HIF inhibitor topotecan has a neuroprotective effect in a murine retinal ischemia-reperfusion model

Hiromitsu Kunimi; Yukihiro Miwa; Yusaku Katada; Kazuo Tsubota; Toshihide Kurihara

doi:10.7717/peerj.7849

HIF inhibitor topotecan has a neuroprotective effect in a murine retinal ischemia-reperfusion model

PeerJ. 2019 Oct 4:7:e7849. doi: 10.7717/peerj.7849. eCollection 2019.

Authors

Hiromitsu Kunimi^{1

2}, Yukihiro Miwa^{1

2}, Yusaku Katada^{1

2}, Kazuo Tsubota¹, Toshihide Kurihara^{1

2}

Affiliations

¹ Department of Ophthalmology, School of Medicine, Keio University, Tokyo, Japan.
² Laboratory of Photobiology, School of Medicine, Keio University, Tokyo, Japan.

Abstract

Purpose: The therapeutic approach for retinal ganglion cell (RGC) degeneration has not been fully established. Recently, it has been reported that hypoxia-inducible factor (HIF) may be involved with retinal neurodegeneration. In this study, we investigated neuroprotective effects of a HIF inhibitor against RGC degeneration induced in a murine model of retinal ischemia-reperfusion (I/R).

Methods: Eight-weeks-old male C57/BL6J mice were treated with intraperitoneal injection of a HIF inhibitor topotecan (1.25 mg/kg) for 14 days followed by a retinal I/R procedure. Seven days after the I/R injury, the therapeutic effect was evaluated histologically and electrophysiologically.

Results: The increase of HIF-1α expression and the decrease of retinal thickness and RGC number in I/R were significantly suppressed by administration of topotecan. Impaired visual function in I/R was improved by topotecan evaluated with electroretinogram and visual evoked potentials.

Conclusions: Topotecan administration suppressed HIF-1a expression and improved RGC survival resulting in a functional protection against retinal I/R. These data indicated that the HIF inhibitor topotecan may have therapeutic potentials for RGC degeneration induced with retinal ischemia or high intraocular pressure.

Keywords: Hypoxia-inducible factor; Ischemia-repufusion; Neuroprotection; Retinal ganglion cell; Topotecan.

Grants and funding

This work was supported by Grants-in-Aid for Scientific Research (KAKENHI, number 15K10881 and 18K09424) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to Toshihide Kurihara. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.