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V. I. Shestopalov, G. Dvoriantchikova, D. Ivanov, R. Brambilla, J. R. Bethea; Inactivation of Astroglial NF-kB Reduces RGC Loss in Optic Neuritis in EAE Model. Invest. Ophthalmol. Vis. Sci. 2008;49(13):791.
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In the central nervous system (CNS) activation of the transcription factor NF-ΚB, a key regulator of inflammation and secondary injury processes, leads to both protective and detrimental effects on CNS after injury. Here we sought to examine the effect of targeted inactivation of NF-ΚB in astrocytes, glial cells known to play both proinflammatory neurodistructive and trophic neuroprotective roles in CNS injury, on optic nerve and retina pathology in experimental autoimmune encephalomyelitis (EAE).
We employed a transgenic GFAP-IΚBα-dn (IΚBα-dn) mouse where NF-ΚB is specifically inactivated in astrocytes through overexpression of a dominant negative form of the NF-ΚB super-repressor under the control of the GFAP promoter. We induced EAE in IΚBα-dn mice and WT littermates and compared retinal ganglion cell loss and optic nerve pathology between the two strains.
Our data indicated that blocking the activation of astroglial NF-ΚB significantly reduces disease severity and improves functional recovery following EAE. The results of our analyses showed significant protection of RGCs in transgenic animals, which correlated with better morphology of these cells. At 80 days post injury (dpi), the neuronal density in the ganglion cell layer of WT retinas was reduced to about 50% of the number measured in naïve animals, while in IΚBα-dn mice the loss was limited to 19%. Interestingly, immunohistochemical studies showed an increased infiltration of blood leukocytes into the retina and optic nerve of the transgenic animals compared to WT at 80 dpi. Gene expression data indicate that the neuroprotective effects of astroglial NF-ΚB inactivation were likely due to lower levels of inflammation: chemokines, cytokines and other inflammatory molecules were decreased in IΚBα-dn mice compared to WT animals.
Our data indicate that inhibiting NF-ΚB in astrocytes results in neuroprotective effects following EAE, suggesting an active role for this cell population in the pathophysiology of this disease.
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