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Salvatore Cuzzocrea - One of the best experts on this subject based on the ideXlab platform.
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an update of Palmitoylethanolamide and luteolin effects in preclinical and clinical studies of neuroinflammatory events
Antioxidants, 2020Co-Authors: Marika Cordaro, Salvatore Cuzzocrea, Rosalia CrupiAbstract:The inflammation process represents of a dynamic series of phenomena that manifest themselves with an intense vascular reaction. Neuroinflammation is a reply from the central nervous system (CNS) and the peripheral nervous system (PNS) to a changed homeostasis. There are two cell systems that mediate this process: the glia of the CNS and the lymphocites, monocytes, and macrophages of the hematopoietic system. In both the peripheral and central nervous systems, neuroinflammation plays an important role in the pathogenesis of neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases, and in neuropsychiatric illnesses, such as depression and autism spectrum disorders. The resolution of neuroinflammation is a process that allows for inflamed tissues to return to homeostasis. In this process the important players are represented by lipid mediators. Among the naturally occurring lipid signaling molecules, a prominent role is played by the N-acylethanolamines, namely N-arachidonoylethanolamine and its congener N-palmitoylethanolamine, which is also named Palmitoylethanolamide or PEA. PEA possesses a powerful neuroprotective and anti-inflammatory power but has no antioxidant effects per se. For this reason, its co-ultramicronization with the flavonoid luteolin is more efficacious than either molecule alone. Inhibiting or modulating the enzymatic breakdown of PEA represents a complementary therapeutic approach to treating neuroinflammation. The aim of this review is to discuss the role of ultramicronized PEA and co-ultramicronized PEA with luteolin in several neurological diseases using preclinical and clinical approaches.
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Palmitoylethanolamide and polydatin combination reduces inflammation and oxidative stress in vascular injury
Pharmacological Research, 2017Co-Authors: Enrico Gugliandolo, Rosanna Di Paola, Salvatore Cuzzocrea, Roberta Fusco, Flavia Biundo, Ramona Damico, Filippo BenedettoAbstract:Acute and chronic inflammation responses are important risk factors for vascular remodeling processes such as in atherosclerosis, arteriosclerosis and restenosis. Inflammation and oxidative stress in the intimal region after vascular damage are a key event in the development of neointimal hyperplasia. In this study, we used this model of vascular damage, which involves the complete ligature of the left carotid artery for 14days, to observe the role of N-palmitoylethanolamine in combination with Polydatin at the dose of 30mg/kg, on regulation of inflammatory process, and oxidative stress. Palmitoylethanolamide (PEA), an endogenous fatty acid amide belonging to the N-acylethanolamine family, has anti-inflammatory and neuroprotective effects. However, PEA lacks direct capacity to prevent formation of free radicals. Polydatin (PLD) that is a natural precursor of resveratrol has antioxidant activity. Thus, the combination of PEA and PLD could have beneficial effects on inflammatory process and oxidative stress. This model shows that 14days after carotid artery ligation there is a significant structural change within the vessel, and that there is an important involvement of the inflammatory pathway in the progression of this disease. In this study we demonstrated that PEA/PLD combination treatment reduces vessel damage, adhesion molecules expression such as intercellular adhesion molecules-1(ICAM-1) and vascular cell adhesion molecules-1(V-CAM), proinflammatory cytokines production (Tumor Necrosis Factor alpha (TNF-α) and Interleukin 1 beta (IL-1β), the inducible nitric oxide synthase (iNOS) and Poly (ADP-ribose) polymerase (PAR), formation, Nuclear factor kappa-B expression and apoptosis (BAX, Fas-Ligand) activation. Our results clearly demonstrated that treatment with PEA/PLD 30mg/Kg is able to reduce vascular damage and attenuates the inflammatory process.
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ultramicronized Palmitoylethanolamide pea um in the treatment of idiopathic pulmonary fibrosis
Pharmacological Research, 2016Co-Authors: Rosanna Di Paola, Daniela Impellizzeri, Emanuela Esposito, Salvatore Cuzzocrea, Marika Cordaro, Rosalia Crupi, Roberta Fusco, Rosalba SiracusaAbstract:Pulmonary fibrosis is a chronic condition characterized by progressive scarring of lung parenchyma. The aim of this study was to examine the effects of an ultramicronized preparation of Palmitoylethanolamide (PEA-um(®)), an endogenous fatty acid amide, in mice subjected to idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis was induced in male mice by a single intratracheal administration of saline with bleomycin sulphate (1mg/kg body weight) in a volume of 100μL. PEA-um(®) was injected intraperitoneally at 1, 3 or 10mg/kg 1h after bleomycin instillation and daily thereafter. Animals were sacrificed after 7 and 21days by pentobarbitone overdose. One cohort of mice was sacrificed after seven days of bleomycin administration, followed by bronchoalveloar lavage and determination of myeloperoxidase activity, lung edema and histopathology features. In the 21-day cohort, mortality was assessed daily, and surviving mice were sacrificed followed by the above analyses together with immunohistochemical localization of CD8, tumor necrosis factor-α, CD4, interleukin-1β, transforming growth factor-β, inducible nitric oxide synthase and basic fibroblast growth factor. Compared to bleomycin-treated mice, animals that received also PEA-um(®) (3 or 10mg/kg) had significantly decreased weight loss, mortality, inflammation, lung damage at the histological level, and lung fibrosis at 7 and 21days. PEA-um(®) (1mg/kg) did not significantly inhibit the inflammation response and lung fibrosis. This study demonstrates that PEA-um(®) (3 and 10mg/kg) reduces the extent of lung inflammation in a mouse model of idiopathic pulmonary fibrosis.
