Anticonvulsant Activity of <i>N</i>‐Palmitoylethanolamide, a Putative Endocannabinoid, in Mice

Lambert, Didier; Vandevoorde, Séverine; Diependaele, Gérald; Govaerts, Sophie S.J.; Robert, Annie

doi:10.1046/j.1528-1157.2001.41499.x

Cited by 136 publications

(88 citation statements)

References 42 publications

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“…Anandamide (arachidonoylethanolamide, AEA) and its analogue palmitoylethanolamide (PEA) regulate many of the same pathophysiological processes, including pain perception, convulsions, neurotoxicity and inflammation (Calignano et al 1998;Lo Verme et al 2005;Jaggar et al 1998;Lambert et al 2001;Skaper et al 1996). They both fulfill the three criteria required to be considered bona fide lipid transmitters: stimulus-dependent production, interaction with specific receptors and enzymatic inactivation.…”

Section: Introductionmentioning

confidence: 99%

Microglia produce and hydrolyze palmitoylethanolamide

Muccioli

Stella

2008

Neuropharmacology

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Microglial cell activation and migration play an important role in neuroinflammation propagation. While it is known that the lipid transmitter palmitoylethanolamide (PEA) regulates microglial migration by interacting with a cannabinoid-like receptor, the production and inactivation of this lipid by microglia has never been addressed directly. Here we show that the mouse microglial cell line BV-2 produces and hydrolyzes PEA. The carbamate compound URB602 inhibits PEA hydrolysis in BV-2 cell homogenates and increases PEA levels in intact cells, whereas the FAAH inhibitor URB597 and serine-hydrolase inhibitor MAFP do not affect PEA levels in intact cells. This unique pharmacological profile of inhibitors on PEA hydrolysis suggests the involvement of a previously undescribed enzyme that degrades PEA. This enzyme expressed by microglia constitutes a promising target for controlling the propagation of neuroinflammation.

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Section: Introductionmentioning

confidence: 99%

Microglia produce and hydrolyze palmitoylethanolamide

Muccioli

Stella

2008

Neuropharmacology

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“…However, interest in this compound faded until the discovery that one of its structural analogs, anandamide (arachidonoylethanolamide), serves as an endogenous ligand for cannabinoid receptors, the molecular target of ⌬ 9 -tetrahydrocannabinol in marijuana (Devane et al, 1992). Since this finding, PEA has been shown to inhibit peripheral inflammation and mast cell degranulation (Berdyshev et al, 1998), as well as to exert neuroprotective (Lambert et al, 2001) and antinociceptive (Calignano et al, 1998) effects in rats and mice. These actions are mediated by PPAR-␣ activation and are accompanied by a decrease in nitric oxide production (Ross et al, 2000), neutrophil influx (Farquhar-Smith et al, 2002), and expression of proinflammatory proteins such as inducible nitric-oxide synthase (iNOS) and cyclooxygenase-2 (Costa et al, 2002).…”

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confidence: 99%

Effects of Palmitoylethanolamide on Signaling Pathways Implicated in the Development of Spinal Cord Injury

Genovese

Esposito

Mazzon

et al. 2008

J Pharmacol Exp Ther

102

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Activation of peroxisome proliferator-activated receptor (PPAR)-␣, a member of the nuclear receptor superfamily, modulates inflammation and tissue injury events associated with spinal cord trauma in mice. Palmitoylethanolamide (PEA), the naturally occurring amide of palmitic acid and ethanolamine, reduces pain and inflammation through a mechanism dependent on PPAR-␣ activation. The aim of the present study was to evaluate the effect of the PEA on secondary damage induced by experimental spinal cord injury (SCI) in mice. SCI was induced by application of vascular clips to the dura mater via a four-level T 5 -T 8 laminectomy. This resulted in severe trauma characterized by edema, neutrophil infiltration, and production of inflammatory mediators, tissue damage, and apoptosis. Repeated PEA administration (10 mg/kg i.p.; 30 min before and 1 and 6 h after SCI) significantly reduced: 1) the degree of spinal cord inflammation and tissue injury, 2) neutrophil infiltration, 3) nitrotyrosine formation, 4) proinflammatory cytokine expression, 5) nuclear transcription factor activation-B activation, 6) inducible nitric-oxide synthase expression, and 6) apoptosis. Moreover, PEA treatment significantly ameliorated the recovery of motor limb function. Together, the results indicate that PEA reduces inflammation and tissue injury associated with SCI and suggest a regulatory role for endogenous PPAR-␣ signaling in the inflammatory response associated with spinal cord trauma.Spinal cord injury (SCI) is a highly debilitating pathology (Maegele et al., 2005). Although innovative medical care has improved patient outcome, advances in pharmacotherapy for the purpose of limiting neuronal injury and promoting regeneration have been limited. The complex pathophysiology of SCI may explain the difficulty in finding a suitable therapy. The primary traumatic mechanical injury to the spinal cord causes the death of a number of neurons that cannot be recovered and regenerated. Studies indicate that neurons continue to die for hours following traumatic SCI (Profyris et al., 2004). The events that characterize this successive phase to mechanical injury are called "secondary damage." The secondary damage is determined by a large number of cellular, molecular, and biochemical cascades. A large body of recent data suggests the presence of a local inflammatory response, which amplifies the secondary damage (Blight, 1992).Moreover, evidence has suggested that resident microglia and macrophages originating from blood are two key cell types related to the occurrence of neuronal degeneration in the central nervous system after traumatic injury. In particular, when SCI occurs, microglia in parenchyma is activated, and macrophages in circulation cross the blood-brain barrier (BBB) to act as intrinsic spinal phagocytes. Therefore, these cells can release various neurotrophic peptides such as brainderived neurotrophic factor, glial cell line-derived neurotrophic factor, and laminin, which are excellent substrates for neurite outgrowth.Peroxisome pro...

