A new role for anandamide: defective link between the systemic and skin endocannabinoid systems in hypertrophic human wound healing

Abstract

The use of cannabinoids to treat fibrotic skin diseases is an emergent issue. Therefore, we aimed to evaluate systemic and skin endocannabinoid responses in the wound-healing process in humans. A prospective study was performed in 50 patients who underwent body-contouring surgery. Anandamide (N-arachidonoylethanolamine, AEA), 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were quantified using LC-MS/MS. Ten (20%) patients developed hypertrophic (HT) scars. No significant changes were observed between the normal (N) scar and HT scar groups in terms of plasma and skin endocannabinoids. Nevertheless, a positive correlation between plasma and skin AEA concentrations was found in the N group (r = 0.38, p = 0.015), which was absent in the HT group. Moreover, the AEA concentration was significantly lower in HT scar tissue than in normal scar tissue (0.77 ± 0.12 ng/g vs 1.15 ± 0.15 ng/g, p < 0.001). Interestingly, in all patients, the surgical intervention produced a time-dependent effect with a U shape for AEA, PEA and OEA plasma concentrations. In contrast, 2-AG plasma concentrations increased 5 days after surgery and were reduced and stabilized 3 months later. These results suggest crosstalk between systemic and local skin endocannabinoid systems during human wound healing. AEA appears to be the most likely candidate for this link, which is deficient in patients with HT scars. Endocannabinoids are the endogenous ligands for cannabinoid receptors CB1 and CB2, which are two G-protein coupled receptors that have a widespread distribution throughout the body 1,2. The most studied endocannabinoids are the arachidonic acid derivatives N-arachidonoylethanolamine (AEA) 3 and 2-arachidonoylglycerol (2-AG) 4. Palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are N-acylethanolamines (NAEs) that act by influencing AEA metabolism and binding to peroxisome proliferator-activated receptor alpha (PPAR-α) and to transient receptor potential cation channel subfamily V member 1 (TRPV1) 5-7. Endocannabinoids and related NAEs play an essential role in many physiological central and peripheral processes. These include emotional responses, cognition, memory, motor behaviour, immune function, feeding, energy consumption and metabolic regulation at the systemic and cellular levels 8-13. Endocannabinoids are present in human blood, and their concentrations are dynamic. Food consumption, obesity, exercise, sleep pattern, time of the day, stress, anxiety, inflammation and pain are known to modify the endocannabinoid concentrations in the circulation 14. They have also been quantified in other biological samples obtained from humans, including saliva 15 , hair 16 , semen 17 , breast milk, and amniotic fluid 18 .

Distribution of an Analgesic Palmitoylethanolamide and Other N-Acylethanolamines in Human Placental Membranes

“…We established reference concentrations of PEA, OEA and AEA in all tested tissues, including AM and PL, by averaging values from the central and peripheral part of placenta, which did not differ in their statistical signi cance (Supplementary Table S4). An observed trend in the distribution of NAEs through all measured specimens (PEA > OEA > AEA) is in accordance with previously published results [22,25,53].…”

“…Thus, they may be at least partially responsible for the positive effects associated with AM/ACM in the healing process. It is known that PEA operates primarily through PPAR-α receptor, which is expressed also in the skin [53], the site where AM/ACM grafts are applied. It has been shown that activators of PPAR-α receptor promote differentiation of human epidermal keratinocytes [67].…”

“…Regarding clinical effect of NAEs, it has to be taken into a consideration that their overall wound healing effects depends on their half-life duration in tissue, which is contingent on the ratio between synthesis and degradation rates [53,73]. The observed differences in NAEs concentration in samples from individual subjects are likely to re ect current state of health of donors, such as the presence of obesity, stress, or in ammation [53]. On the other hand, the concentration ratios between tested tissue types (AM, ACM, etc.)…”

“…OEA has mostly anorexigenic properties [49], but its ability to reduce nociceptive responses and in ammation has also been shown [50,51]. AEA has been implicated in possessing anti-nociceptive, vasodilation, and anti-in ammatory effects [22,35,[52][53][54]. Recently its role in physiological wound healing has been also suggested [22,53,54].…”

Exogenous Antioxidants Impact on UV-Induced Changes in Membrane Phospholipids and the Effectiveness of the Endocannabinoid System in Human Skin Cells

“…Moreover, UV radiation has a strong effect on the endocannabinoid system in the skin fibroblasts and keratinocytes, which includes both decreases in basal endocannabinoid (anandamide, 2-AG) levels as well as enhanced expression of their main membrane receptors (CB1/2, TVRP1) [ 3 , 6 ]. So far, the direct role of endocannabinoids in human skin has been described in the case of wound healing [ 7 ], but also under neo-plastic processes [ 8 ], where its increased level promoted cell proliferation and has an antiapoptotic effect. However, their basic action concerns the interactions with specific receptors [ 9 ].…”