Oxidative Stress: A Suitable Therapeutic Target for Optic Nerve Diseases?

Abstract

Optic nerve disorders encompass a wide spectrum of conditions characterized by the loss of retinal ganglion cells (RGCs) and subsequent degeneration of the optic nerve. The etiology of these disorders can vary significantly, but emerging research highlights the crucial role of oxidative stress, an imbalance in the redox status characterized by an excess of reactive oxygen species (ROS), in driving cell death through apoptosis, autophagy, and inflammation. This review provides an overview of ROS-related processes underlying four extensively studied optic nerve diseases: glaucoma, Leber's hereditary optic neuropathy (LHON), anterior ischemic optic neuropathy (AION), and optic neuritis (ON). Furthermore, we present preclinical findings on antioxidants, with the objective of evaluating the potential therapeutic benefits of targeting oxidative stress in the treatment of optic neuropathies.

Keywords: Leber’s hereditary optic neuropathy; glaucoma; ischemic optic neuropathy; optic nerve; optic neuritis; oxidative stress; retinal ganglion cell.

Figure 1

Prevalence (per 100,000) in some of the most frequent optic neuropathies. LHON: Leber’s hereditary optic neuropathy; ON: optic neuritis; NA-AION: nonarteritic anterior ischemic optic neuropathy; A-AION: arteritic anterior ischemic optic neuropathy; GCA: giant cell arteritis. * We used a y-axis break in consideration of the remarkably higher prevalence of glaucoma compared to all other optic nerve disorders. ** LHON prevalence in case of incomplete penetrance is meaningfully higher than in complete penetrance due to the high frequency of the variant mutant carriers.

Figure 2

Anatomy and perfusion of the visual pathway. LGN: lateral geniculate nucleus.

Figure 3

Model representing the ROS impact on the retina and on the optic nerve. ROS: reactive oxidative species; NOX2: NADPH oxidase type 2; XO: xanthine oxidase; eNOS: endothelial nitric oxide synthase; RGC: retinal ganglion cell; RNFL: retinal nerve fiber layer; RPE: retinal pigment epithelium; BM: Brunch’s membrane. Up arrows mean increase or upregulation.

Figure 4

Anatomic overview of aqueous humor outflow, with focus on the drainage system through the trabecular meshwork and the Schlemm’s canal to the superficial veins.

Figure 5

Model of etiopathogenesis in glaucomatous optic neuropathies. AH: aqueous humor; TM: trabecular meshwork; TMC: trabecular meshwork cell; ONH: optic nerve head; OPA1: optic atrophy 1 gene; TNF-α: tumor necrosis factor alpha; NF-kB: nuclear factor “kappa-light-chain-enhancer” of activated B-cells; ATP: adenosintriphosphat; RGC: retinal ganglion cell; oxLDL: oxidized low density lipoprotein; AGE: advanced glycation end product; pJNK: c-Jun N-terminal kinase; pERK: extracellular-signal-regulated kinase.

Figure 6

Role of calcium and reactive oxygen species in the interplay between ER and mitochondria. ER: endoplasmic reticulum; PERK: protein kinase RNA-like ER kinase; ATF: activating transcription factor; IRE-1: inositol-requiring protein 1; CHOP: CCAAT-enhancer-binding protein homologous protein; eIF2α: eukaryotic initiation factor 2α; sXBP1: spliced X-box binding protein-1; TNFR-2: tumor necrosis factor alpha receptor 2; ASK-1: apoptosis signal-regulating kinase 1; JNK: c-Jun N-terminal kinase; ERAD: ER-associated degradation; NF-kB: nuclear factor “kappa-light-chain-enhancer” of activated B-cells. Up arrows mean increase or upregulation. Down arrows mean decrease.

Figure 7

Direct and indirect effect of idebenone on the mitochondrial oxidative metabolism. COQ₁₀: cofactor Q 10; Cyt c: cytochrome c; GSH: glutathione; SOD: superoxide dismutase; GPX: glutathione peroxidase; NQO1: NAD(P)H quinone oxidoreductase 1; NOX2: nicotinamide adenine dinucleotide phosphate oxidase 2; Nrf2: nuclear factor erythroid-derived 2-related factor 2.

Figure 8

Model of LHON pathogenesis. NAD: nicotinamide dinucleotide; ETC: electron transport chain; ATP: adenosine triphosphate; cyt c: cytochrome c; Bid: BH3 interacting-domain death agonist; Apaf-1: apoptotic protease-activating factor 1; PTP: permeability transition pore.