The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations

Petrosino, Stefania; Marzo, Vincenzo Di

doi:10.1111/bph.13580

Cited by 265 publications

(328 citation statements)

References 182 publications

(262 reference statements)

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“…Taken together, our data provide evidence that NAEs are not altered in the AD‐like Tg model, and that no overt alterations of NAEs‐mediated signaling are detectable from presymptomatic (T1), mid‐symptomatic (T2), to symptomatic disease stages (T3). PEA is reduced in postmortem brains from AD patients and has shown marked anti‐inflammatory and neuroprotective activities in several cellular and in vivo models of AD . For instance, gliosis, amyloidogenesis, and tau hyperphosphorylation were reduced after exogenous PEA administration in animals that underwent Aβ 1–42 brain infusion .…”

Section: Resultsmentioning

confidence: 99%

Targeted Lipidomics Investigation of N‐acylethanolamines in a Transgenic Mouse Model of AD: A Longitudinal Study

Piscitelli¹,

Coccurello

Totaro

et al. 2019

Euro J Lipid Sci & Tech

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In the present work, mice overexpressing mutant amyloid precursor protein (Tg2576), a transgenic model of Alzheimer's disease (AD), are used to investigate a specific lipid profile over the course of disease progression. Using a targeted lipidomic approach, plasma levels of N‐acylethanolamines with different length and unsaturation at presymptomatic, mild‐symptomatic, and symptomatic disease stages are measured. Moreover, N‐acylethanolamines are also assessed in the brain areas most affected in AD. The ethanolamides of palmitic, oleic, arachidonic, eicosapentaenoic, and docosahexaenoic acids do not show any significant alteration in blood of Tg2576 mice at the different stages analyzed, as compared to wild‐type. Except for N‐docosahexaenoylethanolamine, a general tendency to decrease is instead detected for all measured N‐acylethanolamines in the cortex, hippocampus, striatum, and cerebellum of symptomatic Tg2576 mice. Together, the data can help to redefine the range of lipid‐associated signals in Alzheimer pathophysiology. Practical Application: The development of novel therapies for AD is strongly narrowed not only by the lack of a full comprehension of underlying pathophysiological mechanisms but also by the absence of affordable, reliable, and noninvasive biomarkers. Hence, there is the practical necessity to acquire accessible blood biomarkers to provide rapid, cost‐effective, and critical information to timely identify disease stage and implement preventive strategies aimed at slowing down cognitive decline. In this study, a targeted lipidomics investigation of N‐acylethanolamines at different stages of disease progression, clearly indicates that the discovery of innovative blood biomarkers should be refocused on different indices of deranged lipid metabolism for a realistic prediction of the risk of AD. It is investigated that potential alterations of N‐acylethanolamines content during disease development in a transgenic mouse model of Alzheimer's disease (AD). Circulating and central N‐acylethanolamine levels did not show any alteration in Tg2576 mice at different disease stages.

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Section: Resultsmentioning

confidence: 99%

Targeted Lipidomics Investigation of N‐acylethanolamines in a Transgenic Mouse Model of AD: A Longitudinal Study

Piscitelli¹,

Coccurello

Totaro

et al. 2019

Euro J Lipid Sci & Tech

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“…11 The ability of this nuclear receptor to integrate metabolic and inflammatory pathways makes it an attractive target for intervention in metabolic diseases, such as NAFLD and IR. Indeed, beyond the well-known analgesic and anti-inflammatory effects, 15 PEA shows a metabolic activity, modulating energy balance in animals 16 and humans. Indeed, beyond the well-known analgesic and anti-inflammatory effects, 15 PEA shows a metabolic activity, modulating energy balance in animals 16 and humans.…”

