N-Acylethanolamines (NAEs) (fatty acid ethanolamides) are naturally occurring hydrophobic molecules usually present in a very small amount in many mammalian tissues and cells  and . Moreover, NAEs are normally present in biological fluids, such as blood , in very low concentrations. The physiological levels of important NAEs in mammalian blood plasma are in the range 2.8–5.2 pmol/ml for anandamide (AEA); 9.4–16.7 pmol/ml for PEA; 8.1–10.3 pmol/ml for oleylethanolamide (OEA) ,  and . However, the NAEs levels in blood plasma could be modified in pathological conditions, e.g., the physiological concentrations of AEA in human plasma are 4 pmol/ml, but these concentrations are increased up to 18–30 pmol/ml in sera of patients with endotoxic shocks . In vivo studies demonstrated that NAEs could accumulate in injured tissues, such as, e.g., in myocardium infarcted areas , and in post decapitative brain ischemia .
Palmitoylethanolamide (C16:0) (PEA), a shorter and fully saturated analogue of anandamide, exhibits a number of biochemical, physiological and pharmacological effects  and . However, its mechanism of action remains unclear  and  and its effects are not always reproducible. Among the others, it was identified as the anti-inflammatory principle present in many natural products, and its anti-inflammatory properties were confirmed by recent research ,  and , although they seem less marked in human systems . In vitro studies demonstrated that PEA inhibits the nitric oxide production in macrophages , affects the time course of capacitation of human spermatozoa , and increases the PLA2 hydrolytic activity . In those studies, PEA concentrations inducing significant effects ranged from 5  to 30 μM . Physiologically relevant concentrations of PEA (3 nM–3 μM)  may also have important physiological and/or pharmacological effects. For example, 300 nM PEA was shown to protect rat isolated heart against ischemia .
Forms the introduction of a hallmark paper on the protective aspects of the natural painkiller palmitoylethanolamide, written by Zolese et al. Based on their knowledge of blood fats (cholesterol etc) and the detrimental effects of oxydation, the authors conducted a study in order to evaluate the possible effect of physiologically relevant concentrations of PEA on the resistance of plasma lipoproteins to oxidation.
They found in their in vitro experiments indicatations of anti-oxidative effects of PEA on the oxidation of LDL, isolated from plasma after incubation with this endogenous fatty acid amide.The protective effect of PEA occurs in physiological and supraphysiological conditions, such also takes place during for instance septic shock:
It has to be stressed that the anti-oxidant effect is obtained at low PEA concentrations in plasma is similar to those observed in pathological conditions, such as endotoxic shock
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