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Hiromitsu Kunimi, Yukihiro Miwa, Yusaku Katada, Kazuo Tsubota, Toshihide Kurihara; A neuroprotective effect of HIF inhibitor topotecan in a murine model of retinal ganglion cell degeneration. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5884.
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© ARVO (1962-2015); The Authors (2016-present)
Therapeutic opportunities against the retinal ganglion cell (RGC) degeneration such as glaucoma are limited to lowering intraocular pressure to date. Recent studies show that hypoxia-inducible factor (HIF) plays roles including neurodegeneration in retinal diseases. We hypothesize that a HIF inhibitor topotecan may have a neuroprotective effect to the retinal ganglion cell degeneration, and examined the effect electrophysiologically using a murine N-methyl-D- aspartic acid (NMDA)-induced RGC degeneration model.
Intraperitoneal injections of vehicle or topotecan (0.625mg/kg/day) in 8 week-old C57/B6J were performed for 4 weeks (Control group; n=5, Topotecan group; n=6, respectively). Flash visual evoked potentials (VEPs) were measured on the last day of the drug injection for each group. On the same day, all mice were injected NMDA intravitreally (10mM in 1ul) in bilateral eyes. The effect of topotecan was evaluated by comparing changes of VEP amplitudes 24hours after NMDA injections.
The VEP amplitudes (P1-N1) showed no significant difference (p=0.50) between the groups after 4 week drug injections (Control group; 127±35µV, Topotecan group; 117±32µV, respectively). Topotecan group showed a significantly (p<0.01) lower decrease in amplitudes (31±24µV) compared to control group (59±24µV) whereas both groups exhibited amplitude decreases after NMDA injections.
An administration of topotecan significantly suppressed a decrease of VEP amplitudes induced by intravitreal NMDA injections in mice. These results suggested that HIF inhibition may have therapeutic effects against RGC degeneration.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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