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co ultramicronized Palmitoylethanolamide luteolin in the treatment of cerebral ischemia from rodent to man
Translational Stroke Research, 2016Co-Authors: Carlo Caltagirone, Emanuela Esposito, Rosanna Di Paola, Marika Cordaro, Carlo Cisari, Carlo Schievano, Giuseppe Bruschetta, Salvatore CuzzocreaAbstract:Acute ischemic stroke, the most frequent cause of permanent disability in adults worldwide, results from transient or permanent reduction in regional cerebral blood flow and involves oxidative stress and inflammation. Despite the success of experimental animal models of stroke in identifying anti-inflammatory/neuroprotective compounds, translation of these putative neuroprotectants to human clinical trials has failed to produce a positive outcome. Tissue injury and stress activate endogenous mechanisms which function to restore homeostatic balance and prevent further damage by upregulating the synthesis of lipid signaling molecules, including N-palmitoylethanolamine (PEA or Palmitoylethanolamide). PEA exerts neuroprotection and reduces inflammatory secondary events associated with brain ischemia reperfusion injury (middle cerebral artery occlusion (MCAo)). Here, we examined the neuroprotective potential of a co-ultramicronized composite containing PEA and the antioxidant flavonoid luteolin (10:1 by mass), nominated co-ultraPEALut. The study consisted of two arms. In the first, rats subjected to MCAo and treated with co-ultraPEALut post-ischemia showed reduced edema and brain infract volume, improved neurobehavioral functions, and reduced expression of pro-inflammatory markers and astrocyte markers. In the second arm, a cohort of 250 stroke patients undergoing neurorehabilitation on either an inpatient or outpatient basis were treated for 60 days with a pharmaceutical preparation of co-ultraPEALut (Glialia). At baseline and after 30 days of treatment, all patients underwent a battery of evaluations to assess neurological status, impairment of cognitive abilities, the degree of spasticity, pain, and independence in daily living activities. All indices showed statistically significant gains at study end. Despite its observational nature, this represents the first description of co-ultraPEALut administration to human stroke patients and clinical improvement not otherwise expected from spontaneous recovery. Further, controlled trials are warranted to confirm the utility of co-ultraPEALut to improve clinical outcome in human stroke.
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micronized ultramicronized Palmitoylethanolamide displays superior oral efficacy compared to nonmicronized Palmitoylethanolamide in a rat model of inflammatory pain
Journal of Neuroinflammation, 2014Co-Authors: Daniela Impellizzeri, Emanuela Esposito, Salvatore Cuzzocrea, Marika Cordaro, Rosalia Crupi, Giuseppe Bruschetta, Rosalba SiracusaAbstract:Background: The fatty acid amide Palmitoylethanolamide (PEA) has been studied extensively for its antiinflammatory and neuroprotective actions. The lipidic nature and large particle size of PEA in the native state may limit its solubility and bioavailability when given orally, however. Micronized formulations of a drug enhance its rate of dissolution and reduce variability of absorption when orally administered. The present study was thus designed to evaluate the oral anti-inflammatory efficacy of micronized/ultramicronized versus nonmicronized PEA formulations. Methods: Micronized/ultramicronized PEA was produced by the air-jet milling technique, and the various PEA preparations were subjected to physicochemical characterization to determine particle size distribution and purity. Each PEA formulation was then assessed for its anti-inflammatory effects when given orally in the carrageenan-induced rat paw model of inflammation, a well-established paradigm of edema formation and thermal hyperalgesia. Results: Intraplantar injection of carrageenan into the right hind paw led to a marked accumulation of infiltrating inflammatory cells and increased myeloperoxidase activity. Both parameters were significantly decreased by orally given micronized PEA (PEA-m; 10 mg/kg) or ultramicronized PEA (PEA-um; 10 mg/kg), but not nonmicronized PeaPure (10 mg/kg). Further, carrageenan-induced paw edema and thermal hyperalgesia were markedly and significantly reduced by oral treatment with micronized PEA-m and ultramicronized PEA-um at each time point compared to nonmicronized PeaPure. However, when given by the intraperitoneal route, all PEA formulations proved effective. Conclusions: These findings illustrate the superior anti-inflammatory action exerted by orally administered, micronized PEA-m and ultramicronized PEA-um, versus that of nonmicronized PeaPure, in the rat paw carrageenan model of inflammatory pain.
Kazuhito Tsuboi - One of the best experts on this subject based on the ideXlab platform.
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Glycerophosphodiesterase GDE4 as a novel lysophospholipase D: a possible involvement in bioactive N-acylethanolamine biosynthesis.
