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Gulgun Tezel, Xiangjun Yang; Antioxidant treatment responses on the neuroinflammatory outcomes of ocular hypertension in rats. Invest. Ophthalmol. Vis. Sci. 2013;54(15):408.
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Findings of our recent in vitro and in vivo studies and studies of human donor eyes indicated that besides primary neurotoxic consequences, oxidative stress may induce glial dysfunction, compromise immune regulation, and shift the immune homoeostasis toward neurodegenerative inflammation. To further determine the importance of oxidative stress for neuroinflammatory outcomes of glaucoma, we tested antioxidant treatment responses in an experimental rat model.
IOP elevation was induced in rats by hypertonic saline injections into episcleral veins in one eye. We gave Tempol (200 mg/kg/day), a superoxide dismutase mimetic and peroxynitrite-derived free radical scavenger that also reduces the formation of hydroxyl radicals, or vehicle (saline), using subcutaneously implanted osmotic mini-pumps for drug delivery by constant infusion. Following a 6-week treatment period, retina samples were analyzed for a number of inflammation markers. We analyzed markers of astroglial and microglial activation (including GFAP, CD-11b, Iba-1) by Western blot analysis and immunohistochemistry, markers of oxidative stress (including antioxidant response, protein carbonyls, and HNE adducts) by specific immunoassays, and cytokine profiles by multiplexed bioassays. In addition, we analyzed the activation of NF-κB, a redox-sensitive transcription factor that regulates glial inflammatory responses in human glaucoma and experimental models.
Retinal antioxidant capacity exhibited a significant increase, and retinal protein carbonyls and HNE adducts exhibited a significant decrease in ocular hypertensive samples (p<0.01) with Tempol treatment and thereby verified drug delivery and biological function. Among a range of cytokines measured, IL-2, IFN-γ, and TNF-α, exhibited an over two-fold decreased titers in antioxidant-treated samples (p<0.05). Antioxidant treatment also resulted in a prominent decrease in NF-κB activation, based on Western blot analysis using phosphorylation site-specific antibodies to NF-κB subunits, including p105/50, and p65 (p<0.05).
These findings support oxidative stress-related neuroinflammatory mechanisms during glaucomatous neurodegeneration, and the potential of antioxidant treatment to restore immune homeostasis. Further work should help better determine the importance of oxidative stress as an immunomodulatory treatment target to provide neuroprotection in glaucoma.
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