Targeting Oxidative Stress for Treatment of Glaucoma and Optic Neuritis

Abstract

Glaucoma is a neurodegenerative disease of the eye and it is one of the leading causes of blindness. Glaucoma is characterized by progressive degeneration of retinal ganglion cells (RGCs) and their axons, namely, the optic nerve, usually associated with elevated intraocular pressure (IOP). Current glaucoma therapies target reduction of IOP, but since RGC death is the cause of irreversible vision loss, neuroprotection may be an effective strategy for glaucoma treatment. One of the risk factors for glaucoma is increased oxidative stress, and drugs with antioxidative properties including valproic acid and spermidine, as well as inhibition of apoptosis signal-regulating kinase 1, an enzyme that is involved in oxidative stress, have been reported to prevent glaucomatous retinal degeneration in mouse models of glaucoma. Optic neuritis is a demyelinating inflammation of the optic nerve that presents with visual impairment and it is commonly associated with multiple sclerosis, a chronic demyelinating disease of the central nervous system. Although steroids are commonly used for treatment of optic neuritis, reduction of oxidative stress by approaches such as gene therapy is effective in ameliorating optic nerve demyelination in preclinical studies. In this review, we discuss oxidative stress as a therapeutic target for glaucoma and optic neuritis.

Figure 1

Spermidine reduces oxidative stress levels in the EAAC1 KO mouse retina. (a) Representative images of 4-HNE in the retina at 8 weeks old. Scale bar: 100 μm. (b) Quantitative analyses of (a). Data are normalized to the 4-HNE intensity at the GCL in control WT mice (100%). n = 6 in each group. (c) Representative images of immunoblot analyses of 4-HNE in the retina at 8 weeks old. (d) Quantitative analyses of (c). Data are normalized to the 4-HNE intensity in control WT mice (1.0). n = 6 in each group. ^∗∗P < 0.01; ^∗P < 0.05. Reproduced from Noro et al. [20].

Figure 2

The proposed model of the effect of candesartan in EAAC1 KO mice. Increased oxidative stress in EAAC1 KO mice induces the upregulation of AT1-R and TLR4, resulting in increased NO expression via the ASK1 signalling pathway, which leads to RGC death. NO further stimulates AT1-R expression levels through a positive feedback loop. Candesartan blocks AT1-R and exerts neuroprotective effects by suppressing the upregulation of TLR4 and thus reducing ASK1-mediated NO production. This also results in inhibition of the positive feedback loop between NO and AT1-R. Reproduced from Semba et al., [17].