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Jeremy M Sivak, Izzy Livne-Bar; Quiescent Retinal Glia are Protective, but their Activation Increases Vulnerability to Acute RGC Injury In Vivo. Invest. Ophthalmol. Vis. Sci. 2014;55(13):825.
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Astrocytes and related Müller glia play critical homeostatic roles in the inner retina, and rapidly activate with disease or injury. However, the positive and/or negative influence of activation on retinal ganglion cells (RGCs) has remained controversial. We tested the influence of quiescent and activated astrocytes on RGC survival using an acute injury model, combined with pharmacologic methods and direct transplantation of primary cells.
An acute mouse excitotoxic RGC damage model was combined with pharmacologic inhibitors of glial activation, induced gliosis, or direct injection of quiescent primary astrocytes. The drugs withaferin A (WFA) and SB203580 (SB) target intermediate filaments, and p38α and β MAPKs, respectively, to block glial reactivity. In some experiments prominent glial reactivity was induced prior to retinal injury by mechanical corneal debridement, as recently reported (PMID: 20048155). Alternatively, quiescent retinal astrocytes were injected intravitreally prior to retinal injury.
Administration of WFA or SB strongly reduced GFAP staining in retinal astrocytes and Müller cells, and significantly blocked RGC death by approximately 80% (p<0.01). Conversely, mechanically induced gliosis exacerbated subsequent RGC death by over 7 fold (p<0.01), which was blocked by WFA or SB. Finally, intravitreal transplantation of quiescent retinal astrocytes two weeks prior to injury inhibited RGC death by nearly 80% (p<0.01).
We have used a variety of strategies to consistently demonstrate that retinal astrocytes are protective to RGCs when quiescent, but that activation increases vulnerability to acute injury in vivo.
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