatory reaction in response to carrageenan administration in vivo. Our findings suggest that proinflammatory stimuli suppress NAPE-PLD expression and PEA biosynthesis in macrophages and that this effect might contribute to the inflammatory response.

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“…Behavioral effects produced by activation of central CB 1 receptors include reduced locomotion and body temperature, catalepsy, alterations in memory, sedation, and euphoria-effects that are also commonly observed with recreational marijuana use (Adams and Martin, 1996). In the periphery, activation of CB 1 receptors on nerve endings produces analgesia (Calignano et al, 1998;Jaggar et al, 1998), reduces cough (Calignano et al, 2000), and inhibits intestinal transit (Capasso et al, 2001). The functions served by CB 2 receptors are less clear, but recent evidence suggests that they may modulate immune cell function (Klein et al, 2001) to produce peripheral analgesia and anti-inflammation Malan et al, 2003;Quartilho et al, 2003)-although the mechanism by which these phenomena occur remains enigmatic.…”

Section: Cannabinoid Receptorsmentioning

confidence: 99%

The search for the palmitoylethanolamide receptor

et al. 2005

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Palmitoylethanolamide (PEA), the naturally occurring amide of ethanolamine and palmitic acid, is an endogenous lipid that modulates pain and inflammation. Although the anti-inflammatory effects of PEA were first characterized nearly 50 years ago, the identity of the receptor mediating these actions has long remained elusive. We recently identified the ligand-activated transcription factor, peroxisome proliferator-activated receptor-alpha (PPAR-a), as the receptor mediating the anti-inflammatory actions of this lipid amide. Here we outline the history of PEA, starting with its initial discovery in the 1950s, and discuss the pharmacological properties of this compound, particularly in regards to its ability to activate PPAR-a. Discovery of PEAThe discovery of naturally occurring fatty acid ethanolamides (FAEs) (Fig. 1) stems from an interesting clinical finding in the early 1940s, when investigators noted that supplementing the diets of 0024-3205/$ -see front matter D

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Inhibitory effect of palmitoylethanolamide on gastrointestinal motility in mice

Abstract: 1 We have studied the eect of palmitoylethanolamide (PEA, 2.5 ± 30 mg kg

Cited by 103 publications

References 25 publications

An Important Role for N-Acylethanolamine Acid Amidase in the Complete Freunds Adjuvant Rat Model of Arthritis

An Important Role for N-Acylethanolamine Acid Amidase in the Complete Freunds Adjuvant Rat Model of Arthritis

Proinflammatory Stimuli ControlN-Acylphosphatidylethanolamine-Specific Phospholipase D Expression in Macrophages

The search for the palmitoylethanolamide receptor

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