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Amena W. Smith, Baerbel Rohrer, Mitsuyoshi Azuma, Jun Inoue, Naren L. Banik; The Effect Of Calpain Inhibition On Inflammation And Retinal Ganglion Cell Function During The Course Of Experimental Optic Neuritis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2945.
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© ARVO (1962-2015); The Authors (2016-present)
Optic neuritis (ON), inflammation of the optic nerve, is primarily due to influx of auto-reactive T cells and is manifested by visual dysfunction. Decreased amplitude of pattern electroretinogram (PERG) responses in ON patients indicate that retinal damage occurs subsequent to optic nerve insult. The Ca2+-activated protease calpain plays roles in T cell chemotaxis, demyelination, and axonal degeneration. Thus, we hypothesized that calpain inhibition will attenuate the acute inflammatory response and limit damage to retinal ganglion cells (RGCs) in the chronic phase of experimental optic neuritis.
B10.PL mice were immunized with complete Freund's adjuvant and myelin basic protein. Treated ON mice received twice-daily oral dosing of 25mg/kg SNJ-1945 until Day (D) 17 or 35. Visual function was measured by PERG recordings and optokinetic response testing. Peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry and retinal tissue was processed for immunohistochemistry and TUNEL staining.
A significant decline in visual acuity (c/d) occurred by D6, which coincided with an increase in the mean spleen weight of ON mice (32%; P<0.05). By D17, there was no difference in the spleen weights of treated vs. untreated mice, but we observed a 3-fold reduction in the population of IL-17-producing CD4+ PBMCs of mice treated with SNJ-1945. PERG amplitudes in response to a sinusoidal grating of low spatial (0.1c/d) and temporal (1Hz) frequency were compared; on D17 there was no significant difference in P1N2 amplitude (P=0.949) or latency to P1 (P=0.204) between treatment groups. By D35, P1N2 amplitudes were markedly reduced in ON mice treated with vehicle (4.2µV) versus control animals (6.6µV; P<0.05), whereas ON mice treated with SNJ-1945 were significantly protected (8.9µV; P<0.05). The response latency was also normalized in treated vs. untreated mice (38.5ms vs. 78.4ms; P<0.05). Furthermore, the number of TUNEL+ cells in the RGC layer was increased in ON-vehicle versus control or ON-SNJ-1945-treated retinas.
Daily, oral dosing of calpain inhibitor appears to negatively regulate proliferation of Th17 cells during the acute phase of experimental ON, and ultimately protects RGC function. Ongoing studies are examining the mechanisms by which calpain inhibition is modifying the immune cell response in this model.
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