The beginning: PEA as anti-flu compound

PEA as an inhibitor of inflammation

PEA is a member of the N-acylethanolamines and can be found in most mammalian and human tissues. PEA tissue concentration increase during inflammation and acts as a body-own modulator with anti-inflammatory properties. This has been substantiated in various relevant animal models of inflammation and inflammatory pain. ^[6]  Its precise mechanism of action has ben a debate since the last 40 years, and major shifts in understanding can be documented if publications are analysed in a chronological sequence.

PEA was comnpared to the synthetic cannabinoid nabilone in the rat model of carrageenan-induced acute hindpaw inflammation together with the nonsteroidal antiinflammatory drug indomethacin. Nabilone 2.5 mg kg(-1), PEA 10 mg kg(-1) and indomethacin 5 mg kg(-1), given p.o. 1 h before carrageenan, all reduced the inflammatory parameters in a time-dependent manner. ^[7] This anti-infalmmatory effect of PEA has been duplicated in many different experiments ^[8]  

The resemblance between PEA and anandamide became known in the nineties of last century, and in that time people started to believe the biological actions of PEA were mediated via the Cannabis receptors, CB1 and/or CB2 ^[9] Especially the CB 2 receptor was seen as the major inroad for PEA's biological actions, as the CB2 receptor is expressed in many while blood cells and the mast cells. The CB(2) receptor selective agonist AM1241 also diminishes edema produced as a result of mast cell degranulation in vivo.

It is, however, not known whether other structurally different CB(2) agonists share this effect, and whether this is due to a direct effect on mast cell function. In the present study, we have investigated the effects of JWH133, a CB(2) receptor selective agonist, together with the anti-inflammatory agent palmitoylethanolamide and its analogue palmitoylisopropylamide, on compound 48/80-induced oedema and degranulation in vivo and in vitro. JWH133 (20 and 200 microg/mouse i.p.) significantly reduced the ability of compound 48/80 to induce oedema in vivo in the anaesthetised mouse following its injection into the ear pinna. Palmitoylethanolamide (200 microg/mouse i.p) also reduced the response to compound 48/80, whereas no firm conclusions could be drawn for palmitoylisopropylamide (20 and 200 microg/mouse i.p.). The CB(2) selective antagonist/inverse agonist SR144528 (60 microg/mouse i.p.) appeared to produce anti-inflammatory effects per se in this model, making it hard to interpret the effects of JWH133 in terms of CB(2) receptor mediated activation. In contrast to the situation in vivo, neither JWH133 (0.3 and 3 microM) nor palmitoylethanolamide (10 microM) affected mast cell degranulation, measured by following the release of the granular protein beta-hexosaminidase, produced by compound 48/80 in vitro in mouse skin slices. The two compounds were also ineffective in inhibiting the binding of [(3)H]pyrilamine to histamine H(1) receptors in vitro. It is concluded that the ability of JWH133 to affect mast cell dependent inflammation in vivo may be mediated by an indirect action upon the mast cells.^[10]

 'Autacoid Local Inflammation Antagonism' (ALIA) was coined for PEA, anandamide and other endogenous ligands of the CB receptors, and the term 'ALIAmides' was used as a container term. ^[11] 

PEA, also found in many peripheral tissues, was then proposed as a local autacoid with the function to downregulating mast cell activation and inflammation.^[9]  Many well-documented effects of PEA upon mast cell function in vivo.have been documented.^[15]  Since the last 10 years new biological targets have been identified to understand the physiological roles PEA plays in various tissues and during inflammation: inhibition cyclo-oxygenase (COX) activity, activator of the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-alpha), inhibitor of inducible nitric oxide synthase (iNOS) to mention a few related to the compounds anti-inflammatory activities.

