Antiepileptic action of N-palmitoylethanolamine through CB1 and PPAR-α receptor activation in a genetic model of absence epilepsy

Citraro, Rita; Russo, Emilio; Scicchitano, Francesca; Rijn, Clementina M. van; Cosco, Donato; Avagliano, Carmen; Russo, Roberto; D’Agostino, Giuseppe; Petrosino, Stefania; Guida, Francesca; Gatta, Luisa Benerini; Luijtelaar, Gilles van; Maione, Sabatino; Marzo, Vincenzo Di; Calignano, Antonio; Sarro, Giovambattista De

doi:10.1016/j.neuropharm.2012.11.017

Cited by 94 publications

(80 citation statements)

References 64 publications

(67 reference statements)

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“…PEA has been shown to inhibit peripheral inflammation and mast cell degranulation [7], as well as exerts antinociceptive effects in rats and mice [8,9]. These actions are in part mediated by the activation of peroxisome proliferator-activated receptors (PPARs), accompanied by a decrease in neutrophil influx and a decrease in expression of pro-inflammatory proteins, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) [10,11]. Moreover, our previous works clearly demonstrated that treatment with PEA at 10 mg/kg significantly reduced the inflammation process associated with experimental SCI in mice [12] and in a traumatic brain injury (TBI) model [13].…”

Section: Introductionmentioning

confidence: 99%

A new co-ultramicronized composite including palmitoylethanolamide and luteolin to prevent neuroinflammation in spinal cord injury

Paterniti

Impellizzeri

Paola

et al. 2013

J Neuroinflammation

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BackgroundIt has recently been demonstrated that palmitoylethanolamide (PEA), an endogenous lipid amide belonging to the N-acylethanolamine family, exerts neuroprotection in central nervous system (CNS) pathologies. In recent studies, we have demonstrated that treatment with PEA significantly reduced inflammatory secondary events associated with spinal cord injury (SCI). Since oxidative stress is considered to play an important role in neuroinflammatory disorders, in the present work we studied a new composite, a formulation including PEA and the antioxidant compound luteolin (Lut), subjected to an ultramicronization process, co-ultraPEALut. We investigated the effect of co-ultraPEALut (in the respective fixed doses of 10:1 in mass) in both an ex vivo organotypic spinal cord culture model and an in vivo model of SCI.MethodsFor the organotypic cultures, spinal cords were prepared from mice at postnatal day 6 and were cut into transverse slices of 400 μm thickness to generate the lumbar organotypic slice cultures. After 7 days of culturing, the slices were mechanically injured onto the center of the slice and the co-ultraPEALut was applied at different concentrations (0.00009, 0.0009 and 0.009 g/l) 1 hour before damage. For in vivo studies, SCI was induced in mice through spinal cord compression by the application of vascular clips (force of 24 g) to the dura via a four-level T5 to T8 laminectomy, and co-ultraPEALut (1 mg/kg ip) was administered at 1 and 6 hours after SCI. At 24 hours after SCI, mice were sacrificed and the spinal cords were collected for further evaluation. Additional animals were treated similarly and sacrificed 10 days after SCI.ResultsPretreatment with co-ultraPEALut significantly reduced cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression in a concentration-dependent manner, restored neuronal nitric oxide synthase (nNOS) expression at all three tested concentrations, and protected cells by cell death (MTT assay) in spinal cord organotypic cultures. Moreover, we demonstrated in vivo that co-ultraPEALut 1 mg/kg reduced the severity of trauma induced by compression and improved the motor activity evaluated at 10 days post-injury.ConclusionThe present study demonstrates that the protective effect of PEA on SCI-associated neuroinflammation could be improved by co-ultramicronization with Lut possibly due to its antioxidant properties.

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Section: Introductionmentioning

confidence: 99%

A new co-ultramicronized composite including palmitoylethanolamide and luteolin to prevent neuroinflammation in spinal cord injury

Paterniti

Impellizzeri

Paola

et al. 2013

J Neuroinflammation

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“…Therefore, the protective effects of PEA against radiation-induced intestinal injury reported here likely result from the action of PEA at multiple targets. For example, PEA has been shown to indirectly and/or directly activate CB1 [35,36] and CB2 receptors [8,37] via an “ entourage effect ” producing elevated levels of the endocannabinoid anandamide [11]. Activation of CB1 receptors inhibits development of colitis induced by mustard oil and dextran sulfate sodium [38], and CB1-deficient mice show elevated levels of intestinal CB1 receptors and enhanced inflammation in response to chemically-induced colitis [39].…”

