Concomitant treatment with a 5-lipoxygenase inhibitor improves the anti-inflammatory effect of the inhibition of nitric oxide synthase during the early phase of endotoxin-induced uveitis in the rabbit.
Nitric oxide (NO) synthase inhibitors, such as NG-nitro-L-arginine methyl ester (L-NAME), have been shown to attenuate endotoxin-induced uveitis (EIU) but they could increase leukocyte adhesion to the vascular endothelium. We hypothesize that a concomitant treatment with the 5-lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) in 50% dimethylsulfoxide (DMSO, a hydroxyl radical scavenger) could improve the anti-inflammatory activity of L-NAME. EIU was induced in albino rabbits by intravitreal injection of 100 ng lipopolysaccharide. Animals were treated with multiple intraperitoneal injections of 50% DMSO in phosphate-buffered saline (PBS), NDGA (10 mg/kg) in 50% DMSO, L-NAME (50 mg/ kg) in PBS, or the combination NDGA+L-NAME. Uveitis was assessed by slit lamp examination, protein levels in aqueous humor, and myeloperoxidase (MPO) activity in the iris/ciliary body 6 h after induction. Nitrite, leukotriene B4 (LTB4), prostaglandin E2 (PGE2), platelet-activating factor (PAF) and interleukin-1 beta (IL-1 beta) levels in aqueous humor were also determined. NDGA or L-NAME alone did not show a significant reduction of uveitis intensity, although a significant decrease in MPO or in proteins was found, respectively. The combination NDGA+L-NAME significantly reduced the uveitis intensity, MPO in the iris/ciliary body, and the levels of nitrites, LTB4, PGE2, and PAF in aqueous humor. IL-1 beta levels were lower than the detection limit of the radioimmunoassay in all treatment groups. We conclude that concomitant treatment with NDGA in DMSO improves the anti-inflammatory activity of L-NAME during the early phase of EIU, suggesting that the inhibition of NO synthesis could enhance leukocyte infiltration and the release of oxygen free radicals.
Bellot
J L
JL
Ciba Vision, Barcelona, Spain.
Palmero
M
M
Alcoriza
N
N
Blanco
A
A
García-Cabanes
C
C
Hariton
C
C
Orts
A
A
D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001082:Aqueous Humor / Q000378:metabolism; D002924:Ciliary Body / Q000187:drug effects / Q000201:enzymology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004731:Endotoxins / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007375:Interleukin-1 / Q000378:metabolism; D007498:Iris / Q000187:drug effects / Q000201:enzymology; D007975:Leukotriene B4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D009637:Masoprocol / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009195:Peroxidase / Q000378:metabolism; D011817:Rabbits; D012486:Salmonella typhimurium; D016896:Treatment Outcome; D014605:Uveitis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology
D000893:Anti-Inflammatory Agents; D004731:Endotoxins; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4; D009637:Masoprocol; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D015232:Dinoprostone; D019331:NG-Nitroarginine Methyl Ester; D004121:Dimethyl Sulfoxide