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Caroline Lupien, Philip Horner, David Calkins; NFkB signaling in retinal glia mediates progressive neural degeneration and vision decline in glaucoma. Invest. Ophthalmol. Vis. Sci. 2013;54(15):415.
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Glaucoma is a neurodegenerative disease of the retina, characterized by a loss of vision due to the progressive decline of retinal ganglion cells (RGCs). A number of hypotheses have been proposed to explain the mechanisms underlying RGC death in glaucoma, one of them is glial cells activation. Glial cells are important structural and functional components of the nervous system, including the optic nerve and retina. It has been demonstrated that the retinal glial cells exhibit molecular and morphological signs of reactive gliosis in glaucoma. We have previously shown that pharmacological blockade of the NFkB pathway in a mouse model of glaucoma leads to improved RGCs survival. However, it is postulated that neuronal NFkB is neuroprotective while NFkB activation in glial cells promote neuronal death. The goal of this study is to selectively inhibit the NFkB pathway in retinal glial cells in order to establish the role of gliosis in glaucomatous degeneration.
To perform this study, we used NFkB transgenic mice expressing a dominant negative form of the inhibitor subunit of IkBα under the control of the GFAP promoter (GFAP-IkBα-dn). To induce glaucoma in these animals, we performed an acute ocular hypertension model. Immunohistochemistry, qPCR and Western blot analysis were performed to measure activity of the NFkB pathway and the function of neurons and glia. RGC counts, anterograde and retrograde transport were also assessed. We used an optokinetic testing system (optomotry) to measure visual acuity.
We observed by quantitative PCR analysis a significant decrease in retinal GFAP expression in experimental animals (microbeads injection) compared to control animals (saline injection). We also noted decreased NFkB and IkB expression in the experimental group. GFAP protein expression was also decreased in experimental animals reflective of decreased gliosis. Retrograde labelling with fluorogold demonstrated a remarkable 95% sparing of RGCs when NFkB was inhibited compared to 66% in control animals. The experimental animals also recovered almost all their visual acuity 15 days after glaucoma was induced.
These results demonstrate that gliosis is detrimental for RGC survival and function during the course of glaucoma. Importantly, selective inhibition of the NFkB pathway in glial may be a potent clinical approach for the treatment of vision loss in glaucoma.
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