PEA and indomethacin were administered daily after the onset of inflammation for three days in a  paw oedema rat paw model and 24 h after the last dose the rats were killed and the COX activity and the content of nitrite/nitrate (NO(2)(-)/NO(3)(-)), malondialdehyde (MDA), endothelial and inducible nitric oxide synthase (eNOS and iNOS) were evaluated in the paw tissues. PEA inhibited inflammation in a dose- and time-dependent manner and that effect could not be reversed by the selective CB(2) receptor antagonist (N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3 carboxamide) (SR144528).On the fourth day after carrageenan injection, COX activity and the level of NO(2)(-)/NO(3)(-), eNOS and MDA were increased in the inflamed paw, and both PEA  and indomethacin could markedly reduce these increases. ^[16] 

In a different experiment the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-alpha) was identified as one of the molecular targets related to PEA's anti-inflammatory properties. PEA is as well an activator as a endogenious ligand of this nuclear receltor. PEA selectively activates PPAR-alpha in vitro with an EC(50) value of 3.1 +/- 0.4 microM and induces the expression of PPAR-alpha mRNA when applied topically to mouse skin.

In two animal models PEA could attenuate inflammation in wild-type mice but not in mice deficient in PPAR-alpha. ^[17] In a different model PEA also significantly reduced the expression COX-2 and iNOS in a sciatic nerves model and restored carrageenan-induced reductions of PPAR-alpha in dorsal root ganglia (DRG). PEA prevented IkB-alpha degradation and p65 NF-kappaB nuclear translocation. ^[18]

Another target might be the human vanilloid receptor, VR1, were PEA potentiates the activity of that receptor, which may play an important role under conditions where their synthesis is increased, such as in severe inflammation.^[19]  

Due to PEA's activity in chronic inflammatory disorders and animal models, various clinical entities have been mentioned as targets for PEA, such as psoriasis, topical dermatitis, inflammatory bowel disorder, multiple sclerosis to mention just a few. Therefore is reasonable to that various authors suggest that PEA and other cannabinomimetic compounds could represent possible candidates for treating several of these chronic inflammatory diseases.^[20] 

PEA as an analgesic compound 

When PEA and anandamide are administered together, the two compounds act synergistically, reducing pain responses 100-fold more potently than does each compound alone. CB1 antagonist SR141716A and the CB2 antagonist SR144528 prolong and enhance the pain behaviour produced by tissue damage. These pharmacological experiments lead invstigators to believe that peripheral CB1-like and CB2-like receptors participate in pain initiation and control and that that locally generated anandamide and PEA may mediate analgesic effects via these receptors.^[24]Anandamide (via CB1 receptors) and PEA (putatively via CB2 receptors) attenuated hyperalgesia in a dose-dependent fashion.^[25] 

Both anandamide (at a dose of 25 mg/kg) and PEA (at doses of 10-30 mg/kg) were able to attenuate the viscero-visceral hyper-reflexia (VVH) induced by inflammation of the urinary bladder. ^[26] Later new findings pointed out that the mechanism of action of PEA might also be found via the PPAR pathway. The PPAR-alpha agonists GW7647 [2-(4-(2-(1-cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid], Wy-14643 [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid], and PEA both reduced nocifensive behaviors elicited in mice by intraplantar injection of formalin. These effects were absent in PPAR-alpha-null mice. PPAR-alpha is expressed in dorsal root ganglia neurons of wild-type but not PPAR-alpha-null mice. PEA also reduced hyperalgesic responses in the chronic constriction injury model of neuropathic pain, and were dependent on the PPAR mechanism of action. ^[27] 

In an experimental spinal cord injury (SCI) model in mice repeated PEA administration (10 mg/kg i.p.; 30 min before and 1 and 6 h after SCI) significantly reduced the degree of spinal cord inflammation and tissue injury, the neutrophil infiltration, the proinflammatory cytokine expression, the nuclear transcription factor activation-kappaB activation, the inducible nitric-oxide synthase expression, and apoptosis. Moreover, PEA also significantly ameliorated the recovery of motor limb function.^[28]  

December 2010, Jan M. Keppel Hesselink 

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