Biochimica et biophysica acta, 2015Co-Authors: Kazuhito Tsuboi, Toru Uyama, Iffat Ara Sonia Rahman, Yoko Okamoto, Tomohito Inoue, Akira TokumuraAbstract:Abstract Bioactive N-acylethanolamines include anti-inflammatory Palmitoylethanolamide, anorexic oleoylethanolamide, and an endocannabinoid arachidonoylethanolamide (anandamide). In animal tissues, these molecules are biosynthesized from N-acylethanolamine phospholipids directly by phospholipase D-type enzyme or through multi-step routes via N-acylethanolamine lysophospholipids. We previously found that mouse brain has a lysophospholipase D (lysoPLD) activity hydrolyzing N-acylethanolamine lysophospholipids to N-acylethanolamines and that this activity could be partially attributed to glycerophosphodiesterase (GDE) 1. In the present study, we examined catalytic properties of GDE4, another member of the GDE family. When overexpressed in HEK293 cells, murine GDE4 mostly resided in the membrane fraction. Purified GDE4 showed lysoPLD activity toward various lysophospholipids, including N-acylethanolamine lysophospholipids as well as lysophosphatidylethanolamine and lysophosphatidylcholine. When HEK293 cells were metabolically labeled with N-[14C]palmitoylethanolamine lysophospholipid, the transient expression of GDE4 increased the [14C]Palmitoylethanolamide level, while the knockdown of endogenous GDE4 decreased this level. These results suggested that GDE4 functions as an N-acylethanolamine-generating lysoPLD in living cells. Moreover, the expression of GDE4 increased most species of lysophosphatidic acid (LPA), which can be produced from various lysophospholipids by the lysoPLD activity of GDE4. GDE4 mRNA was widely distributed among mouse tissues including brain, stomach, ileum, colon, and testis. In conclusion, GDE4 may act as a lysoPLD, which is involved in the generation of N-acylethanolamines and LPA.
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metabolism of endocannabinoids and related n acylethanolamines canonical and alternative pathways
FEBS Journal, 2013Co-Authors: Kazuhito Tsuboi, Toru UyamaAbstract:: Endocannabinoids are endogenous ligands of the cannabinoid receptors CB1 and CB2. Two arachidonic acid derivatives, arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol, are considered to be physiologically important endocannabinoids. In the known metabolic pathway in mammals, anandamide and other bioactive N-acylethanolamines, such as Palmitoylethanolamide and oleoylethanolamide, are biosynthesized from glycerophospholipids by a combination of Ca(2+)-dependent N-acyltransferase and N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D, and are degraded by fatty acid amide hydrolase. However, recent studies have shown the involvement of other enzymes and pathways, which include the members of the tumor suppressor HRASLS family (the phospholipase A/acyltransferase family) functioning as Ca(2+)-independent N-acyltransferases, N-acyl-phosphatidylethanolamine-hydrolyzing phospholipaseD-independent multistep pathways via N-acylated lysophospholipid, and N-acylethanolamine-hydrolyzing acid amidase, a lysosomal enzyme that preferentially hydrolyzes Palmitoylethanolamide. Although their physiological significance is poorly understood, these new enzymes/pathways may serve as novel targets for the development of therapeutic drugs. For example, selective N-acylethanolamine-hydrolyzing acid amidase inhibitors are expected to be new anti-inflammatory and analgesic drugs. In this minireview, we focus on advances in the understanding of these enzymes/pathways. In addition, recent findings on 2-arachidonoylglycerol metabolism are described.
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enzymatic formation of n acylethanolamines from n acylethanolamine plasmalogen through n acylphosphatidylethanolamine hydrolyzing phospholipase d dependent and independent pathways
Biochimica et Biophysica Acta, 2011Co-Authors: Kazuhito Tsuboi, Natsuki Ikematsu, Toru Uyama, Yasuo Okamoto, Yoshibumi Shimizu, Manami Inoue, Dale G DeutschAbstract:Abstract Bioactive N-acylethanolamines include anandamide (an endocannabinoid), N-palmitoylethanolamine (an anti-inflammatory), and N-oleoylethanolamine (an anorexic). In the brain, these molecules are formed from N-acylphosphatidylethanolamines (NAPEs) by a specific phospholipase D, called NAPE-PLD, or through NAPE-PLD-independent multi-step pathways, as illustrated in the current study employing NAPE-PLD-deficient mice. Although N-acylethanolamine plasmalogen (1-alkenyl-2-acyl-glycero-3-phospho(N-acyl)ethanolamine, pNAPE) is presumably a major class of N-acylethanolamine phospholipids in the brain, its enzymatic conversion to N-acylethanolamines is poorly understood. In the present study, we focused on the formation of N-acylethanolamines from pNAPEs. While recombinant NAPE-PLD catalyzed direct release of N-palmitoylethanolamine from N-palmitoylethanolamine plasmalogen, the same reaction occurred in the brain homogenate of NAPE-PLD-deficient mice, suggesting that this reaction occurs through both the NAPE-PLD-dependent and -independent pathways. Liquid chromatography-mass spectrometry revealed a remarkable accumulation of 1-alkenyl-2-hydroxy-glycero-3-phospho(N-acyl)ethanolamines (lyso pNAPEs) in the brain of NAPE-PLD-deficient mice. We also found that brain homogenate formed N-palmitoylethanolamine, N-oleoylethanolamine, and anandamide from their corresponding lyso pNAPEs by a Mg2+-dependent “lysophospholipase D”. Moreover, the brain levels of alkenyl-type lysophosphatidic acids, the other products from lyso pNAPEs by lysophospholipase D, also increased in NAPE-PLD-deficient mice. Glycerophosphodiesterase GDE1 can hydrolyze glycerophospho-N-acylethanolamines to N-acylethanolamines in the brain. In addition, we discovered that recombinant GDE1 has a weak activity to generate N-palmitoylethanolamine from its corresponding lyso pNAPE, suggesting that this enzyme is at least in part responsible for the lysophospholipase D activity. These results strongly suggest that brain tissue N-acylethanolamines, including anandamide, can be formed from N-acylated plasmalogen through an NAPE-PLD-independent pathway as well as by their direct release via NAPE-PLD.
