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Gulgun Tezel, Xiangjun Yang; Oxidative Stress is an Immunomodulatory Treatment Target in Glaucoma. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3670.
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© ARVO (1962-2015); The Authors (2016-present)
Recent studies of human glaucoma and experimental models indicated that oxidative stress reduces the ability of RGCs and their axons to cope with the IOP-related stress by both generating direct neurotoxicity and stimulating glia-driven neuroinflammation. Our following pilot study supported the potential of antioxidant treatment (with Tempol protecting against multiple oxidants) to restore immune homeostasis and protect neurons in experimental glaucoma. This new study aims to further determine the importance of oxidative stress for glaucomatous neurodegeneration using an alternative experimental paradigm, the overloaded oxidative stress model in superoxide dismutase 1 (SOD1)-/- mice.
To determine the effects of deficient antioxidant response on neuroinflammation in experimental glaucoma, IOP elevation was induced in SOD1-/- mice and C57BL/6J wild-type controls by anterior chamber microbead/viscoelastic injections in one eye. Retina samples were analyzed for oxidative stress (total antioxidant response, protein carbonyls, and HNE adducts by specific immunoassays) and inflammation (cytokine profiles by multiplexed bioassays and glial immunolabeling). We also analyzed the activation status of NF-κB (a redox-sensitive transcription factor linked to glia-driven neuroinflammation in glaucoma) by immunoblotting with phosphorylation site-specific antibodies to p105/50 and p65.
Compared to ocular hypertensive wild-type controls, ocular hypertensive SOD1-/- mice exhibited decreased antioxidant capacity and increased protein oxidation in the retina (p<0.01). Over the ocular hypertensive period of up to 6 weeks, inflammatory activation was detectable in the retina of wild-type mice; however, SOD1-/- resulted in increased glial production of proinflammatory cytokines (including TNF-α) and increased activation of NF-κB (p<0.04). Based on retinal immunolabeling, the amplified neuroinflammation with SOD1-/- involved both macroglia and microglia.
Thus, endogenous antioxidant response in the ocular hypertensive retina may repress the proinflammatory activation by possibly affecting the redox-sensitive transcriptional activation of immune mediators by glial NF-κB (besides affecting other inflammatory consequences of oxidative stress as well as neuronal survival). These findings stimulate further research to value oxidative stress as an immunomodulatory treatment target to provide neuroprotection in glaucoma.
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