Neuroprotective effects of VCP modulators in mouse models of glaucoma.

Noriko Nakano,Yuki Muraoka,Masaki Nakano,Hanako Ohashi Ikeda,Nagahisa Yoshimura,Toshiyuki Shudo,Sachiko Iwai,Tatsuaki Tsuruyama,Tomoko Hasegawa,Tomohiro Fuchigami,Akira Kakizuka

doi:10.1016/j.heliyon.2016.e00096

Noriko Nakano, Yuki Muraoka + Show 9 more

Open Access

https://doi.org/10.1016/j.heliyon.2016.e00096

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Abstract

Glaucoma is a major cause of adult blindness due to gradual death of retinal ganglion cells. Currently, no therapeutics are available for the protection of these cells from the cell death. We have recently succeeded in synthesizing novel compounds, KUSs (Kyoto University Substances), which can reduce cellular ATP consumption by specifically inhibiting the ATPase activities of VCP, a major ATPase in the cell, and we have shown that KUSs could mitigate the disease progression of rd10, a mouse model of retinitis pigmentosa, without any apparent side effects. Here we show that KUSs (e.g. KUS121 and KUS187) can prevent antimycin- and oligomycin-induced ATP depletion, endoplasmic reticulum (ER) stress, and cell death in neuronally differentiated PC12 cells. Furthermore, KUSs manifest significant efficacies on several mouse models of glaucoma. KUS administration prevented or mitigated ER stress and subsequent apoptotic cell death of retinal ganglion cells in an acute injury mouse model of retinal ganglion cell loss, which was induced with N-methyl-D-aspartate. In a mouse model of glaucoma with high intraocular pressure, KUSs prevented the typical glaucoma pathologies, i.e. enlargement of optic disc cupping and thinning of the retinal nerve fiber layer. KUSs also preserved visual functions in GLAST knockout mice, a mouse model for chronic retinal ganglion cell loss. We propose “ATP maintenance” via inhibition of ATPase activities of VCP as a promising new neuroprotective strategy for currently incurable eye diseases, such as glaucoma.

Highlights

Glaucoma, which is caused by the loss of retinal nerve fibers and retinal ganglion cells, is a leading cause of vision loss worldwide
We first examined the effects of KUSs, namely KUS121 and KUS187, on neuronally differentiated PC12 cells treated with antimycin or oligomycin, which inhibit mitochondrial respiratory chain complex III and V, respectively
We provided several lines of evidence that KUSs, which we previously developed as specific inhibitors of the ATPase activities of VCP

Summary

Introduction

Glaucoma, which is caused by the loss of retinal nerve fibers and retinal ganglion cells, is a leading cause of vision loss worldwide. Lowering intraocular pressure by drugs and/or surgery is the only evidence-based treatment. It is not always effective; even after the success in reducing the intraocular pressure, visual field loss gradually progresses in many patients. There have been no such definitive treatments to protect retinal ganglion cells from cell death. The involvement of endoplasmic reticulum (ER) stress in the death of ganglion cells has been proposed (Anholt and Carbone, 2013; Doh et al, 2010; Shimazawa et al, 2007; Yang et al., 2011). New drugs or compounds with ER stress-reducing activities would be promising therapeutics for the protection of retinal ganglion cells from glaucoma-causing insults

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