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Proteolytic activation and glycosylation of N-acylethanolamine-hydrolyzing acid amidase, a lysosomal enzyme involved in the endocannabinoid metabolism
Biochimica et biophysica acta, 2007Co-Authors: Liying Zhao, Yasuo Okamoto, Kazuhito Tsuboi, Shunichiro NagahataAbstract:N-acylethanolamine-hydrolyzing acid amidase (NAAA) is a lysosomal enzyme hydrolyzing bioactive N-acylethanolamines, including anandamide and N-palmitoylethanolamine. Previously, we suggested that NAAA is glycosylated and proteolytically cleaved. Here, we investigated the mechanism and significance of the cleavage of human NAAA overexpressed in human embryonic kidney 293 cells. Western blotting with anti-NAAA antibody revealed that most of NAAA in the cell homogenate was the cleaved 30-kDa form. However, some of NAAA were released outside the cells and the extracellular enzyme was mostly the uncleaved 48-kDa form. When incubated at pH 4.5, the 48-kDa form was time-dependently converted to the 30-kDa form with concomitant increase in the N-palmitoylethanolamine-hydrolyzing activity. The purified 48-kDa form was also cleaved and activated. However, the cleavage did not proceed at pH 7.4 or in the presence of p-chloromercuribenzoic acid. The mutant C126S was resistant to the cleavage and remained inactive. These results suggested that this specific proteolysis is a self-catalyzed activation step. We next determined N-glycosylation sites of human NAAA by site-directed mutagenesis addressed to asparagine residues in six potential N-glycosylation sites. The results exhibited that Asn-37, Asn-107, Asn-309, and Asn-333 are actual N-glycosylation sites. The glycosylation appeared to play an important role in stabilizing the enzyme protein.
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molecular characterization of n acylethanolamine hydrolyzing acid amidase a novel member of the choloylglycine hydrolase family with structural and functional similarity to acid ceramidase
Journal of Biological Chemistry, 2005Co-Authors: Kazuhito Tsuboi, Yasuo Okamoto, Nobukazu Araki, Takeharu TonaiAbstract:Abstract Bioactive N-acylethanolamines, including anandamide (an endocannabinoid) and N-palmitoylethanolamine (an anti-inflammatory and neuroprotective substance), are hydrolyzed to fatty acids and ethanolamine by fatty acid amide hydrolase. Moreover, we found another amidohydrolase catalyzing the same reaction only at acidic pH, and we purified it from rat lung (Ueda, N., Yamanaka, K., and Yamamoto, S. (2001) J. Biol. Chem. 276, 35552–35557). Here we report complementary DNA cloning and functional expression of the enzyme termed “N-acylethanolamine-hydrolyzing acid amidase (NAAA)” from human, rat, and mouse. The deduced primary structures revealed that NAAA had no homology to fatty acid amide hydrolase but belonged to the choloylglycine hydrolase family. Human NAAA was essentially identical to a gene product that had been noted to resemble acid ceramidase but lacked ceramide hydrolyzing activity. The recombinant human NAAA overexpressed in HEK293 cells hydrolyzed various N-acylethanolamines with N-palmitoylethanolamine as the most reactive substrate. Most interestingly, a very low ceramide hydrolyzing activity was also detected with NAAA, and N-lauroylethanolamine hydrolyzing activity was observed with acid ceramidase. By the use of tunicamycin and endoglycosidase, NAAA was found to be a glycoprotein. Furthermore, the enzyme was proteolytically processed to a shorter form at pH 4.5 but not at pH 7.4. Expression analysis of a green fluorescent protein-NAAA fusion protein showed a lysosome-like distribution in HEK293 cells. The organ distribution of the messenger RNA in rats revealed its wide distribution with the highest expression in lung. These results demonstrated that NAAA is a novel N-acylethanolamine-hydrolyzing enzyme that shows structural and functional similarity to acid ceramidase.
Stefania Petrosino - One of the best experts on this subject based on the ideXlab platform.
