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D. V. Ivanov, G. Dvoriantchikova, D. Barakat, R. Brambilla, E. Hernandez, J. R. Bethea, V. I. Shestopalov; Role of Astroglial NF-kB in Retinal Ischemia. Invest. Ophthalmol. Vis. Sci. 2009;50(13):370.
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Reactive astrocytes were implicated in neuronal loss following ischemic stroke, however, molecular pathways facilitating cell death remain obscure. In this work, we tested a hypothesis that astroglial NF-kB, a key regulator of inflammation, is a major contributor neuronal death in ischemic injury.
In this work we used the GFAP-IkB-DN transgenic mice (TG) possessing astrocyte-specific suppression of the NF-kB pathway. We induced retinal ischemia by unilateral elevation of intraocular pressure via direct corneal canulation. Neurons were labeled, their density stereologically assessed and their survival rate calculated as the percentage of experimental vs. control eye. We analyzed retinas for changes in expression of the pro-inflammatory, immunomodualtory, pro-survival and stress response genes; corresponding proteins were analyzed by immunohistochemistry.
TG mice showed significantly better survival of ganglion cell layer (GCL) neurons to ischemic injury, as compared to wild type (WT) control animals. To dissect the molecular mechanisms underlying the elevated tolerance, we compared expression of pro- and anti-inflammatory genes, genes implicated in ROS and RNS generation in WT and TG retinas. Inhibition of astroglial NF-kB resulted in reduced expression of pro-inflammatory genes including Tnf-, Ccl2, Cxcl10, Icam1, Vcam1and genes encoding NADPH oxidase and NO synthase, known to facilitating oxiradical production following ischemia. However, expression of immunomodulatory molecules and neurotrophic factors did not vary between the two mouse strains.
This study shows that inhibition of NF-kB activity in astrocytes protects neurons in retinal ischemia, providing the evidence that reactive astrocytes are implicated in the pathophysiology of ischemic injury. Our results demonstrate that NF-kB-dependent inflammation and oxidative stress are major contributors to astrocyte-mediated neurotoxicity in ischemic retina.
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