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Oculus

Editors Selection IGR 20-2

Basic Science: Glaucoma Pathophysiology

Toru Nakazawa

Comment by Toru Nakazawa on:

79859 Differential effects of N-acetylcysteine on retinal degeneration in two mouse models of normal tension glaucoma, Sano H; Namekata K; Kimura A et al., Cell Death and Disease, 2019; 10: 75


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The pathophysiology of glaucoma-induced retinal ganglion cell (RGC) death remains unclear. However, the suppression of oxidative stress may be an effective therapeutic strategy for the prevention of visual field loss.1 N-acetylcysteine (NAC) is clinically used to treat paracetamol overdose and is relatively safe and well tolerated, with occasional mild side effects. NAC is cell permeable, serves as a precursor of cysteine and stimulates the synthesis of glutathione in neural cells.

In this study, Sano et al. investigated the neuroprotective effect of the intraperitoneal administration of NAC (200 mg/kg, similar to the clinical dose) in two mouse models of normal-tension glaucoma. The authors previously developed these mouse models,2 in which one of two genes was deleted: excitatory amino-acid carrier 1 (EAAC1, localized in the RGCs) or glutamate/aspartate transporter (GLAST, localized in the Muller glial cells). Intraperitoneal administration of NAC prevented RGC degeneration and visual impairment in the EAAC1 knockout (KO) mice, but not in the GLAST KO mice. The treatment mechanism of NAC treatment in the EAAC1 KO mice was demonstrated to include the induction of glutathione in the retina and the suppression of oxidative stress and autophagy.

The plasma level of glutathione decreases in primary open-angle glaucoma, including NTG.3 In addition, mutations in optineurin, an adaptor protein that is involved in autophagy, are associated with glaucoma, suggesting that autophagy plays a role in the pathogenesis of glaucoma.4 Thus, these findings raise the intriguing possibility that systemic administration of NAC may be effective for subtypes of glaucoma that are associated with increased oxidative stress.

References

  1. Nakazawa T. Ocular blood flow and influencing factors for glaucoma. Asia Pac J Ophthalmol (Phila). 2016;5:38-44.
  2. Harada C, Kimura A, Guo X, Namekata K, Harada T. Recent advances in genetically modified animal models of glaucoma and their roles in drug repositioning. Br J Ophthalmol 2019;103:161-166.
  3. Gherghel D, Mroczkowska S, Qin L. Reduction in blood glutathione levels occurs similarly in patients with primary-open angle or normal tension glaucoma. Invest. Ophthalmol. Vis. Sci. 2013;54:3333-3339.
  4. Minegishi Y, Nakayama M, Iejima D, Kawase K, Iwata T. Significance of optineurin mutations in glaucoma and other diseases. Prog Retin Eye Res. 2016;55:149-181.


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