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increased levels of Palmitoylethanolamide and other bioactive lipid mediators and enhanced local mast cell proliferation in canine atopic dermatitis
BMC Veterinary Research, 2014Co-Authors: Francesca Abramo, Vincenzo Di Marzo, Stefania Petrosino, L Campora, Francesco Albanese, Maria Federica Della Valle, Luigia Cristino, Vincenzo MiragliottaAbstract:Background Despite the precise pathogenesis of atopic dermatitis (AD) is unknown, an immune dysregulation that causes Th2-predominant inflammation and an intrinsic defect in skin barrier function are currently the two major hypotheses, according to the so-called outside-inside-outside model. Mast cells (MCs) are involved in AD both by releasing Th2 polarizing cytokines and generating pruritus symptoms through release of histamine and tryptase. A link between MCs and skin barrier defects was recently uncovered, with histamine being found to profoundly contribute to the skin barrier defects. Palmitoylethanolamide and related lipid mediators are endogenous bioactive compounds, considered to play a protective homeostatic role in many tissues: evidence collected so far shows that the anti-inflammatory effect of Palmitoylethanolamide depends on the down-modulation of MC degranulation. Based on this background, the purpose of the present study was twofold: (a) to determine if the endogenous levels of Palmitoylethanolamide and other bioactive lipid mediators are changed in the skin of AD dogs compared to healthy animals; (b) to examine if MC number is increased in the skin of AD dogs and, if so, whether it depends on MC in-situ proliferation.
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Palmitoylethanolamide counteracts reactive astrogliosis induced by β-amyloid peptide
Journal of cellular and molecular medicine, 2011Co-Authors: Caterina Scuderi, Luca Steardo, Giuseppe Esposito, Angelo Blasio, Marta Valenza, Pierluca Arietti, Rosa Carnuccio, Daniele De Filippis, Stefania Petrosino, Teresa IuvoneAbstract:Emerging evidence indicates that astrogliosis is involved in the pathogenesis of neurodegenerative disorders. Our previous findings suggested cannabinoids and Autacoid Local Injury Antagonism Amides (ALIAmides) attenuate glial response in models of neurodegeneration. The present study was aimed at exploring Palmitoylethanolamide (PEA) ability to mitigate β-amyloid (Aβ)-induced astrogliosis. Experiments were carried out to investigate PEA’s (10−7M) effects upon the expression and release of pro-inflammatory molecules in rat primary astrocytes activated by soluble Aβ1–42 (1 μg/ml) as well as to identify mechanisms responsible for such actions. The effects of Aβ and exogenous PEA on the astrocyte levels of the endocannabinoidsand of endogenous ALIAmides were also studied. The peroxisome proliferator-activated receptor (PPAR)-α (MK886, 3 μM) or PPAR-γ (GW9662, 9 nM) antagonists were co-administered with PEA. Aβ elevated endogenous PEA and d5–2-arachidonoylglycerol (2-AG) levels. Exogenous PEA blunted the Aβ-induced expression of pro-inflammatory molecules. This effect was reduced by PPAR-α antagonist. Moreover, this ALIAmide, like Aβ, increased 2-AG levels. These results indicate that PEA exhibits anti-inflammatory properties able to counteract Aβ-induced astrogliosis, and suggest novel treatment for neuroinflammatory/ neurodegenerative processes.
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Palmitoylethanolamide counteracts reactive astrogliosis induced by β-amyloid peptide
'Wiley', 2011Co-Authors: Caterina Scuderi, Luca Steardo, Giuseppe Esposito, Angelo Blasio, Marta Valenza, Pierluca Arietti, Rosa Carnuccio, Daniele De Filippis, Stefania Petrosino, Teresa IuvoneAbstract:Emerging evidence indicates that astrogliosis is involved in the pathogenesis of neurodegenerative disorders. Our previous findings suggested cannabinoids and Autacoid Local Injury Antagonism Amides (ALIAmides) attenuate glial response in models of neurodegeneration. The present study was aimed at exploring Palmitoylethanolamide (PEA) ability to mitigate beta-amyloid (A beta)-induced astrogliosis. Experiments were carried out to investigate PEAs (10-7M) effects upon the expression and release of pro-inflammatory molecules in rat primary astrocytes activated by soluble A beta(1-42) (1 mu g/ml) as well as to identify mechanisms responsible for such actions. The effects of A beta and exogenous PEA on the astrocyte levels of the endocannabinoidsand of endogenous ALIAmides were also studied. The peroxisome proliferator-activated receptor (PPAR)-alpha (MK886, 3 mu M) or PPAR-gamma (GW9662, 9 nM) antagonists were co-administered with PEA. A beta elevated endogenous PEA and d5-2-arachidonoylglycerol (2-AG) levels. Exogenous PEA blunted the A beta-induced expression of pro-inflammatory molecules. This effect was reduced by PPAR-alpha antagonist. Moreover, this ALIAmide, like A beta, increased 2-AG levels. These results indicate that PEA exhibits anti-inflammatory properties able to counteract A beta-induced astrogliosis, and suggest novel treatment for neuroinflammatory/ neurodegenerative processes
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possible anandamide and Palmitoylethanolamide involvement in human stroke
Lipids in Health and Disease, 2010Co-Authors: Marcello Naccarato, Stefania Petrosino, D Pizzuti, Marco Simonetto, Laura Ferigo, Fabio Chiodo Grandi, Gilberto Pizzolato, Vincenzo Di MarzoAbstract:Background Endocannabinoids (eCBs) are ubiquitous lipid mediators that act on specific (CB1, CB2) and non-specific (TRPV1, PPAR) receptors. Despite many experimental animal studies proved eCB involvement in the pathogenesis of stroke, such evidence is still lacking in human patients. Our aim was to determine eCB peripheral levels in acute stroke patients and evaluate their relationship with clinical disability and stroke volume.
