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

Hata, Masaharu; Ikeda, Hanako Ohashi; Kikkawa, Chinami; Iwai, Shigehisa; Muraoka, Yuki; Hasegawa, Tomoko; Kakizuka, Akira; Yoshimura, Nagahisa

doi:10.1038/srep44873

Cited by 28 publications

(25 citation statements)

References 31 publications

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“…Furthermore, KUS administration was able to inhibit in vivo retinal neuronal cell death and mitigate disease phenotypes in several mouse models of retinal diseases, e.g. retinitis pigmentosa, glaucoma, and ischemic retinal disease ( Hasegawa et al, 2016b , Hata et al, 2017 , Ikeda et al, 2014 , Nakano et al, 2016 ). On the other hand, our previous results indicated that activation of nuclear receptors, specifically ERRs, would lead to increased ATP production in the targeted cells or organs ( Kamei et al, 2003 ).…”

Section: Discussionmentioning

confidence: 99%

“…Under various stress conditions in cultured cells, the chemicals (KUSs) were able to significantly maintain cellular ATP levels, and consequently suppress ER stress and cell death ( Ikeda et al, 2014 , Nakano et al, 2016 ). In addition, KUSs showed significant efficacies in preventing retinal neuronal cell death in in vivo mouse models of retinitis pigmentosa, glaucoma, and ischemic retinal disease ( Hasegawa et al, 2016b , Hata et al, 2017 , Ikeda et al, 2014 , Nakano et al, 2016 ). In this manuscript, we show that two classes of small chemicals, one for limiting ATP consumption, and the other for enhancing ATP production via ERRs, possess strong efficacies in maintaining ATP levels and in protecting neuronal cells from death in both in vitro cell culture and in vivo mouse models of Parkinson's disease.…”

Section: Introductionmentioning

confidence: 99%

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ATP Maintenance via Two Types of ATP Regulators Mitigates Pathological Phenotypes in Mouse Models of Parkinson's Disease

et al. 2017

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Parkinson's disease is assumed to be caused by mitochondrial dysfunction in the affected dopaminergic neurons in the brain. We have recently created small chemicals, KUSs (Kyoto University Substances), which can reduce cellular ATP consumption. By contrast, agonistic ligands of ERRs (estrogen receptor-related receptors) are expected to raise cellular ATP levels via enhancing ATP production. Here, we show that esculetin functions as an ERR agonist, and its addition to culture media enhances glycolysis and mitochondrial respiration, leading to elevated cellular ATP levels. Subsequently, we show the neuroprotective efficacies of KUSs, esculetin, and GSK4716 (an ERRγ agonist) against cell death in Parkinson's disease models. In the surviving neurons, ATP levels and expression levels of α-synuclein and CHOP (an ER stress-mediated cell death executor) were all rectified. We propose that maintenance of ATP levels, by inhibiting ATP consumption or enhancing ATP production, or both, would be a promising therapeutic strategy for Parkinson's disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ATP Maintenance via Two Types of ATP Regulators Mitigates Pathological Phenotypes in Mouse Models of Parkinson's Disease

et al. 2017

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“…Furthermore, KUS121 has been shown to be one of the most potent neuroprotective KUSs and has not shown any obvious safety issues in these animal experiments. Additionally, in rats with ischemic retinal injuries, either systemic or intravitreal administration of KUS121 suppressed death of the retinal ganglion cells, as well as subsequent deterioration of visual functions [19].…”

Section: Introductionmentioning

confidence: 93%

“…KUSs have been shown to maintain cellular ATP levels, function as intracellular ATP regulators, and consequently suppress ER stress and cell death under various cell death-inducing insults, both in vitro and in several pathological conditions in vivo [15,[17][18][19][20]. We have shown that KUSs can mitigate retinal pathologies in animal models of retinitis pigmentosa [15,17], glaucoma [18], age-related macular degeneration [20], and retinal ischemia [19]. Furthermore, KUS121 has been shown to be one of the most potent neuroprotective KUSs and has not shown any obvious safety issues in these animal experiments.…”

Section: Introductionmentioning

confidence: 99%

Safety and effectiveness of a novel neuroprotectant, KUS121, in patients with non-arteritic central retinal artery occlusion: An open-label, non-randomized, first-in-humans, phase 1/2 trial

et al. 2020

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Kyoto University Substance (KUS) 121, an ATPase inhibitor of valosin-containing protein, is a novel neuroprotectant. We tested the safety and effectiveness of KUS121 in patients with acute central retinal artery occlusion (CRAO). We conducted an investigator-initiated, firstin-humans, phase 1/2 clinical trial. Nine patients with non-arteritic CRAO symptoms lasting for 4-48 h were enrolled. These patients received daily intravitreal injections of KUS121 for 3 days: 25 μg (low-dose) in the first three patients and 50 μg (high-dose) in the next six patients. The primary endpoint was the safety of the drug. As a secondary endpoint, pharmacokinetics was evaluated. Other key secondary endpoints were changes in best-corrected visual acuity (BCVA), measured using the Early Treatment Diabetic Retinopathy Study chart, visual field scores, and retinal sensitivities between baseline and week 12; and decimal BCVA at week 12. Administration of KUS121 did not result in serious adverse events. All nine patients (100%) showed significant improvement of BCVA. Average readable letter counts, visual field scores, and retinal sensitivities also improved. Decimal BCVA at week 12 was better than 0.1 in four patients (44%) and equal to or better than 0.05 in seven patients (78%). This first-in-humans clinical trial provides support for the safety and efficacy of intravitreal KUS121 injection. To substantiate the safety and effectiveness for patients with acute CRAO, further larger scale clinical studies will be needed.

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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 .…”

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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

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

Cited by 28 publications

References 31 publications

ATP Maintenance via Two Types of ATP Regulators Mitigates Pathological Phenotypes in Mouse Models of Parkinson's Disease

ATP Maintenance via Two Types of ATP Regulators Mitigates Pathological Phenotypes in Mouse Models of Parkinson's Disease

Safety and effectiveness of a novel neuroprotectant, KUS121, in patients with non-arteritic central retinal artery occlusion: An open-label, non-randomized, first-in-humans, phase 1/2 trial

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

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