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C. Lupien, D. J. Calkins, P. J. Horner; Decreasing Gliosis by Inhibition of the Stat3 Pathway in a Microbead Mouse Model of Glaucoma. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3192.
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Glaucoma, the second leading cause of blindness worldwide, is actually a family of ocular diseases with a common endpoint, the progressive loss of vision.The retinal glial cells play an inherently vital homeostatic role in the retina, but exhibit classic molecular and morphological signs of chronic, reactive gliosis in multiple models of glaucoma. This begins at the earliest stages of the disease and little is known regarding the nature and the specific consequences of the injury signals that cause reactive gliosis. Retinal gliosis is potentially trigged by several cytokines known to be upregulated in glaucoma, such as the IL-6 family, which are activators of STAT3 pathway. The goal of this study is to specifically inhibit the STAT3 pathway in retinal glial cells to temper gliosis and determine the role of this pathway in disease.
We performed an acute ocular hypertension model (microbeads) on transgenic mice that lack STAT3 in GFAP-expressing cells (GFAP-STAT3-CKO). The microbead model is a novel method for inducing a highly consistent and repeatable elevation in IOP for rats and mice. The injection of microbeads in the interior chamber of the mouse eye elevated IOP by 21-34%; also the features of RGC decline are similar to what has been observed in other glaucoma models. We thus, injected microbeads in the right eye of non transgenic animal (control) and STAT3 transgenic animal (experimental) with the contralateral eye serving as a saline control. Immunohistochemistry, qPCR and Western blot analysis as well as RGC counts and functional status of their axons were analyzed.
We observed by quantitative PCR analysis an important decrease of GFAP expression in both the retina and optic nerve of GFAP-STAT3-CKO mice compared to controls. The expression of other gliosis markers such as reactive proteoglycans and STAT3 activators were also reduced. Importantly, an analysis of retrograde labelling with fluorogold revealed an increase in the sparing of RGCs in the STAT3 KO mice compared to control.
These results demonstrate that gliosis is detrimental for RGCs during the initial course of glaucoma (first month). Hence, inhibition of the STAT3 pathway in GFAP-expressing glial cells of the retina and optic nerve is a potentially targetable pathway for neuroprotection of RGCs clinically. However further studies in more chronic models are necessary to fully address the importance of gliosis in RGCs degeneration.
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