Section: Introductionmentioning

confidence: 99%

Palmitoylethanolamide counteracts hepatic metabolic inflexibility modulating mitochondrial function and efficiency in diet‐induced obese mice

et al. 2019

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Peroxisome proliferator-activated receptor (PPAR)-α activation controls hepatic lipid homeostasis, stimulating fatty acid oxidation, and adapting the metabolic response to lipid overload and storage. Here, we investigate the effect of palmitoylethanolamide (PEA), an endogenous PPAR-α ligand, in counteracting hepatic metabolic inflexibility and mitochondrial dysfunction induced by high-fat diet (HFD) in mice.Long-term PEA administration (30 mg/kg/die per os) in HFD mice limited hepatic lipid accumulation, increased energy expenditure, and markedly reduced insulin resistance. In isolated liver mitochondria, we have demonstrated PEA capability to modulate mitochondrial oxidative capacity and energy efficiency, leading to the reduction of intracellular lipid accumulation and oxidative stress. Moreover, we have evaluated the effect of PEA on mitochondrial bioenergetics of palmitate-challenged HepG2 cells, using Seahorse analyzer. In vitro data showed that PEA recovered mitochondrial dysfunction and reduced lipid accumulation in insulin-resistant HepG2 cells, increasing fatty acid oxidation. Mechanistic studies showed that PEA effect on lipid metabolism was limited by AMP-activated protein kinase (AMPK) inhibition, providing evidence for a pivotal role of AMPK in PEA-induced adaptive metabolic setting. All these findings identify PEA as a modulator of hepatic lipid and glucose homeostasis, limiting metabolic inflexibility induced by nutrient overload. K E Y W O R D Sadenosine monophosphate-activated protein kinase (AMPK), high-fat diet, metabolic flexibility, mitochondrial dysfunction, oxidative stress, peroxisome proliferator-activated receptor (PPAR)-α

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“…In the present ex vivo model, exposing skin organ cultures to PEA‐um for 96 h did not elicit any change in either the epidermal or dermal skin compartments, in terms of epidermal thickness or keratinocyte proliferation, the same pattern of keratinocyte differentiation markers, unchanged MC density and degranulation state, compared to vehicle‐treated samples. These findings are consistent with results of previous studies on the lack of PEA‐um cytotoxicity and its overall in vivo safety profile …”

Section: Discussionmentioning

confidence: 99%

“…First, very few data are available at present on the pharmacokinetic profile (PK) of PEA‐um. One factor may be the endogenous presence (and endogenous changes) of PEA levels in the mammalian body, which likely render PK studies more difficult and require its isotopic labelling. Second, the mechanism of action of PEA appears to invoke multiple pathways, both of a direct nature (e.g.…”

Section: Discussionmentioning

confidence: 99%

Ultramicronized palmitoylethanolamide counteracts the effects of compound 48/80 in a canine skin organ culture model

Abramo

Lazzarini

Pirone

et al. 2017

Veterinary Dermatology

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Background -Ultramicronized palmitoylethanolamide (PEA-um) has been reported to reduce pruritus and skin lesions in dogs with moderate atopic dermatitis and pruritus.Hypothesis/Objectives -A canine ex vivo skin model was used to investigate the ability of PEA-um to counteract changes induced by compound 48/80, a well-known secretagogue that causes mast cell degranulation.Animals -Normal skin was obtained from three donor dogs subjected to surgery for reasons unrelated to the study.Methods -Cultured skin biopsy samples in triplicate were treated with 10 and 100 lg/mL compound 48/80, without or with 30 lM PEA-um. Mast cell (MC) degranulation, histamine release into the culture medium, local microvascular dilatation, epidermal thickness, keratinocyte proliferation and epidermal differentiation markers were evaluated.Results -Exposure of the skin organ culture to PEA-um 24 h before and 72 h concomitantly to compound 48/80 resulted in a significant decrease of degranulating MCs. PEA-um also reduced the histamine content in the culture medium by half, although the effect did not reach statistical significance. PEA-um significantly counteracted vasodilation induced by 100 lg/mL compound 48/80. Finally, PEA-um alone did not induce changes in epidermal thickness, differentiation markers, keratinocyte proliferation, MC density and/or degranulation.Conclusions and clinical importance -Collectively, these results support the protective action PEA-um on the skin of dogs undergoing allergic changes.

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The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations

Abstract: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.

Cited by 265 publications

References 182 publications

Targeted Lipidomics Investigation of N‐acylethanolamines in a Transgenic Mouse Model of AD: A Longitudinal Study

Targeted Lipidomics Investigation of N‐acylethanolamines in a Transgenic Mouse Model of AD: A Longitudinal Study

Palmitoylethanolamide counteracts hepatic metabolic inflexibility modulating mitochondrial function and efficiency in diet‐induced obese mice

Ultramicronized palmitoylethanolamide counteracts the effects of compound 48/80 in a canine skin organ culture model

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