Palmitoylethanolamide exerts neuroprotective effects in mixed neuroglial cultures and organotypic hippocampal slices via peroxisome proliferator-activated receptor-α

<p>Abstract</p> <p>Background</p> <p>In addition to cytotoxic mechanisms directly impacting neurons, β-amyloid (Aβ)-induced glial activation also promotes release of proinflammatory molecules that may self-perpetuate reactive gliosis and damage neighbouring neurons, thus amplifying neuropathological lesions occurring in Alzheimer's disease (AD). Palmitoylethanolamide (PEA) has been studied extensively for its anti-inflammatory, analgesic, antiepileptic and neuroprotective effects. PEA is a lipid messenger isolated from mammalian and vegetable tissues that mimics several endocannabinoid-driven actions, even though it does not bind to cannabinoid receptors. Some of its pharmacological properties are considered to be dependent on the expression of peroxisome proliferator-activated receptors-α (PPARα).</p> <p>Findings</p> <p>In the present study, we evaluated the effect of PEA on astrocyte activation and neuronal loss in models of Aβ neurotoxicity. To this purpose, primary rat mixed neuroglial co-cultures and organotypic hippocampal slices were challenged with Aβ_1-42and treated with PEA in the presence or absence of MK886 or GW9662, which are selective PPARα and PPARγ antagonists, respectively. The results indicate that PEA is able to blunt Aβ-induced astrocyte activation and, subsequently, to improve neuronal survival through selective PPARα activation. The data from organotypic cultures confirm that PEA anti-inflammatory properties implicate PPARα mediation and reveal that the reduction of reactive gliosis subsequently induces a marked rebound neuroprotective effect on neurons.</p> <p>Conclusions</p> <p>In line with our previous observations, the results of this study show that PEA treatment results in decreased numbers of infiltrating astrocytes during Aβ challenge, resulting in significant neuroprotection. PEA could thus represent a promising pharmacological tool because it is able to reduce Aβ-evoked neuroinflammation and attenuate its neurodegenerative consequences.</p

A neuroscientist's guide to lipidomics

Nerve cells mould the lipid fabric of their membranes to ease vesicle fusion, regulate ion fluxes and create specialized microenvironments that contribute to cellular communication. The chemical diversity of membrane lipids controls protein traffic, facilitates recognition between cells and leads to the production of hundreds of molecules that carry information both within and across cells. With so many roles, it is no wonder that lipids make up half of the human brain in dry weight. The objective of neural lipidomics is to understand how these molecules work together; this difficult task will greatly benefit from technical advances that might enable the testing of emerging hypotheses

Cold exposure stimulates synthesis of the bioactive lipid oleoylethanolamide in rat adipose tissue

Oleoylethanolamide (OEA) is an endogenous lipid mediator that inhibits feeding and stimulates lipolysis by activating the nuclear receptor peroxisome proliferator-activating receptor-alpha. Little is known about the physiological regulation of this compound outside of the gastrointestinal tract, where its production is regulated by feeding. Here we show that cold exposure increases OEA levels in rat white adipose tissue but not in liver or intestine. This change is accompanied by parallel elevations in the activity of N-acyltransferase, a key enzyme responsible for OEA synthesis, without concomitant changes in fatty acid amide hydrolase, an enzyme responsible for OEA degradation. Moreover, cold stimulates the production of two species of N-oleoylphosphatidylethanolamine OEA precursors. The changes in OEA biosynthesis are reversed by pretreatment with the beta-receptor antagonist propranolol, suggesting a role for beta-adrenoreceptors in this response. In agreement with these findings, the beta-agonists noradrenaline and isoproterenol stimulate OEA production in isolated adipocytes, an effect that is mimicked by the adenylyl cyclase activator forskolin. Collectively, these results identify cold exposure as a natural stimulus for OEA formation in white fat and suggest a role for the sympathetic nervous system in regulating OEA biosynthesis

Detrimental effects of ethanol on murine frostbite.

Many references have been made concerning the adverse effects of ethanol in human frostbite. The lack of experimental evidence to support this belief prompted the authors to undertake this investigation. Nineteen Swiss-Webster mice (25 +/- 2 gm) were given intraperitoneal injections of 0.2 cm3 of 50 per cent ethanol (group A) or 0.2 cm3 saline (group B). Thirty minutes later, the animals were anesthetized with pentobarbital (group A 30 mg/kg; group B 50 mg/kg). Lower barbiturate dose was used in group A because of the synergistic central nervous system depressant effect when combined with alcohol. Tail lengths of all animals were measured. The tails were immersed in a 50 per cent ethylene glycol solution (-18 C) for 6 min and then thawed at room temperature (24 C). At 24 hrs, tail circulation was assessed by length of tail perfused with the vital dye alphazurine 2 gm given intraperitoneally. Mortality to 14 days was recorded. All animals survived the initial anesthetic and/or alcohol administration. Group A had a statistically significant (P less than 0.001 Students t test) decrease in length of tail perfused compared with group B at 24 hours (0.98 +/- 0.19 cm versus 2.58 +/- 0.23 cm). Fourteen day survival was 10 per cent in group A compared with 89 per cent in group B (P less than 0.001, chi-square test). We conclude that ethanol has significant adverse effects on tissue perfusion and mortality associated with severe murine frostbite

Regulation of food intake by oleoylethanolamide

Oleoylethanolamide (OEA), the naturally occurring amide of ethanolamine and oleic acid, is an endogenous lipid that modulates feeding, body weight and lipid metabolism by binding with high affinity to the ligand-activated transcription factor, peroxisome proliferator-activated receptor-alpha (PPAR-α). In the present article, we describe the biochemical pathways responsible for the initiation and termination of OEA signaling, and outline the pharmacological properties of this compound in relation to its ability to activate PPAR-α. Finally, we discuss the possible role of OEA as a peripheral satiety hormone. © Birkhäuser Verlag, Basel, 2005