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Meredith S Gregory-Ksander, Fei Fei, Ann Marshak-Rothstein, Bruce Ksander, Anitha Krishnan; Soluble Fas ligand provides long-term protection in a chronic mouse model of glaucoma by inhibiting glial activation, inflammation, and apoptosis. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
We previously demonstrated in the DBA/2J mouse model of glaucoma that a single intravitreal administration of AAV2.sFasL prior to the elevation of intraocular pressure (IOP) protected the RGCs and axons in DBA/2J mice up to 9 months of age. The following studies were performed to determine (i) the mechanism by which AAV2.sFasL protects RGCs and axons, (ii) whether AAV2.sFasL can provide long-term protection in DBA/2J mice for up to 15 months of age, and (ii) whether AAV2.sFasL is effective even when administered after IOP elevation.
DBA/2J (D2) mice received an intravitreal injection of AAV2.sFasL or AAV2.eGFP (AAV2 control) at 3 or 7 months of age. Untreated D2 mice were positive controls for glaucoma and untreated D2-Gpnmb+ mice were negative controls for glaucoma. Rebound tonometry was used to monitor IOP. Mice were euthanized at 9, 12, and 15 months of age and retina and optic nerve processed for: (i) RGC counts (β-III tubulin), (ii) axon counts (PPD), (iii) western blots (FasL), (iv) Immunofluorescence (GFAP), and (v) mRNA expression of apoptotic (FADD, Fas/FasL, BAX), anti apoptotic (c-FLIP, BCL2, cIAP-1, cIAP-2), and pro inflammatory (IL-1β, TNF-α, CD11b) mediators.
Increased retinal expression of sFasL in AAV2.sFasL mice was confirmed by western blot and had no effect on IOP or pigment dispersion and iris atrophy when compared to controls. D2 mice treated with AAV2.sFasL before IOP elevation displayed significant protection of RGCs and axons out to 15 months of age when compared to AAV2.eGFP and D2-uninjected controls. Moreover, even D2 mice treated with AAV2.sFasL after IOP elevation displayed significant protection of RGCs and axons when compared to controls. RT-PCR revealed that protection of RGCs and axons in AAV2.sFasL mice correlated with a significant decrease in the mRNA levels of several factors that mediate glial activation, inflammation, and apoptosis (GFAP, IL-1β, TNFα, CD11b, FADD, Fas, BAX) and a significant increase in mRNA levels of pro-survival factors (cFLIP, BCL2, cIAP-2) when compared to controls.
These data demonstrate that sFasL inhibits glial activation, inflammation, and apoptosis and serve as proof-of-principal that AAV2.sFasL can provide long-term neuroprotection in a chronic mouse model of glaucoma, even when administered after IOP elevation.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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