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Won-Kyu Ju, Dong Wook Lee, Keun-Young Kim, You Hyun Noh, Robert N. Weinreb; α2-adrenergic Receptor Agonist Restores Mitochondrial Transcription Factor A And Oxidative Phosphorylation, And Protects Retinal Ganglion Cells Against Retinal Ischemic Injury. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6587.
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The goal of this study is to determine whether acute intraocular pressure (IOP) elevation alters mitochondrial transcription factor A (TFAM) and oxidative phosphorylation (OXPHOS), as well as whether brimonidine, α2-adrenergic receptor agonist, restores TFAM and OXPHOS, and increases retinal ganglion cells (RGCs) survival against retinal ischemic injury.
Sprague-Dawley rats received brimonidine (1 mg/kg/day) or vehicle (0.9% saline) by subcutaneous pump and then transient ischemia was induced by acute IOP elevation. RGC survival was measured by Brn3a wholemount immunohistochemistry. Glial fibrillary acidic protein (GFAP), TFAM and OXPHOS protein expression were assessed by Western blot or immunohistochemisty. Cell death was assessed by TUNEL staining, and Bax, Bcl-xL and phosphorylated Bad (pBad) protein expression were assessed by Western blot.
GFAP, TFAM, OXPHOS complexes I, II and IV protein expression were significantly increased but OXPHOS complexes III and ATP synthase were not changed in ischemic retina. Brimonidine treatment significantly increased RGC survival at 4 weeks after ischemia. At 24 hours after ischemia, brimonidine treatment significantly reduced GFAP, TFAM, OXPHOS complexes, I II, III, and IV, but not ATP synthase. TFAM immunoreactivity was increased in the ganglion cell layer of vehicle-treated ischemic retina at 24 hours. In addition, TFAM-positive neurons colocalized with Thy1.1, a marker for RGCs. Brimonidine treatment significantly decreased Bax, but increased Bcl-xL and pBad protein expression, as well as blocked apoptotic cell death in ischemic retina at 24 hours.
Our results suggest that increases in TFAM and OXPHOS may provide not only important mitochondria-related defense mechanisms but new therapeutic strategies in ischemic retina. In addition, systemic brimonidine treatment may be useful for protecting RGCs against high IOP-relateded optic neuropathies including glaucoma.
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