Suppression of Oxidative Stress as Potential Therapeutic Approach for Normal Tension Glaucoma

Abstract

Glaucoma is a neurodegenerative disease of the eye, which involves degeneration of retinal ganglion cells (RGCs): the output neurons of the retina to the brain, which with their axons comprise the optic nerve. Recent studies have shown the possible involvement of oxidative stress in the pathogenesis of glaucoma, especially in the subtype of normal tension glaucoma. Basic experiments utilizing rodent and primate models of glaucoma revealed that antioxidants protect RGCs under various pathological conditions including glutamate neurotoxicity and optic nerve injury. These results suggested that existing drugs and food factors may be useful for prevention and hence therapy of glaucoma. In this review, we highlight some therapeutic candidates, particularly those with antioxidant properties, and discuss the therapeutic potential of RGC protection by modulating gene expressions that prevent and ameliorate glaucoma.

Keywords: ASK1; drug repositioning; food factor; glaucoma; glutamate transporters; marmoset; neuroprotection; optic nerve; oxidative stress; retinal ganglion cell.

Figure 1

EAAT1 variants identified in patients with glaucoma and the functional impact of missense mutations on EAAT1 protein functions. (A) The predicted topology of the EAAT1 protein showing transmembrane domains 1–8 and re-entrant hairpin loops (HPs) 1 and 2, which flank transmembrane domain 7. The locations of all missense mutations found in the study by Yanagisawa et al. are illustrated. (B) Saturation curves for ³H-glutamate uptake into human embryonic kidney (HEK) cells transfected with wild-type EAAT1 or the missense variants (A169G, E219D, T318A, and A329T). Each data point corresponds to the mean and s.e.m. of three individually transfected wells. Representative results of three separate experiments are shown. Reproduced from Yanagisawa et al. [20].

Figure 2

Follow-up studies of a glaucomatous marmoset (13 years old) over 12 months. (A) Ocular fundus photographs of initial examination (Year 0) and one year later (Year 1) in the glaucomatous marmoset. Dotted lines indicate the cupping of the optic disc. (B) In vivo imaging of the optic disc by the horizontal and vertical scan through the center of the optic disc by spectral-domain optical coherence tomography (SD-OCT). Arrowheads indicate the cupping of the optic disc and dotted lines indicate the lamina cribrosa (LC). (C) Three-dimensional plots of the retinal responses as examined by multifocal electroretinogram. Values are given in nV per square degree (nV/deg²). Reproduced from Noro et al. [10].

Figure 3

Increased oxidative stress in glaucomatous marmosets. (A) 4-hydroxynonenal (4-HNE) expression in the retina detected by immunohistochemistry. Scale bar: 100 μm. (B) Quantitative analyses of the intensity of 4-HNE. n = 3 per group. (C) 4-HNE expression in the blood detected by immunoblot analyses. n = 9 (aged) and 3 (glaucoma). (D) GSH concentrations in the blood. n = 4 (aged) and 3 (glaucoma). The data are presented as means ± s.e.m. *p < 0.05; ***p < 0.001. Reproduced from Noro et al. [10].