The antiinflammatory action of guanabenz is mediated through 5-lipoxygenase and cyclooxygenase inhibition.
Guanabenz (2,6-dichlorobenzylidene amino guanidine acetate), an alpha 2-agonist, possesses antiinflammatory activity. Since leukotrienes (LT) and prostaglandins (PG) are proinflammatory substances, the effect of guanabenz on LT and PG synthesis by inflammatory cells was investigated. Guanabenz, but not clonidine, B-HT 920 or B-HT 933 inhibited zymosan-induced LTC4 (IC50 = 13 microM) and PGE2 (IC50 = 10.9 microM) synthesis with no concomitant reduction in zymosan phagocytosis or cell viability. Similarly, guanabenz reduced LTB4 (IC50 = 37.4 microM) and PGE2 (IC50 = 13.8 microM) synthesis by A23187-stimulated rat glycogen elicited neutrophils. Furthermore, guanabenz did not inhibit platelet 12-lipoxygenase or phospholipase A2. In vivo, guanabenz was orally active against rat carrageenan paw edema and adjuvant arthritis (ED50s = 9 and 10 mg/kg, respectively). Topically applied guanabenz reduced arachidonic acid (AA)- or tetradecanoyl phorbol acetate (TPA)-induced ear inflammation (ED50s: AA-induced ear edema, 1.4 mg/ear; PMA-induced ear edema, 0.013 mg/ear). Therefore, the antiinflammatory activity of guanabenz may be due to its ability to inhibit the formation of 5-lipoxygenase and cyclooxygenase products.
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001169:Arthritis, Experimental / Q000188:drug therapy; D001792:Blood Platelets / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors; D004487:Edema / Q000188:drug therapy; D005260:Female; D006143:Guanabenz / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains
D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D006146:Guanidines; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D016718:Arachidonic Acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001091:Arachidonate Lipoxygenases; D010741:Phospholipases A; D054467:Phospholipases A2; D006143:Guanabenz