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levels of endocannabinoids and Palmitoylethanolamide and their pharmacological manipulation in chronic granulomatous inflammation in rats
Pharmacological Research, 2010Co-Authors: D De Filippis, Stefania Petrosino, Pierangelo Orlando, A Damico, Mariateresa Cipriano, V Di Marzo, Teresa IuvoneAbstract:Abstract The endocannabinoids anandamide and 2-arachidonoylglycerol, and the anandamide-congener, Palmitoylethanolamide, are all substrates for the enzyme fatty acid amide hydrolase, and are endowed with anti-inflammatory actions exerted via cannabinoid receptors or, in the case of Palmitoylethanolamide, also via other targets. We investigated the role of the endocannabinoid system during granuloma formation, a model of chronic inflammation sustained by neoangiogenesis, in rats. Granuloma was induced by subcutaneous λ-carrageenin-soaked sponge implants on the back of male Wistar rats. After 96 h, granulomas were detached and tissue formation was evaluated as wet weight; the endocannabinoid system was evaluated by the measurement of endocannabinoid levels, by LC–MS, and of cannabinoid receptor expression, by western blot analysis. Moreover, angiogenesis was evaluated by the measurement of both hemoglobin content and CD31 protein expression. Arachidonoylserotonin (AA-5-HT, 12.5–50 μg/ml), an inhibitor of FAAH, and Palmitoylethanolamide (PEA, 200–800 μg/ml) were given locally only once at the time of implantation. Granuloma formation was accompanied by a significant decrease in endocannabinoid and Palmitoylethanolamide levels paralleled by increased levels of the fatty acid amide hydrolase, responsible for their breakdown. Moreover, an increase of cannabinoid receptor expression was also observed. Pharmacological elevation of endocannabinoids and Palmitoylethanolamide, obtained separately by arachidonoylserotonin and exogenous Palmitoylethanolamide treatment, dose-dependently reduced inflammatory hallmarks including tumor necrosis factor-α as well as granuloma-dependent angiogenesis. The effect of arachidonoylserotonin was accompanied by near-normalization of 2-arachidonoylglycerol and Palmitoylethanolamide levels in the tissue. These findings suggest that chronic inflammation might develop also because of endocannabinoid and Palmitoylethanolamide tissue concentration impairment, the correction of which might be exploited to develop new anti-inflammatory drugs.
Christopher J Fowler - One of the best experts on this subject based on the ideXlab platform.
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Palmitoylethanolamide for the treatment of pain pharmacokinetics safety and efficacy
British Journal of Clinical Pharmacology, 2016Co-Authors: Linda Gabrielsson, Sofia Mattsson, Christopher J FowlerAbstract:Palmitoylethanolamide (PEA) has been suggested to have useful analgesic properties and to be devoid of unwanted effects. Here, we have examined critically this contention, and discussed available data concerning the pharmacokinetics of PEA and its formulation. Sixteen clinical trials, six case reports/pilot studies and a meta-analysis of PEA as an analgesic have been published in the literature. For treatment times up to 49 days, the current clinical data argue against serious adverse drug reactions (ADRs) at an incidence of 1/200 or greater. For treatment lasting more than 60 days, the number of patients is insufficient to rule out a frequency of ADRs of less than 1/100. The six published randomized clinical trials are of variable quality. Presentation of data without information on data spread and nonreporting of data at times other than the final measurement were among issues that were identified. Further, there are no head-to-head clinical comparisons of unmicronized vs. micronized formulations of PEA, and so evidence for superiority of one formulation over the other is currently lacking. Nevertheless, the available clinical data support the contention that PEA has analgesic actions and motivate further study of this compound, particularly with respect to head-to-head comparisons of unmicronized vs. micronized formulations of PEA and comparisons with currently recommended treatments.
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the cannabinoid cb2 receptor selective agonist jwh133 reduces mast cell oedema in response to compound 48 80 in vivo but not the release of beta hexosaminidase from skin slices in vitro
Life Sciences, 2006Co-Authors: Kentolov Jonsson, Emma Persson, Christopher J FowlerAbstract:In a recent study so far published in abstract form, it was reported that the CB(2) receptor selective agonist AM1241 diminishes oedema produced as a result of mast cell degranulation in vivo. It is, however, not known whether other structurally different CB(2) agonists share this effect, and whether this is due to a direct effect on mast cell function. In the present study, we have investigated the effects of JWH133, a CB(2) receptor selective agonist, together with the anti-inflammatory agent Palmitoylethanolamide and its analogue palmitoylisopropylamide, on compound 48/80-induced oedema and degranulation in vivo and in vitro. JWH133 (20 and 200 microg/mouse i.p.) significantly reduced the ability of compound 48/80 to induce oedema in vivo in the anaesthetised mouse following its injection into the ear pinna. Palmitoylethanolamide (200 microg/mouse i.p) also reduced the response to compound 48/80, whereas no firm conclusions could be drawn for palmitoylisopropylamide (20 and 200 microg/mouse i.p.). The CB(2) selective antagonist/inverse agonist SR144528 (60 microg/mouse i.p.) appeared to produce anti-inflammatory effects per se in this model, making it hard to interpret the effects of JWH133 in terms of CB(2) receptor mediated activation. In contrast to the situation in vivo, neither JWH133 (0.3 and 3 microM) nor Palmitoylethanolamide (10 microM) affected mast cell degranulation, measured by following the release of the granular protein beta-hexosaminidase, produced by compound 48/80 in vitro in mouse skin slices. The two compounds were also ineffective in inhibiting the binding of [(3)H]pyrilamine to histamine H(1) receptors in vitro. It is concluded that the ability of JWH133 to affect mast cell dependent inflammation in vivo may be mediated by an indirect action upon the mast cells.
