Therapeutic utility of palmitoylethanolamide in the treatment of neuropathic pain associated with various pathological conditions: a case series

Hesselink, Jan M Keppel; Hekker, T. A. M.

doi:10.2147/jpr.s32143

Cited by 72 publications

(52 citation statements)

References 30 publications

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“…could influence host immune systems through G2A activation via the production of commendamide. Interestingly, GPCR-mediated signaling pathways modulated by endogenous N-acyl-amides that are structurally related to commendamide have been extensively explored as targets for the therapeutic modulation of pain sensation, depression, diabetes, and inflammation (72)(73)(74)(75). The fact that commendamide is produced by a commensal bacterium suggests that bacteria may already represent a natural exogenous delivery system for these types of metabolites and thus a potential method for the therapeutic delivery of such metabolites.…”

Section: Comparative Phylogenetic and Functional Analysis Of Effectormentioning

confidence: 99%

Functional metagenomic discovery of bacterial effectors in the human microbiome and isolation of commendamide, a GPCR G2A/132 agonist

Cohen

Kang

Chu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

151

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The trillions of bacteria that make up the human microbiome are believed to encode functions that are important to human health; however, little is known about the specific effectors that commensal bacteria use to interact with the human host. Functional metagenomics provides a systematic means of surveying commensal DNA for genes that encode effector functions. Here, we examine 3,000 Mb of metagenomic DNA cloned from three phenotypically distinct patients for effectors that activate NF-κB, a transcription factor known to play a central role in mediating responses to environmental stimuli. This screen led to the identification of 26 unique commensal bacteria effector genes (Cbegs) that are predicted to encode proteins with diverse catabolic, anabolic, and ligand-binding functions and most frequently interact with either glycans or lipids. Detailed analysis of one effector gene family (Cbeg12) recovered from all three patient libraries found that it encodes for the production of N-acyl-3-hydroxypalmitoyl-glycine (commendamide). This metabolite was also found in culture broth from the commensal bacterium Bacteroides vulgatus, which harbors a gene highly similar to Cbeg12. Commendamide resembles long-chain N-acyl-amides that function as mammalian signaling molecules through activation of G-protein–coupled receptors (GPCRs), which led us to the observation that commendamide activates the GPCR G2A/GPR132. G2A has been implicated in disease models of autoimmunity and atherosclerosis. This study shows the utility of functional metagenomics for identifying potential mechanisms used by commensal bacteria for host interactions and outlines a functional metagenomics-based pipeline for the systematic identification of diverse commensal bacteria effectors that impact host cellular functions.

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Section: Comparative Phylogenetic and Functional Analysis Of Effectormentioning

confidence: 99%

Functional metagenomic discovery of bacterial effectors in the human microbiome and isolation of commendamide, a GPCR G2A/132 agonist

Cohen

Kang

Chu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

151

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“…[1,[2][3][4][5][6][7][8][9][10][11][12][13][14] C]ethanolamine HCl was from Moravek Biochemicals (Brea, CA). Horseradish peroxidaselinked anti-mouse and anti-rabbit IgGs were from GE Healthcare (Piscataway, NJ).…”

Section: -[1′-mentioning

confidence: 99%

Comparative analyses of isoforms of the calcium-independent phosphatidylethanolamine N-acyltransferase PLAAT-1 in humans and mice

