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D Shen, N Tuaillon, RR Buggage, CC Chan; The Effect of a Secretory Phospholipase A2 Inhibitor, 12-epi-scalaradial, on Toxoplasma gondii Infection . Invest. Ophthalmol. Vis. Sci. 2002;43(13):4297.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:Induction of NO and IFN-γ, a Th1 cytokine, from activated macrophages and lymphocytes is triggered by Toxoplasma gondii (T. gondii)infection and is critical for the host defense against the intracellular pathogen. The secretory group II phospholipase A2 (sPLA2) is known to stimulate inducible NO synthase (iNOS) expression and nitrite production. We investigated the effect of a sPLA2 inhibitor, 12-epi-scalaradial (12-epi), in a murine model of T. gondii infection. Methods:Two repeated experiments were performed. Two groups of C57BL/6 mice (8 per group) were infected intraperitoneally with 20-50 T. gondiicysts in PBS. The treated group received 40 µg of 12-epi in 0.1 ml PBS at day 7 and day 21 after infection by intraperitoneal injection. The control group received PBS injection only. Two other uninfected mice received only PBS. All mice were sacrificed at day 28. The eyes and brains were collected for routine histology, nitrite measurement and RT-PCR for ß-Actin, IFN-γ and IL -10. Serum IL-2, IL-4, IL-10, IL-12 and IFN-γ were measured by ELISA. Statistical analyses were performed using StatView version 4.5. Results:The two experiments produced similar results. All infected mice developed encephalitis and retinouveitis typically seen in this murine model of toxoplasmosis. Although no significant difference was found in the tissue cyst number in the brains of the treatment and control groups, the inflammatory response in the brains and eyes of the mice treated with 12-epi were significantly higher than that of control mice. The respective grades of the inflammation (meanSD) for the 12-epi and PBS treated mice were: Exp.1, 8.811.03 vs 6.251.41, p<0.001, in brain and 7.251.77 vs 5.941.76, p=0.129, in eye; Exp.2, 10.310.75 vs 9.000.96, p<0.005, in brain and 7.251.44 vs 4.382.25, p<0.005, in eye. Significantly lower nitrite concentrations in the target tissues of 12-epi treated mice were measured compared to the control groups [0.3050.027 nmol vs 1.1090.184, p<0.0001, in eye, and 0.9300.055 vs 1.1380.137, p<0.01, in brain]. RT-PCR showed a lower expression of IFN-γ and IL-10 mRNA in the eyes and brains of 12-epi treated mice than the control mice. Serum IFN-γ levels were also lower in 12-epi treated mice than in control mice (Exp. 1, 2786 pg/ml vs 3801 and Exp. 2, 3915 vs 4220). Conclusion:Our data shows that blocking of the sPLA2 pathway with 12-epi enhances the inflammatory response in the brain and eye of murine toxoplasmosis. The mechanism involves the inhibition of both iNOS and IFN-γ production in the host. Modulation of sPLA2 may be considered as a future treatment for toxoplasmosis in humans.
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