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entourage effects of n acyl ethanolamines at human vanilloid receptors comparison of effects upon anandamide induced vanilloid receptor activation and upon anandamide metabolism
British Journal of Pharmacology, 2002Co-Authors: Darren Smart, Kentolov Jonsson, Severine Vandevoorde, Didier M Lambert, Christopher J FowlerAbstract:1 The abilities of a series of saturated N-acyl ethanolamines and related compounds to affect the ability of anandamide (AEA) to produce a Ca2+ influx into human embryonic kidney cells expressing the human vanilloid receptor (hVR1-HEK293 cells) has been investigated. 2 The C3:0, C4:0, C6:0 and C10:0 ethanolamides neither affected basal Ca2+-influx, nor the influx in response to a submaximal concentration of AEA (1 muM). In contrast, the C12:0, C17:0, C18:0 ethanolamides and the monounsaturated compound oleoylethanolamide (C18:1) greatly potentiated the response to AEA. Palmitoylethanolamide (C16:0) produced both a response per se and an augmentation of the response to AEA. 3 Lauroylethanolamide (C12:0) produced a leftward shift in the dose-response curve for AEA. EC50 values for AEA to produce Ca2+ influx into hVR1-HEK293 cells were 1.8, 1.5, 1.1 and 0.22 muM in the presence of 0, 1, 3 and 10 muM lauroylethanolamide, respectively. Lauroylethanolamide did not affect the dose-response curves to capsaicin. 4 Palmitoylethylamide was synthesized and found to be a mixed-type inhibitor (K-i(slope) 4.1 muM, K-i(intercept) 66 muM) of [H-3]-AEA metabolism by rat brain membranes. 5 The -amide, -ethylamide, -isopropylamide, -butylamide, -cyclohexamide and -trifluoromethyl ketone analogues of Palmitoylethanolamide had little or no effect on the Ca2+ influx response to 1 muM AEA. 6 There was no obvious relation between the abilities of the compounds to enhance the Ca2+-influx response to 1 muM EA into hVR1-HEK293 cells and to prevent the hydrolysis of AEA by rat brain membranes. 7 It is concluded that although Palmitoylethanolamide has entourage-like effects at VR1 receptors expressed on hVR1-HEK293 cells, other N-acyl ethanolamines have even more dramatic potentiating effects. It is possible that they may play an important role under conditions where their synthesis is increased, such as in severe inflammation.
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the Palmitoylethanolamide family a new class of anti inflammatory agents
Current Medicinal Chemistry, 2002Co-Authors: Didier M Lambert, Kentolov Jonsson, Severine Vandevoorde, Christopher J FowlerAbstract:The discovery of anandamide as an endogenous ligand for the cannabinoid receptors has led to a resurgence of interest in the fatty acid amides. However, N-palmitoylethanolamine (PEA), a shorter and fully saturated analogue of anandamide, has been known since the fifties. This endogenous compound is a member of the N-acylethanolamines, found in most mammalian tissues. PEA is accumulated during inflammation and has been demonstrated to have a number of anti-inflammatory effects, including beneficial effects in clinically relevant animal models of inflammatory pain. It is now engaged in phase II clinical development, and two studies regarding the treatment of chronic lumbosciatalgia and multiple sclerosis are in progress. However, its precise mechanism of action remains debated. In the present review, the biochemical and pharmacological properties of PEA are discussed, in particular with respect to its analgesic and anti-inflammatory properties.
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Fatty acid amide hydrolase: biochemistry, pharmacology, and therapeutic possibilities for an enzyme hydrolyzing anandamide, 2-arachidonoylglycerol, Palmitoylethanolamide, and oleamide.
Biochemical pharmacology, 2001Co-Authors: Christopher J Fowler, Kentolov Jonsson, Gunnar TigerAbstract:Fatty acid amide hydrolase (FAAH) is responsible for the hydrolysis of a number of important endogenous fatty acid amides, including the endogenous cannabimimetic agent anandamide (AEA), the sleep-inducing compound oleamide, and the putative anti-inflammatory agent Palmitoylethanolamide (PEA). In recent years, there have been great advances in our understanding of the biochemical and pharmacological properties of the enzyme. In this commentary, the structure and biochemical properties of FAAH and the development of potent and selective FAAH inhibitors are reviewed, together with a brief discussion on the therapeutic possibilities for such compounds in the treatment of inflammatory pain and ischaemic states.