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“…The width (in mm) of the erythema induced by IFN-β1a at its injection site was evaluated over its maximum diameter at 1 month, and after 6 and 12 months of PEA or placebo treatment. Blood samples were collected from all the patients to quantify NAE plasma levels (1, 3, 6, 9, and 12 months) and proinflammatory cytokines (1,3,6, and 12 months). The primary endpoints of the study were to evaluate the efficacy of um-PEA in 1) reducing IFN-β1a-related adverse effects in patients with RR-MS (pain and erythema width at the injection site); and 2) improving the patients' QoL.…”

Section: Palmitoylethanolamide In Ms Therapy 429mentioning

confidence: 99%

“…Since the 1990s, interest in the therapeutic potential of PEA has increased owing to the discovery of the effects of PEA in many preclinical paradigms for pain and chronic inflammation [2]. PEA has antinociceptive properties in several animal models [3][4][5], prevents neurotoxicity and neurodegeneration [6][7][8], and inhibits peripheral inflammation and mast cell degranulation [9,10]. These effects of PEA are not only observed when used as a drug (i.e., after direct administration) [11,12], but also when its endogenous levels are increased by blocking its catabolism [13].…”

Section: Introductionmentioning

confidence: 99%

Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing–Remitting Multiple Sclerosis

et al. 2016

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Palmitoylethanolamide (PEA) is an endogenous lipid mediator known to reduce pain and inflammation. However, only limited clinical studies have evaluated the effects of PEA in neuroinflammatory and neurodegenerative diseases. Multiple sclerosis (MS) is a chronic autoimmune and inflammatory disease of the central nervous system. Although subcutaneous administration of interferon (IFN)-β1a is approved as first-line therapy for the treatment of relapsing-remitting MS (RR-MS), its commonly reported adverse events (AEs) such as pain, myalgia, and erythema at the injection site, deeply affect the quality of life (QoL) of patients with MS. In this randomized, double-blind, placebocontrolled study, we tested the effect of ultramicronized PEA (um-PEA) added to IFN-β1a in the treatment of clinically defined RR-MS. The primary objectives were to estimate whether, with um-PEA treatment, patients with MS perceived an improvement in pain and a decrease of the erythema width at the IFN-β1a injection site in addition to an improvement in their QoL. The secondary objectives were to evaluate the effects of um-PEA on circulating interferon-γ, tumor necrosis factor-α, and interleukin-17 serum levels, N-acylethanolamine plasma levels, Expanded Disability Status Scale (EDSS) progression, and safety and tolerability after 1 year of treatment. Patients with MS receiving um-PEA perceived an improvement in pain sensation without a reduction of the erythema at the injection site. A significant improvement in QoL was observed. No significant difference was reported in EDSS score, and um-PEA was well tolerated. We found a significant increase of palmitoylethanolamide, anandamide and oleoylethanolamide plasma levels, and a significant reduction of interferon-γ, tumor necrosis factor-α, and interleukin-17 serum profile compared with the placebo group. Our results suggest that um-PEA may be considered as an appropriate add-on therapy for the treatment of IFN-β1a-related adverse effects in RR-MS.

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Anticonvulsant Activity of N‐Palmitoylethanolamide, a Putative Endocannabinoid, in Mice

Cited by 136 publications

References 42 publications

Microglia produce and hydrolyze palmitoylethanolamide

Microglia produce and hydrolyze palmitoylethanolamide

Effects of Palmitoylethanolamide on Signaling Pathways Implicated in the Development of Spinal Cord Injury

Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing–Remitting Multiple Sclerosis

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