A new dual inhibitor of arachidonate metabolism isolated from Helichrysum italicum.
Six acetophenones (1-6) and one gamma-pyrone (7), previously isolated from Helichrysum italicum, were tested for their ability to inhibit enzymatic and non-enzymatic lipid peroxidation, the stable 1,1-diphenyl-2-pycryl-hydrazyl free radical, superoxide scavenging and arachidonic acid metabolism. In addition, they were studied in different experimental models such as the chronic inflammation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA), the phospholipase A(2)-induced mouse paw oedema test, the carrageenan-induced mouse paw oedema test, and the writhing induced by acetic acid in the mouse. Of the assayed compounds, only 1 inhibited enzymatic lipid peroxidation but had no effect on non-enzymatic lipid peroxidation. None of them scavenged the superoxide radical. Study of the inhibition of arachidonic acid metabolism demonstrated that 1 was an inhibitor of both cyclooxygenase and 5-lipoxygenase, whereas 2 was a selective inhibitor of 5-lipoxygenase. In the assay of phospholipase A(2)-induced mouse paw oedema, the gamma-pyrone derivative inhibited oedema formation, showing a similar profile to that obtained with cyproheptadine. The acetophenones were effective at 30 and 60 min. In the carrageenan test, acetophenone 1 gave the best results and had analgesic effects in the acetic acid writhing test. In conclusion acetophenone 1 (4-hydroxy-3-(3-methyl-2-butenyl)acetophenone) is a new dual inhibitor of arachidonate metabolism, and could be a useful tool for obtaining anti-inflammatory and analgesic drugs.
Sala
Araceli
A
Departament de Farmacologia, Facultat de Farmàcia, Universitat de València, Av. Vicent Andrés Estellés s/n. 46100 Burjassot, Spain.
Recio
M Carmen
MC
Schinella
Guillermo R
GR
Máñez
Salvador
S
Giner
Rosa M
RM
Ríos
José-Luis
JL
D000098:Acetophenones / Q000737:chemistry / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002351:Carrageenan / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004423:Ear / Q000473:pathology; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D005960:Glucosides / Q000737:chemistry / Q000494:pharmacology*; D036562:Helichrysum; D006614:Hindlimb / Q000187:drug effects / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D007975:Leukotriene B4 / Q000096:biosynthesis; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010741:Phospholipases A / Q000008:administration & dosage; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013755:Tetradecanoylphorbol Acetate / Q000008:administration & dosage
C440950:12-hydroxytremetone-12-O-beta-D-glucopyranoside; C474242:4-hydroxy-3-(2-hydroxy-3-isopentenyl)acetophenone; C474241:4-hydroxy-3-(3-methyl-2-butenyl)acetophenone; D000098:Acetophenones; D000700:Analgesics; D005609:Free Radicals; D005960:Glucosides; D010936:Plant Extracts; D007975:Leukotriene B4; D016718:Arachidonic Acid; D002351:Carrageenan; D009195:Peroxidase; D010741:Phospholipases A; D013755:Tetradecanoylphorbol Acetate