Neuroprotective effects of VCP modulators in mouse models of glaucoma

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

doi:10.1016/j.heliyon.2016.e00096

Cited by 39 publications

(55 citation statements)

References 42 publications

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“…Similar results were obtained using three different mouse models of glaucoma but without observable side effects18. KUSs exhibited ER stress-reducing effects, demonstrating the neuroprotective effects on retinal cells in these mouse models.…”

Section: Discussionsupporting

confidence: 82%

KUS121, a VCP modulator, attenuates ischemic retinal cell death via suppressing endoplasmic reticulum stress

Hata

Ikeda

Kikkawa

et al. 2017

Sci Rep

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Ischemic neural damages cause several devastating diseases, including brain stroke and ischemic retinopathies, and endoplasmic reticulum (ER) stress has been proposed to be the underlying mechanism of the neuronal cell death of these conditions. We previously synthesized Kyoto University substances (KUSs) as modulators of valosin-containing protein (VCP); KUSs inhibit VCP ATPase activity and protect cells from different cell death-inducing insults. Here, we examined the efficacy of KUS121 in a rat model of retinal ischemic injury. Systemic administration of KUS121 to rats with ischemic retinal injury significantly suppressed inner retinal thinning and death of retinal ganglion and amacrine cells, with a significant functional maintenance of visual functions, as judged by electroretinography. Furthermore, intravitreal injection of KUS121, which is the clinically preferred route of drug administration for retinal diseases, appeared to show an equal or better neuroprotective efficacy in the ischemic retina compared with systemic administration. Indeed, induction of the ER stress marker C/EBP homologous protein (CHOP) after the ischemic insult was significantly suppressed by KUS121 administration. Our study suggests VCP modulation by KUS as a promising novel therapeutic strategy for ischemic neuronal diseases.

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Section: Discussionsupporting

confidence: 82%

KUS121, a VCP modulator, attenuates ischemic retinal cell death via suppressing endoplasmic reticulum stress

Hata

Ikeda

Kikkawa

et al. 2017

Sci Rep

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“…Subsequently, cytochrome c contributes to the formation of apoptosome through activating apoptotic protease activating factor (Apaf)-1 (Saleh et al, 1999; Li et al, 1997), which in turn recruits, cleaves and activates caspase-9 and the effector caspases-3 (Li et al, 1997). In GLAST +/− mice, both increased oxidative stress and glutamate toxicity contribute to RGC apoptosis (Harada et al, 2007a; Harada et al, 2007b Harada et al, 2010; Semba et al, 2014; Kimura et al, 2015; Nakano et al, 2016). In this study, we confirmed increased activities of both caspase-9 and -3 in GLAST +/− mice compared to normal littermates, indicating increased caspase activities were involved in RGC apoptosis as the pathogenesis of NTG.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that loss of a glutamate transporter, glutamate/aspartate transporter (GLAST) or excitatory amino-acid carrier 1 (EAAC1), in mice leads to RGC degeneration similar to human NTG (Harada et al, 2007a; Harada et al, 2007b; Harada et al, 2010; Semba et al, 2014; Kimura et al, 2015; Nakano et al, 2016). In these mice, not only glutamate neurotoxicity but also oxidative stress is involved in their mechanisms.…”

Section: Introductionmentioning

confidence: 99%

“…Glutamate neurotoxicity and oxidative stress have been proposed to contribute to retinal damage in various eye diseases including glaucoma (Osborne, 2008). Together with the decrease of glutamate transporters and glutathione levels observed in glaucoma patients (Gherghel et al, 2013; Naskar et al, 2000; Goyal et al, 2014), these mice seem to be useful as the animal models of NTG (Harada et al, 2007a; Harada et al, 2007b; Harada et al, 2010; Semba et al, 2014; Kimura et al, 2015; Nakano et al, 2016). In this study, we investigated the cytoprotective effect of oral GGA on RGC loss observed in GLAST heterozygous (GLAST +/− ) mice, as well as underlying molecular mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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Effect of geranylgeranylacetone on the protection of retinal ganglion cells in a mouse model of normal tension glaucoma

