The Basal Pharmacology of Palmitoylethanolamide

Abstract

Palmitoylethanolamide (PEA, N-hexadecanoylethanolamide) is an endogenous compound belonging to the family of N-acylethanolamines. PEA has anti-inflammatory and analgesic properties and is very well tolerated in humans. In the present article, the basal pharmacology of PEA is reviewed. In terms of its pharmacokinetic properties, most work has been undertaken upon designing formulations for its absorption and upon characterising the enzymes involved in its metabolism, but little is known about its bioavailability, tissue distribution, and excretion pathways. PEA exerts most of its biological effects in the body secondary to the activation of peroxisome proliferator-activated receptor-α (PPAR-α), but PPAR-α-independent pathways involving other receptors (Transient Receptor Potential Vanilloid 1 (TRPV1), GPR55) have also been identified. Given the potential clinical utility of PEA, not least for the treatment of pain where there is a clear need for new well-tolerated drugs, we conclude that the gaps in our knowledge, in particular those relating to the pharmacokinetic properties of the compound, need to be filled.

Keywords: N-acylethanolamine acid amidase; atopic eczema; fatty acid amide hydrolase; low back pain–sciatica; palmitoylethanolamide; peroxisome proliferator-activated receptor-α.

Figure 1

Chemical structure of PEA. For the N-acyl side chain, the nomenclature is (16:0) given that there are sixteen carbon atoms and no double bonds between the carbon atoms. The corresponding numbers for OEA and AEA are (18:1) and (20:4), respectively.

Figure 2

Results of a PubMed search conducted on 17 September 2020 with the search word “palmitoylethanolamide” and range 1968–present. Subsections with “clinical trial” and “review” indicated as article type were also downloaded from PubMed.

Figure 3

Absorption, distribution, metabolism, and excretion of PEA. Abbreviations: FAAH, fatty acid amide hydrolase; NAAA, N-acylethanolamine acid amidase; PA, palmitic acid. For details with respect to the metabolism of PA, see [7].

Figure 4

Schematic showing demonstrated and potential molecular targets of PEA. ↑, activation; ┴, inhibition (in the case of FAAH by substrate competition). The canonical pathway via PPAR-α is shown in red. Grey arrows indicate possible pathways not yet identified. Abbreviations (where not already indicated), TRPV1, Transient receptor potential vanilloid 1; MC, mast cell; COX-2, cyclooxygenase-2; PGs, prostaglandins.

Figure 5

The canonical pathway for the synthesis of PEA via N-acyltransferases (NATs) and N-acylphosphatidylethanolamines (NAPE)–phospholipase D. The catabolism of PEA is also shown in the figure, which is based upon Figure 2 of [84] and Figure 1 of [86].

Figure 6

mRNA levels of Napepld, coding for NAPE-hydrolysing phospholipase D (NAPE-PLD) in J774 cells cultured in 24-well plates for 24 h and treated for 2, 4, and 6 h with lipopolysaccharide (LPS, 0.1 µg/mL) + interferon-γ (100 U/mL) and/or 10 µM PEA. Shown are box and whisker plots, N = 8. The mRNA values are determined using Rpl19 as reference gene and are given as ∆Ct with the mean values relative to the unstimulated controls at the 2 h time point on the right y-axis. A decrease of 1 ∆Ct unit represents a doubling in the mRNA concentration. The box shows the results of a 3-way ANOVA (ti, time; L, LPS + interferon-γ; P, PEA. These indicate a time-dependent effect of the inflammatory stimulus on Napepld expression, but no significant effect of PEA treatment. Figure redrawn from [87].