Palmitoylethanolamide

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, belonging to the class of nuclear factor agonists. PEA has been demonstrated to bind to a receptor in the cell-nucleus (a nuclear receptor) and exerts a great variety of biological functions related to chronic pain and inflammation. The main target is thought to be the peroxisome proliferator-activated receptor alpha (PPAR-α). PEA also has affinity to cannabinoid-like G-coupled receptors GPR55 and GPR119. PEA cannot strictly be considered a classic endocannabinoid because it lacks affinity for the cannabinoid receptors CB1 and CB2. However, the presence of PEA (and other structurally related N-acylethanolamines) has been known to enhance anandamide activity by an 'entourage effect'. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, belonging to the class of nuclear factor agonists. PEA has been demonstrated to bind to a receptor in the cell-nucleus (a nuclear receptor) and exerts a great variety of biological functions related to chronic pain and inflammation. The main target is thought to be the peroxisome proliferator-activated receptor alpha (PPAR-α). PEA also has affinity to cannabinoid-like G-coupled receptors GPR55 and GPR119. PEA cannot strictly be considered a classic endocannabinoid because it lacks affinity for the cannabinoid receptors CB1 and CB2. However, the presence of PEA (and other structurally related N-acylethanolamines) has been known to enhance anandamide activity by an 'entourage effect'. Several papers have demonstrated that an imbalance of the endocannabinoid system (ECS) and alterations in the levels of PEA occur in acute and chronic inflammation. For instance, during β-amyloid-induced neuroinflammation the deregulation of cannabinoid receptors and their endogenous ligands accompanies the development and progression of disease. PEA has been shown to have anti-inflammatory, anti-nociceptive, neuroprotective, and anticonvulsant properties. Palmitoylethanolamide was discovered in 1957. Indications for its use as an anti-inflammatory and analgesic date from before 1980. In that year, researchers described what they called 'N-(2-hydroxyethyl)-palmitamide' as a natural anti-inflammatory agent. They stated: ' We have succeeded in isolating a crystalline anti-inflammatory factor from soybean lecithin and identifying it as (S)-(2-hydroxyethyl)-palmitamide. The compound also was isolated from a phospholipid fraction of egg yolk and from hexane-extracted peanut meal.' In 1975 Czech physicians described the results of a clinical trial using it for joint pain,. The analgesic action of 3 grams of aspirin during the day was compared to PEA 1.8 gram/day. Both drugs were reported to enhance joint movements and decrease pain. In 1970 the drug manufacturer Spofa introduced 'Impulsin' tablets of 500 mg PEA for the treatment and prophylaxis of flu and respiratory infections in Czechoslovakia; the company Almirall introduced 'Palmidrol', as either tablets or as a suspension, in Spain in 1976 for the same indications. In the 1990s, the relation between anandamide and PEA was described; the expression of mast cell receptors sensitive to the two molecules was first demonstrated by the research group of Nobel prize winner Rita Levi-Montalcini. During this period, more insight into the functions of endogenous fatty acid derivatives emerged, and compounds such as oleamide, palmitoylethanolamide, 2-lineoylglycerol and 2-palmitoylglycerol were explored for their capacity to modulate pain sensitivity and inflammation via what at that time was thought to be the endocannabinoid signalling pathway. One group demonstrated that PEA could alleviate, in a dose-dependent manner, pain behaviors elicited in mice-pain models, and could downregulate hyperactive mast cells. PEA and related compounds such as anandamide also seem to have synergistic effects in models of pain and analgesia. In a variety of animal models, PEA seems to have some promise; researchers have been able to demonstrate relevant clinical efficacy in a variety of disorders, from multiple sclerosis to neuropathic pain. In the mouse forced swimming test, palmitoylethanolamide was comparable to fluoxetine for depression. An Italian study published in 2011 found that PEA reduced the raised intraocular pressure of glaucoma. In a spinal trauma model, PEA reduced the resulting neurological deficit via the reduction of mast cell infiltration and activation. PEA in this model also reduced the activation of microglia and astrocytes. Its activity as an inhibitor of inflammation counteracts reactive astrogliosis induced by beta-amyloid peptide, in a model relevant for neurodegeneration, probably via the PPAR-α mechanism of action. In models of stroke and other CNS trauma, PEA exerted neuroprotective properties. Chronic pain and neuropathic pain are indications for which there is high unmet need in the clinic. PEA has been tested in a variety of animal models for chronic and neuropathic pain. As cannabinoids, such as THC, have been proven to be effective in neuropathic pain states. The analgesic and antihyperalgesic effects of PEA in two models of acute and persistent pain seemed to be explained at least partly via the de novo neurosteroid synthesis. In chronic granulomatous pain and inflammation model, PEA could prevent nerve formation and sprouting, mechanical allodynia, and PEA inhibited dorsal root ganglia activation, which is a hallmark for winding up in neuropathic pain. The mechanism of action of PEA as an analgesic and anti-inflammatory molecule is probably based on different aspects. PEA inhibits the release of both preformed and newly synthesised mast cell mediators, such as histamine and TNF-alpha. PEA, as well as its analogue adelmidrol (di-amide derivative of azelaic acid), can both down-regulate mast cells. PEA reduces the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) and prevents IkB-alpha degradation and p65 NF-kappaB nuclear translocation, the latter related to PEA as an endogenous PPAR-alpha agonist.In 2012 it became clear that PEA can also reduce reperfusion injury and the negative impact of shock on various outcome parameters, such as renal dysfunction, ischemic injury and inflammation, most probably via the PPAR-alpha pathway. Among the reperfusion and inflammation markers measured PEA could reduce the increase in creatinine, γGT, AST, nuclear translocation of NF-κBp65; kidney MPO activity and MDA levels, nitrotyrosine, PAR and adhesion molecules expression, the infiltration and activation of mastcells and apoptosis.