N-(2-hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation.
Mast cells play a key role in inflammatory reactions triggered by tissue injury or immune perturbations. Little is known about endogenous molecules and mechanisms capable of modulating inappropriate mast cell activity. N-(2-Hydroxyethyl)hexadecanamide (palmitoylethanolamide), found in peripheral tissues, has been proposed to act as a local autacoid capable of negatively regulating mast cell activation and inflammation-hence the acronym Autacoid Local Inflammation Antagonism (ALIA). Recently, N-(2-hydroxyethyl)hexadecanamide (LG 2110/1) has been reported to down-modulate mast cell activation in vitro by behaving as an agonist at the peripheral cannabinoid CB2 receptor. Here, we have characterized and functionally correlated the anti-inflammatory actions of LG 2110/1 with its ability to control mast cell activation, when given orally in a battery of rodent models of inflammation. LG 2110/1 diminished, in a dose-dependent and correllated manner, the number of degranulated mast cells and plasma extravasation induced by substance P injection in the mouse ear pinna. In addition, LG 2110/1 reduced dose dependently plasma extravasation induced by passive cutaneous anaphylaxis reaction. In adult rats LG 2110/1 decreased, in a dose-dependent manner, carrageenan-induced hindpaw edema and hyperalgesia, but not phospholipase A2-induced hindpaw edema. Further, anti-edema effects were observed when utilizing dextran and formalin, known to also cause mast cell activation. Locally administered LG 2110/1 was likewise effective in minimizing dextran-induced hind paw edema. In contrast, equivalent amounts of palmitic acid plus ethanolamine were ineffective against plasma extravasation provoked by substance P. LG 2110/1 did not decrease plasma extravasation induced by the substance P fragment, substance P-(6-11), known to be inactive on mast cells. These results indicate that orally administered N-(2-hydroxyethyl)hexadecanamide is effective in: (a) directly down-modulating mast cell activation in vivo; (b) suppressing pathological consequences initiated by mast cell activation independently of the activating stimuli; (c) exerting an anti-inflammatory action distinguishable from that of classical steroidal and non-steroidal anti-inflammatory agents. These findings raise the possibility that N-(2-hydroxyethyl)hexadecanamide and related saturated N-acylamides ('ALIAmides') represent novel therapeutic agents useful in the management of inflammatory disease conditions.
Mazzari
S
S
Researchlife S.c.p.A., Castelfranco Veneto (TV), Italy.
Canella
R
R
Petrelli
L
L
Marcolongo
G
G
Leon
A
A
D000577:Amides; D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002351:Carrageenan; D015550:Cell Degranulation; D003911:Dextrans; D004431:Ear, External / Q000502:physiology; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control*; D063388:Endocannabinoids; D004983:Ethanolamines; D005070:Evans Blue; D005079:Excipients; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000188:drug therapy; D005260:Female; D005557:Formaldehyde; D006930:Hyperalgesia / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D010169:Palmitic Acids / Q000494:pharmacology*; D010323:Passive Cutaneous Anaphylaxis; D051381:Rats; D017208:Rats, Wistar; D013373:Substance P / Q000008:administration & dosage / Q000494:pharmacology*
D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003911:Dextrans; D063388:Endocannabinoids; D004983:Ethanolamines; D005079:Excipients; D010169:Palmitic Acids; D005557:Formaldehyde; D013373:Substance P; D005070:Evans Blue; C005958:palmidrol; D002351:Carrageenan