Section: Discussionmentioning

confidence: 99%

Palmitoylethanolamide Regulates Development of Intestinal Radiation Injury in a Mast Cell-Dependent Manner

et al. 2014

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Background Mast cells and neuroimmune interactions regulate the severity of intestinal radiation mucositis, a dose-limiting toxicity during radiation therapy of abdominal malignancies. Aims Because endocannabinoids regulate intestinal inflammation, we investigated the effect of the cannabimimetic, palmitoylethanolamide (PEA), in a mast competent (+/+) and mast cell deficient (Ws/Ws) rat model. Methods Rats underwent localized, fractionated intestinal irradiation and received daily injections with vehicle or PEA from 1 day before until 2 weeks after radiation. Intestinal injury was assessed non-invasively by luminol bioluminescence, and, at 2 weeks, by histology, morphometry, and immunohistochemical analysis, gene expression analysis, and pathway analysis. Results Compared to +/+ rats, Ws/Ws rats sustained more intestinal structural injury (p=0.01), mucosal damage (p=0.02), neutrophil infiltration (p=0.0003), and collagen deposition (p=0.004). PEA reduced structural radiation injury (p=0.02), intestinal wall thickness (p=0.03), collagen deposition (p=0.03), and intestinal inflammation (p=0.02) in Ws/Ws rats, but not in +/+ rats. PEA inhibited mast cell-derived cellular immune response and anti-inflammatory IL-6 and IL-10 signaling, and activated the prothrombin pathway in +/+ rats. In contrast, while PEA suppressed non-mast cell derived immune responses, it increased anti-inflammatory IL-10 and IL-6 signaling and decreased activation of the prothrombin pathway in Ws/Ws rats. Conclusions These data demonstrate that the absence of mast cells exacerbate radiation enteropathy by mechanisms that likely involve the coagulation system, anti-inflammatory cytokine signaling, and the innate immune system; and that these mechanisms are regulated by PEA in a mast cell-dependent manner. The endocannabinoid system should be explored as target for mitigating intestinal radiation injury.

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“…Another mediator of the pharmacological actions of PEA, such as the analgesic, antiepileptic and anti-inflammatory effects, is the nuclear receptor PPARα (Lo Verme et al, 2005;Citraro et al, 2013;Esposito et al, 2014;Okine et al, 2014). We thus investigated the possible involvement of this receptor by measuring its intestinal mRNA expression 28 days after OM administration and by evaluating the effect of PEA in the presence of GW6471, a PPARα receptor antagonist.…”

Section: Figure 10mentioning

confidence: 99%

Palmitoylethanolamide normalizes intestinal motility in a model of post‐inflammatory accelerated transit: involvement of CB₁ receptors and TRPV1 channels

Capasso

Orlando

Pagano

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEPalmitoylethanolamide (PEA), a naturally occurring acylethanolamide chemically related to the endocannabinoid anandamide, interacts with targets that have been identified in peripheral nerves controlling gastrointestinal motility, such as cannabinoid CB1 and CB2 receptors, TRPV1 channels and PPARα. Here, we investigated the effect of PEA in a mouse model of functional accelerated transit which persists after the resolution of colonic inflammation (post-inflammatory irritable bowel syndrome). EXPERIMENTAL APPROACHIntestinal inflammation was induced by intracolonic administration of oil of mustard (OM). Mice were tested for motility and biochemical and molecular biology changes 4 weeks later. PEA, oleoylethanolamide and endocannabinoid levels were measured by liquid chromatography-mass spectrometry and receptor and enzyme mRNA expression by qRT-PCR. KEY RESULTSOM induced transient colitis and a functional post-inflammatory increase in upper gastrointestinal transit, associated with increased intestinal anandamide (but not 2-arachidonoylglycerol, PEA or oleoylethanolamide) levels and down-regulation of mRNA for TRPV1 channels. Exogenous PEA inhibited the OM-induced increase in transit and tended to increase anandamide levels. Palmitic acid had a weaker effect on transit. Inhibition of transit by PEA was blocked by rimonabant (CB1 receptor antagonist), further increased by 5′-iodoresiniferatoxin (TRPV1 antagonist) and not significantly modified by the PPARα antagonist GW6471. CONCLUSIONS AND IMPLICATIONSIntestinal endocannabinoids and TRPV1 channel were dysregulated in a functional model of accelerated transit exhibiting aspects of post-inflammatory irritable bowel syndrome. PEA counteracted the accelerated transit, the effect being mediated by CB1 receptors (possibly via increased anandamide levels) and modulated by TRPV1 channels.

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Antiepileptic action of N-palmitoylethanolamine through CB1 and PPAR-α receptor activation in a genetic model of absence epilepsy

Cited by 94 publications

References 64 publications

A new co-ultramicronized composite including palmitoylethanolamide and luteolin to prevent neuroinflammation in spinal cord injury

A new co-ultramicronized composite including palmitoylethanolamide and luteolin to prevent neuroinflammation in spinal cord injury

Palmitoylethanolamide Regulates Development of Intestinal Radiation Injury in a Mast Cell-Dependent Manner

Palmitoylethanolamide normalizes intestinal motility in a model of post‐inflammatory accelerated transit: involvement of CB₁ receptors and TRPV1 channels

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Antiepileptic action of N-palmitoylethanolamine through CB1 and PPAR-α receptor activation in a genetic model of absence epilepsy

Cited by 94 publications

References 64 publications

A new co-ultramicronized composite including palmitoylethanolamide and luteolin to prevent neuroinflammation in spinal cord injury

A new co-ultramicronized composite including palmitoylethanolamide and luteolin to prevent neuroinflammation in spinal cord injury

Palmitoylethanolamide Regulates Development of Intestinal Radiation Injury in a Mast Cell-Dependent Manner

Palmitoylethanolamide normalizes intestinal motility in a model of post‐inflammatory accelerated transit: involvement of CB1 receptors and TRPV1 channels

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Palmitoylethanolamide normalizes intestinal motility in a model of post‐inflammatory accelerated transit: involvement of CB₁ receptors and TRPV1 channels