Daniele Piomelli - One of the best experts on this subject based on the ideXlab platform.
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the n acylethanolamine acid amidase inhibitor arn077 suppresses inflammation and pruritus in a mouse model of allergic dermatitis
Journal of Investigative Dermatology, 2017Co-Authors: Oscar Sasso, Silvia Pontis, Andrea Armirotti, Maria Summa, Claudia De Mei, Daniele PiomelliAbstract:N-acylethanolamine acid amidase (NAAA), a cysteine hydrolase highly expressed in macrophages and B lymphocytes, catalyzes the degradation of Palmitoylethanolamide. Palmitoylethanolamide is an agonist of PPAR-α and an important regulator of pain and innate immunity. In this study, we investigated the properties of the NAAA inhibitor, ARN077, in a mouse model of allergic contact dermatitis. Acute topical applications of ARN077 attenuated key signs of DNFB-induced dermatitis in a dose-dependent manner. Moreover, ARN077 increased tissue Palmitoylethanolamide content and normalized circulating levels of cytokines and immunoglobulin E. No such effect was seen in PPAR-α–deficient mice. Moreover, mice lacking NAAA failed to develop edema or scratching behavior after challenge with DNFB, confirming that this enzyme plays an important role in dermatitis. Consistent with this conclusion, subchronic applications of ARN077 suppressed DNFB-induced inflammation when administered either before or after the DNFB challenge. The effects of subchronic ARN077 were dose dependent and comparable in size to those produced by the steroids clobetasol and dexamethasone. Unlike the latter, however, ARN077 did not cause skin atrophy. The results identify NAAA as a promising target for the development of effective and safe treatments for atopic dermatitis and other inflammatory disorders of the skin.
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identification of a widespread Palmitoylethanolamide contamination in standard laboratory glassware
Cannabis and cannabinoid research, 2017Co-Authors: Roberto Angelini, Daniele Piomelli, Donovan A Argueta, Nicholas V DipatrizioAbstract:Introduction: Fatty acid ethanolamides (FAEs) are a family of lipid mediators that participate in a host of biological functions. Procedures for the quantitative analysis of FAEs include organic solvent extraction from biological matrices (e.g., blood), followed by purification and subsequent quantitation by liquid chromatography-mass spectrometry (LC/MS) or gas chromatography-mass spectrometry. During the validation process of a new method for LC/MS analysis of FAEs in biological samples, we observed unusually high levels of the FAE, Palmitoylethanolamide (PEA), in blank samples that did not contain any biological material. Materials and Methods: We investigated a possible source of this PEA artifact via liquid chromatography coupled to tandem mass spectrometry, as well as accurate mass analysis. Results: We found that high levels of a contaminant indistinguishable from PEA is present in new 5.75″ glass Pasteur pipettes, which are routinely used by laboratories to carry out lipid extractions. This artifact might account for discrepancies found in the literature regarding PEA levels in human blood serum and other tissues. Conclusions: It is recommended to take into account this pitfall by analyzing potential contamination of the disposable glassware during the validation process of any method used for analysis of FAEs.
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the search for the Palmitoylethanolamide receptor
Life Sciences, 2005Co-Authors: Jesse Loverme, Antonio Calignano, Giovanna La Rana, Roberto Russo, Daniele PiomelliAbstract: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-alpha), 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-alpha.
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antinociceptive activity of the endogenous fatty acid amide palmitylethanolamide
European Journal of Pharmacology, 2001Co-Authors: Antonio Calignano, Giovanna La Rana, Daniele PiomelliAbstract:The endogenous fatty acid ethanolamide, palmitylethanolamide, alleviated, in a dose-dependent manner, pain behaviors elicited in mice by injections of formalin (5%, intraplantar), acetic acid (0.6%, 0.5 ml per animal, intraperitoneal, i.p.), kaolin (2.5 mg per animal, i.p.), and magnesium sulfate (120 mg per kg, i.p.). The antinociceptive effects of palmitylethanolamide were prevented by the cannabinoid CB2 receptor antagonist SR144528 [N-([1s]-endo-1.3.3-trimethylbicyclo[2.3.1]heptan-2-yl)-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide], not by the cannabinoid CB1 receptor antagonist SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide x HCl]. By contrast, palmitylethanolamide had no effect on capsaicin-evoked pain behavior or thermal nociception. The endogenous cannabinoid, anandamide (arachidonylethanolamide), alleviated nociception in all tests (formalin, acetic acid, kaolin, magnesium sulfate, capsaicin and hot plate). These effects were prevented by the cannabinoid CB1 receptor antagonist SR141716A, not the cannabinoid CB2 receptor antagonist SR141716A. Additional fatty acid ethanolamides (oleylethanolamide, myristylethanolamide, palmitoleylethanolamide, palmitelaidylethanolamide) had little or no effect on formalin-evoked pain behavior, and were not investigated in other pain models. These results support the hypothesis that endogenous palmitylethanolamide participates in the intrinsic control of pain initiation. They also suggest that the putative receptor site activated by palmitylethanolamide may provide a novel target for peripherally acting analgesic drugs.
