June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
The role of oxidative DNA damage and response in NMDA-induced retinal ganglion cell death
Author Affiliations & Notes
  • Ayako Okita
    Kyushu Daigaku, Fukuoka, Fukuoka, Japan
  • Yusuke Murakami
    Kyushu Daigaku, Fukuoka, Fukuoka, Japan
  • Shotaro Shimokawa
    Kyushu Daigaku, Fukuoka, Fukuoka, Japan
  • Yasuhiro Ikeda
    Miyazaki Daigaku, Miyazaki, Miyazaki, Japan
  • Yusaku Nakabeppu
    Kyushu Daigaku, Fukuoka, Fukuoka, Japan
  • Koh-hei Sonoda
    Kyushu Daigaku, Fukuoka, Fukuoka, Japan
  • Footnotes
    Commercial Relationships   Ayako Okita, None; Yusuke Murakami, None; Shotaro Shimokawa, None; Yasuhiro Ikeda, None; Yusaku Nakabeppu, None; Koh-hei Sonoda, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 1628. doi:
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      Ayako Okita, Yusuke Murakami, Shotaro Shimokawa, Yasuhiro Ikeda, Yusaku Nakabeppu, Koh-hei Sonoda; The role of oxidative DNA damage and response in NMDA-induced retinal ganglion cell death. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1628.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose : Oxidative stress has been implicated in the pathophysiology of glaucoma; however, the biological mechanisms by which oxidative damage causes retinal ganglion cell (RGC) death remain to be elucidated. We previously reported that oxidative DNA damage triggers microglial activation and retinal degeneration via the activation of MutY Homolog (MUTYH), a DNA damage-associated glycosylase, in experimental retinitis pigmentosa. In the present study, we investigate the role of MUTYH in RGC cell death induced by N-methyl-D-aspartate (NMDA).

Methods : Mutyh-/- mice and age-matched wild-type (WT) mice was employed in a model of NMDA-induced retinal excitotoxicity. Eight nM NMDA was intravitreally injected in the mouse eyes. Immunohistochemical analysis was performed using anti-8-hydoroxy-deoxyguanosine (8-oxoG) monoclonal antibody (a marker of oxidative DNA damage), anti-Brn3a antibody (a marker of RGC), anti-Iba-1 antibody (a marker of microglia), and anti-ssDNA antibody [a marker of single strand breaks (SSBs)] at 24 hours and 7 days after injection.

Results : Substantial microgliosis and RGC loss were observed in the eyes of NMDA-injected WT mice. In contrast, Mutyh deficiency significantly reduced the density of microglia (P = 0.0152) and attenuated the RGC loss (P = 0.0021). Moreover, 8-oxoG was accumulated within the nucleus of microglia after 24 hours to 7 days and SSBs were developed in WT mice. In contrast, Mutyhdeficiency prevented SSBs formation following NMDA-induced oxidative DNA damage.

Conclusions : MUTYH activation associated with oxidative DNA damage accelerates microgliosis and RGC cell death in NMDA-induced retinal excitotoxicity.

This is a 2021 ARVO Annual Meeting abstract.


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