Hussain

Uyama

Kawai

et al. 2016

Journal of Lipid Research

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Fatty acyl ethanolamides [N-acylethanolamines (NAEs)] are a class of lipid mediators. Among them, arachidonoylethanolamide (anandamide) is known to be an endogenous ligand of cannabinoid receptors (namely, an endocannabinoid) (1). In addition, palmitoylethanolamide and oleoylethanolamide show biological activities such as antiinflammation, analgesia, and appetite suppression via different receptors including PPAR- (2-5). These NAEs are biosynthesized principally through a two-step pathway from membrane glycerophospholipids via N-acylphosphatidylethanolamines (NAPEs) (6). The first reaction is the transfer of an acyl chain from a glycerophospholipid molecule such as phosphatidylcholine (PC) to the amino group of phosphatidylethanolamine (PE), resulting in the formation of NAPE, and the enzyme responsible is known as PE N-acyltransferase. Very recently, cPLA 2 ɛ, a member of the cytosolic phospholipase A 2 (PLA 2 ) family (PLA2G4), has been identified as the calcium-stimulated N-acyltransferase capable of catalyzing this step (7). However, a series of our recent studies revealed that five members of the HRAS-like suppressor (HRASLS) family, which were originally discovered as tumor suppressors, possess calciumindependent phospholipid-metabolizing activities including NAPE-forming N-acyltransferase and PLA 1/2 activities (8-12), and we proposed to give HRASLS-1-5 the names phospholipase A/acyltransferase-1-5 (PLAAT-1-5), respectively (11). Among the five members, PLAAT-1 particularly received our attention because of its relatively high PE N-acyltransferase activity over PLA 1/2 activity in vitro and predominant expression in testis, skeletal muscle, brain, and heart of humans, mice, and rats, where NAPEs accumulate in response to ischemia and inflammation (11,13).Abstract N-Acylphosphatidylethanolamines (NAPEs) are a class of glycerophospholipids, which are known as precursors for different bioactive N-acylethanolamines. We previously reported that phospholipase A/acyltransferase-1 (PLAAT-1), which was originally found in mammals as a tumor suppressor, catalyzes N-acylation of phosphatidylethanolamines to form NAPEs. However, recent online database suggested the presence of an uncharacterized isoform of PLAAT-1 with an extra sequence at the N terminus. In the present study, we examined the occurrence, intracellular localization, and catalytic properties of this longer isoform, as well as the original shorter isoform from humans and mice. Our results showed that human tissues express the longer isoform but not the short isoform at all. In contrast, mice expressed both isoforms with different tissue distribution. Unlike the cytoplasmic localization of the shorter isoform, the long isoform was found in both cytoplasm and nucleus, inferring that the extra sequence harbors a nuclear localization signal. As assayed with purified proteins, neither isoform required calcium for full activity. Moreover, the overexpression of each isoform remarkably increased cellular NAPE levels. These results conclude that the new long is...

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“…10−12 Furthermore, PEA has been indicated to attenuate skin inflammation 13,14 and neuropathic pain in humans. 15 These effects are mainly attributed to the ability of PEA to activate peroxisome proliferator-activated receptor α (PPAR-α), a member of the steroid/nuclear receptor superfamily. 1,2,7,16 PEA is deactivated into free palmitic acid and ethanolamine by two intracellular lipid amidases: fatty acid amide hydrolase (FAAH), which prefers anandamide over PEA and OEA, 17 and N-acylethanolamine acid amidase (NAAA), the main enzyme responsible for PEA cleavage.…”

Section: ■ Introductionmentioning

confidence: 99%

Synthesis, Biological Evaluation, and 3D QSAR Study of 2-Methyl-4-oxo-3-oxetanylcarbamic Acid Esters as N-Acylethanolamine Acid Amidase (NAAA) Inhibitors

et al. 2014

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N-(2-Oxo-3-oxetanyl)carbamic acid esters have recently been reported to be noncompetitive inhibitors of the Nacylethanolamine acid amidase (NAAA) potentially useful for the treatment of pain and inflammation. In the present study, we further explored the structure−activity relationships of the carbamic acid ester side chain of 2-methyl-4-oxo-3-oxetanylcarbamic acid ester derivatives. Additional favorable features in the design of potent NAAA inhibitors have been found together with the identification of a single digit nanomolar inhibitor. In addition, we devised a 3D QSAR using the atomic property field method. The model turned out to be able to account for the structural variability and was prospectively validated by designing, synthesizing, and testing novel inhibitors. The fairly good agreement between predictions and experimental potency values points to this 3D QSAR model as the first example of quantitative structure−activity relationships in the field of NAAA inhibitors.

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Therapeutic utility of palmitoylethanolamide in the treatment of neuropathic pain associated with various pathological conditions: a case series

Abstract: Video abstract Video

Cited by 72 publications

References 30 publications

Functional metagenomic discovery of bacterial effectors in the human microbiome and isolation of commendamide, a GPCR G2A/132 agonist

Functional metagenomic discovery of bacterial effectors in the human microbiome and isolation of commendamide, a GPCR G2A/132 agonist

Comparative analyses of isoforms of the calcium-independent phosphatidylethanolamine N-acyltransferase PLAAT-1 in humans and mice

Synthesis, Biological Evaluation, and 3D QSAR Study of 2-Methyl-4-oxo-3-oxetanylcarbamic Acid Esters as N-Acylethanolamine Acid Amidase (NAAA) Inhibitors

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