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X. Zhou, S. R. Sarkisian, Jr., J. Chodosh, W. Cao; Protection of Retinal Ganglion Cells in Aging DBA/2J Mice by 17-beta-Estradiol via Activation of Akt/CREB/Thioredoxin and Inhibition of MAPK/NF-kB Cascades. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4919.
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Aging DBA/2J mice develop progressive eye abnormalities that closely mimic human pigmentary glaucoma. The onset of the disease symptoms in these mice begins between 3 and 4 months of age and affects 56% of the female mice while only 15% of the males show symptoms. These symptoms include signs of iris pigment epithelium loss and transillumination of the peripheral iris. By 9 months of age, female DBA/2J mice exhibit higher intraocular pressure (IOP) than males (www.jax.org). Several lines of evidence indicate that estrogen has neurotrophic and neuroprotective properties. Neuroprotection of retinal ganglion cells (RGC) becomes an important approach of glaucoma therapy. In this study, we examine the role of estrogen in the delay of disease progression and in the RGC protection in DBA/2J mice.
Female DBA/2J mice at two months old were anesthetized and ovariectomized with or without subcutaneous 17-beta-estradiol pellet implantation. RGC survival was evaluated from flat-mounted retina by counting retrograde labeled cells. The loss of nerve fiber and RGC were also evaluated quantitatively in paraffin-fixed retinal cross sections. Biochemical alterations and the signal cascade in the retinas of DBA/2J mice in response to systemic injection of 17-beta-estradiol were also examined by reverse transcriptase PCR (RT-PCR) and western blot.
17-beta-estradiol treatment reduced the loss of RGC and neurofibers through inhibition of ganglion cell apoptosis. 17-beta-estradiol activated Akt and cAMP-responsive-element-binding-protein (CREB), up-regulated thioredoxin-1 expression. 17-beta-estradiol suppressed the over-expressed interleukin-18 (IL-18) expression, reduced the increased activations of mitogen-activated protein kinases (MAPK) and NF-kB, and inhibited the elevated interleukin-18 expression in the retinas of DBA/2J mice. Pretreatment of tamoxifen, an estrogen receptor antagonist, can block 17-beta-estradiol-mediated activation of Akt and inhibition of MAPK phosphorylation in the retinas of DBA/2J mice.
17-beta-estradiol effectively slows the progression of IOP elevation and reduces retinal ganglion cell loss in DBA/2J mice. Multiple biochemical events including estrogen receptor/Akt/CREB/thioredoxin, and estrogen receptor/MAPK/NF-kB, may be involved in estrogen-mediated retinal ganglion cell protection.
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