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

Abstract

Nitric oxide (NO) synthase inhibitors, such as N^G-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% dimethylsulf-oxide (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-1β (IL·-1β) 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-1β 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.

Effects of Orengedoku-to and Senkanmeimoku-to, Traditional Herbal Medicines, on the Experimental Herbal Medicines, on the Experimental Elevation of Aqueous Flare in Pigmental Rabbits

“…It is likely that Scutellariae radix may be involved in the antiinflammatory actions of these herbal medicines. Nitric oxide reportedly acts as a mediator of LPS-induced uveitis (Parks et al, 1994;Bellot et al, 1997). Scutellariae radix inhibits nitric oxide production induced by LPS (Fukuda, 1998), and inhibits PGE 2 release in C6 rat glioma cells (Nakahata et al, 1998).…”

Effects of Nilvadipine, Nicardipine and Verapamil on Acute Rise of Aqueous Flare Induced by Iris Photocoagulation or Intravenous Lipopolysaccharides in Pigmented Rabbits

“…In LPS-induced uveitis are found several phenomena and factors including altered vascular permeability, leukocyte response, tumor necrosis factor, interleukin-6, interleukin-1·, interleukin-1ß, thromboxane B 2 , prostaglandin E 2 and nitric oxide [9][10][11][12][13][14][15][16][17]. Thus, complex mechanisms may possibly be involved in LPS-induced uveitis.…”

The inhibition of retinal inducible nitric oxide synthase overexpression and the attenuation of experimental uveitis by anti-inflammatory drugs in rats

“…Therefore, when this drug prevents the manifestation of the inflammatory response, the inhibition of NOS II induction seems to be a secondary effect which occurs at higher doses only. Nevertheless, when the inflammation is due to LPS, this secondary effect may be more important than otherwise, because the LPS effect is mediated by the induction of NOS II, in addition to that of cyclooxygenase 2 [27,28] and by the other enzymes of eicosanoid synthesis [29]. Both drugs decreased the protein content in the aqueous humor, indicating their beneficial effect on the inflammation (Table 1), but the protein contents exceeded the control values.…”