Rosmarinic acid: a new inhibitor of complement C3-convertase with anti-inflammatory activity.
Rosmarinic acid (RA) is a naturally occurring compound, isolated from Rosmarinus officinalis or Melissa officinalis which inhibits the in vitro immunohaemolysis of antibody-coated sheep erythrocytes by guinea pig serum. In further experiments this reduced immunohaemolysis was found to be due to inhibition of the C3-convertase of the classical complement pathway. The threshold concentration for inhibition of C3-convertase was 10(-6) mol/l. RA with an optimal inhibitory concentration between 5 and 10 mumol/l., resulting in about 70% inhibition of haemolysis. However, higher concentrations of RA were less effective at inhibiting C3-convertase. The inhibition may not be specific for C3-convertase, since another serine protease, elastase, was also weakly inhibited by RA in vitro. RA also exhibited inhibitory activity in three in vivo models in which complement activation plays a role. Thus, RA (0.316-3.16 mg/kg i.m.) reduced paw oedema induced by cobra venom factor (CVF) in the rat, and at 1-100 mg/kg p.o. inhibited passive cutaneous anaphylaxis in the rat. In addition, at 10 mg/kg i.m. RA impaired in vivo activation by heat-killed Corynebacterium parvum (i.p.) of mouse macrophages, as measured by the decreased capacity of the activated macrophages to undergo the oxidative burst. RA (0.1-10 mg/kg i.m.) did not inhibit t-butyl hydroperoxide-induced paw oedema in the rat, indicating selectivity for complement-dependent processes.
Englberger
W
W
Nattermann Research Laboratories, Cologne, F.R.G.
Hadding
U
U
Etschenberg
E
E
Graf
E
E
Leyck
S
S
Winkelmann
J
J
Parnham
M J
MJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002934:Cinnamates / Q000494:pharmacology*; D003166:Complement Activating Enzymes / Q000037:antagonists & inhibitors*; D003167:Complement Activation / Q000187:drug effects; D050577:Complement C3-C5 Convertases / Q000037:antagonists & inhibitors*; D053630:Depsides; D004487:Edema / Q000188:drug therapy; D004546:Elapid Venoms / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D000097123:Rosmarinic Acid
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002934:Cinnamates; D003166:Complement Activating Enzymes; D050577:Complement C3-C5 Convertases; D053630:Depsides; D004546:Elapid Venoms; D000097123:Rosmarinic Acid; C016310:cobra venom factor