Antioxidant Treatment Limits Neuroinflammation in Experimental Glaucoma

Abstract

PurposeBesides primary neurotoxicity, oxidative stress may compromise the glial immune regulation and shift the immune homeostasis toward neurodegenerative inflammation in glaucoma. We tested this hypothesis through the analysis of neuroinflammatory and neurodegenerative outcomes in mouse glaucoma using two experimental paradigms of decreased or increased oxidative stress.MethodsThe first experimental paradigm tested the effects of Tempol, a multifunctional antioxidant, given through osmotic mini-pumps for drug delivery by constant infusion. Following a 6-week treatment period after microbead/viscoelastic injection-induced ocular hypertension, retina and optic nerve samples were analyzed for markers of oxidative stress and cytokine profiles using specific bioassays. We also analyzed a redox-sensitive transcriptional regulator of neuroinflammation, namely NF-κB. The second paradigm included a similar analysis of the effects of overloaded oxidative stress on retina and optic nerve inflammation in mice knockout for a major antioxidant enzyme (SOD1−/−).ResultsIncreased antioxidant capacity and decreased protein carbonyls and HNE adducts with Tempol treatment verified the drug delivery and biological function. Among a range of cytokines measured, proinflammatory cytokines, including IL-1, IL-2, IFN-γ, and TNF-α, exhibited more than 2-fold decreased titers in Tempol-treated ocular hypertensive eyes. Antioxidant treatment also resulted in a prominent decrease in NF-κB activation in the ocular hypertensive retina and optic nerve. Although pharmacological treatment limiting the oxidative stress resulted in decreased neuroinflammation, ocular hypertension–induced neuroinflammatory responses were increased in SOD1−/− mice with defective antioxidant response.ConclusionsThese findings support the oxidative stress–related mechanisms of neuroinflammation and the potential of antioxidant treatment as an immunomodulation strategy for neuroprotection in glaucoma.

Overexpression of Soluble Fas Ligand following Adeno-Associated Virus Gene Therapy Prevents Retinal Ganglion Cell Death in Chronic and Acute Murine Models of Glaucoma

“…Moreover, the accelerated glial activation in D2-ΔCS mice also correlated with an earlier induction of TNFα when compared to D2-WT mice. There is substantial evidence that TNFα is induced following elevated IOP (10, 12, 13, 53, 54,70) and is required for the death of RGCs (12, 13). Using the TNFα-induced model of glaucoma (12), we previously demonstrated that TNFα increased the expression of mFasL on retinal microglia and/or infiltrating macrophages and that Fas-FasL signaling was required for TNFα-mediated death of RGCs (28).…”

High Pressure-Induced mtDNA Alterations in Retinal Ganglion Cells and Subsequent Apoptosis

“…The mechanisms involved in RGC death in glaucoma are complicated. The elevated intraocular pressure (IOP) is considered to be the major risk factor (Osborne, 2008; Ju et al, 2015; Yang et al, 2016), and lowering the IOP is thus far the only relatively effective treatment clinically (Chen et al, 2013; Itakura et al, 2015). However, lowering the IOP is not sufficient to prevent or delay progressive vision loss, and the molecular mechanisms underlying accelerated RGC loss, even when the raised IOP is lowered to a normal level for many years, remain poorly understood (Gupta and Yücel, 2007; Osborne, 2010).…”

The Effect of Dietary Antioxidant Supplementation in Patients with Cataract and Glaucoma

“…Moreover, antioxidant therapy has shown promising results in animal-and human-based research. Antioxidant treatment can decrease the activation of NF-κβ and decrease the production of cytokines in the optic nerve and retina [25]. In a rat glaucoma model, overexpression of thioredoxins can protect the RGCs [26].…”