NADPH oxidase plays a central role in cone cell death in retinitis pigmentosa

Shinichi Usui, Brian C. Oveson, Sun Young Lee, Young Joon Jo, Tsunehiko Yoshida, Akiko Miki, Katsuaki Miki, Takeshi Iwase, Lili Lu, Peter A. Campochiaro

Research output: Contribution to journalArticlepeer-review

Abstract

Retinitis pigmentosa (RP) is a collection of diseases in which rod photoreceptors die from a variety of mutations. After rods die, the level of tissue oxygen in the outer retina becomes elevated and there is progressive oxidative damage to cones that ultimately triggers apoptosis. In this study, we investigated the hypothesis that NADPH oxidase (Nox) and/or xanthine oxidase serve as critical intermediaries between increased tissue oxygen and the generation of excessive reactive oxygen species that cause oxidative damage to cones. Apocynin, a blocker of Nox, but not allopurinol, a blocker of xanthine oxidase, markedly reduced the superoxide radicals visualized by hydroethidine in the outer retina in the retinal degeneration-1 (rd1+/+) model of RP. Compared to rd1+/+ mice treated with vehicle, those treated with apocynin, but not those treated with allopurinol, had significantly less oxidative damage in the retina measured by ELISA for carbonyl adducts. Apocynin-treated, but not allopurinol-treated, rd1+/+ mice had preservation of cone cell density, increased mRNA levels for m- and s-cone opsin, and increased mean photopic b-wave amplitude. In Q344ter mice, a model of dominant RP in which mutant rhodopsin is expressed, apocynin treatment preserved photopic electroretinogram b-wave amplitude compared to vehicle-treated controls. These data indicate that Nox, but not xanthine oxidase, plays a critical role in generation of the oxidative stress that leads to cone cell death in RP and inhibition of Nox provides a new treatment strategy.

Original languageEnglish (US)
Pages (from-to)1028-1037
Number of pages10
JournalJournal of Neurochemistry
Volume110
Issue number3
DOIs
StatePublished - Aug 2009

Keywords

  • Antioxidants
  • Apoptosis
  • Photoreceptors
  • Reactive oxygen species
  • Retina
  • Retinal dystrophies

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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