4.7 Article

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

Journal

SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/srep44873

Keywords

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Funding

  1. Astellas Foundation for Research on Metabolic Disorders
  2. Japan Foundation for Applied Enzymology
  3. Uehara Memorial Foundation
  4. Mochida Memorial Foundation for Medical and Pharmaceutical Research
  5. YOKOYAMA Foundation for Clinical Pharmacology [YRY1308]
  6. Japan Intractable Diseases Research Foundation
  7. Japan Research Foundation for Clinical Pharmacology
  8. ONO Medical Research Foundation
  9. Takeda Science Foundation
  10. Japan National Society for the Prevention of Blindness
  11. SORST of JST [24791850, 15K20255]
  12. Ministry of Education, Culture, Sports, Science, and Technology of Japan
  13. Ministry of Health, Labour and Welfare of Japan
  14. Ministry of Education, Culture, Sports, Science and Technology of Japan
  15. Grants-in-Aid for Scientific Research [16K20316, 16K11285] Funding Source: KAKEN

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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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