LAAE-14, a new in vitro inhibitor of intracellular calcium mobilization, modulates acute and chronic inflammation.
A new lipidic acid-amido ether derivative (LAAE-14) able to reduce dose-dependently the calcium increases mediated either by calcium ionophore ionomycin, by the endoplasmic reticular Ca(2+)-ATPase inhibitor thapsigargin, or by the chemotactic tripeptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), in human neutrophils as well as in murine peritoneal macrophages, but not ATP, has been evaluated as a potential anti-inflammatory drug. This compound attenuated leukocyte activation by means of its inhibitory effect on the respiratory burst elicited in both types of cells by 12-O-tetradecanoyl phorbol 13-acetate, by inhibition of the degranulation process induced by cytochalasin B+fMLP or cytochalasin B+platelet activating factor, as well as by reduction of leukotriene B(4) synthesis induced by the calcium ionophore A23187. In addition, in zymosan-stimulated mouse peritoneal macrophages LAAE-14 caused a potent inhibition of nitrite and prostaglandin E(2) production. This compound exerted acute and chronic anti-inflammatory effects by oral route, that may be related with several mechanisms such as attenuation of leukocyte activation, inhibition of inducible nitric oxide synthase, cyclo-oxygenase-2 and cytosolic phospholipase A(2) expression as well as reduction in tumour necrosis factor-alpha production. Its anti-inflammatory profile is clearly correlated with its behavior as inhibitor of intracellular calcium mobilization. The profile and potency of this compound may have relevance for the inhibition of the inflammatory response at different levels and may represent a new approach to the development of new anti-inflammatory drugs.
Departamento de Farmacologi;a, Universidad de Valencia, Av. V. Andrés Estelles s/n, 46100, Valencia, Burjassot, Spain.
Rut
R
Lucas
Mario
M
Alves
Esther
E
del Olmo
Arturo
A
San Feliciano
Miguel
M
Payá
D000208:Acute Disease; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D002118:Calcium / Q000378:metabolism*; D002351:Carrageenan; D002465:Cell Movement / Q000187:drug effects; D002908:Chronic Disease; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism; D008163:Luminescent Measurements; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015054:Zymosan / Q000494:pharmacology
D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4; D002351:Carrageenan; D015054:Zymosan; D010196:Pancreatic Elastase; D015232:Dinoprostone; D002118:Calcium