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Nicolas Belforte, Jorge L Cueva-Vargas, Adriana Di Polo; The phosphodiesterase inhibitor Ibudilast attenuates glial cell reactivity, production of proinflammatory cytokines and neuronal loss in experimental glaucoma. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2665.
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© ARVO (1962-2015); The Authors (2016-present)
Ibudilast, a phosphodiesterase inhibitor with glial cell modulation, anti-inflammatory and vasodilator properties, has been used for over 20 years for the treatment of asthma and stroke. Here, we characterized the role of ibudilast on the response of glia and retinal ganglion cells (RGCs) to ocular hypertension (OHT) glaucoma.
OHT was induced by injection of hypertonic saline solution into an episcleral vein in Brown Norway rats. Ibudilast or vehicle was administered by intravitreal injection. Animals were euthanized at 3 weeks after OHT induction, and the retinas and optic nerves were collected for histological and biochemical analyses. Tumor necrosis factor α, (TNFα), interleukin 1 (IL-1β), interleukin 6 (IL-6), macrophage migration inhibitory factor (MIF), glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) expression were evaluated by immunohistochemistry and western blots. RGC soma or axon density was assessed on Brn3a-stained flat-mounted retinas or toluidine blue-stained optic nerve cross sections, respectively.
Our data demonstrate a striking decrease in the number of GFAP-positive astrocytes and Iba1-labeled microglia in ibudilast-treated glaucomatous retinas and optic nerves compared to vehicle-treated controls. Ibudilast treatment also led to a marked reduction in the levels of the pro-inflammatory cytokines TNFα, IL-1β, IL-6, and MIF in ocular hypertensive eyes compared to vehicle treatment. Ibudilast promoted robust RGC soma (91%, 1884±43 RGCs/mm2, n=5) and axonal protection (90%, 90639±2657 axons, n=5) with respect to vehicle (68% soma, 1475±95 RGCs/mm2, n=6; 61% axons, 61318±8112 axons, n=6). Ibudilast did not alter intraocular pressure (IOP) in after hypertonic saline injection; therefore these responses could not be attributed to changes in IOP.
Our data demonstrate that Ibudilast attenuates glial cell reactivity, reduces production of pro-inflammatory cytokines, and promotes RGC soma and axon protection in experimental glaucoma.
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