Dong

Shinmei

Dong

et al. 2016

Heliyon

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Glaucoma is characterized by axonal degeneration of retinal ganglion cells (RGCs) and apoptotic death of their cell bodies, and lowering intraocular pressure is associated with an attenuation of progressive optic nerve damage. Nevertheless, intraocular pressure (IOP) reduction alone was not enough to inhibit the progression of disease, which suggests the contribution of other factors to the glaucoma pathogenesis. In this study, we investigated the cytoprotective effect of geranylgeranylacetone (GGA) on RGCs degeneration using a normal tension glaucoma (NTG) mouse model, which lacks glutamate/aspartate transporter (GLAST) and demonstrates spontaneous RGC and optic nerve degeneration without elevated intraocular pressure (IOP). Three-week-old GLAST+/− mice were given oral administration of GGA at 100, 300, or 600 mg/kg/day or vehicle alone, and littermate control mice were given vehicle alone for 14 days, respectively. At 5 weeks after birth, the number of RGCs was counted in paraffin sections of retinal tissues stained with hematoxylin and eosin. In addition, retrograde labeling technique was also used to quantify the number of RGC. Expression and localization of heat shock protein 70 (HSP70) in retinas were evaluated by reverse transcription polymerase chain reaction and immunohistochemistry, respectively. Activities of caspase-9 and -3 in retinas were also assessed. The number of RGCs of GLAST+/− mice significantly decreased, as compared to that of control mice. RGC loss was significantly suppressed by administration of GGA at 600 mg/kg/day, compared with vehicle alone. Following GGA administration, HSP70 was significantly upregulated together with reduction in the activities of caspase-9 and -3. Our studies highlight HSP70 induction in the retina is available to suppress RGC degeneration, and thus GGA may be applicable for NTG as a promising therapy.

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“…KUSs prevented ATP depletion, endoplasmic reticulum (ER) stress, and consequently cell death in cultured cells. KUSs consistently suppressed retinal neuronal cell death in animal models of ocular diseases, such as retinitis pigmentosa 15,16 , glaucoma 17 , and central retinal artery occlusion 18 .…”

mentioning

confidence: 96%

Effect of VCP modulators on gene expression profiles of retinal ganglion cells in an acute injury mouse model

Hasegawa

Ikeda

Gotoh

et al. 2020

Sci Rep

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In glaucoma, retinal ganglion cells are damaged, leading to the progressive constriction of the visual field. We have previously shown that the valosin-containing protein (VCP) modulators, Kyoto University Substance (KUS)121 and KUS187, prevent the death of retinal ganglion cells in animal models of glaucoma, including the one generated by N-methyl-D-aspartate (NMDA)-induced neurotoxicity. KUSs appeared to avert endoplasmic reticulum (ER) stress by maintaining ATP levels, resulting in the protection of ganglion cells from cell death. To further elucidate the protective mechanisms of KUSs, we examined gene expression profiles in affected ganglion cells. We first injected KUS-treated mice with NMDA and then isolated the affected retinal ganglion cells using fluorescence-activated cell sorting. Gene expression in the cells was quantified using a next-generation sequencer. Resultantly, we found that KUS121 upregulated several genes involved in energy metabolism. In addition, we observed the upregulation of Zfp667, which has been reported to suppress apoptosis-related genes and prevent cell death. These results further support the suitability of KUS121 as a therapeutic drug in protecting retinal ganglion cells in ophthalmic disorders, such as glaucoma.

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Neuroprotective effects of VCP modulators in mouse models of glaucoma

Cited by 39 publications

References 42 publications

KUS121, a VCP modulator, attenuates ischemic retinal cell death via suppressing endoplasmic reticulum stress

KUS121, a VCP modulator, attenuates ischemic retinal cell death via suppressing endoplasmic reticulum stress

Effect of geranylgeranylacetone on the protection of retinal ganglion cells in a mouse model of normal tension glaucoma

Effect of VCP modulators on gene expression profiles of retinal ganglion cells in an acute injury mouse model

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