Abstract
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.
Highlights
As “VCP modulators” or “ATP regulators” and inhibit the ATPase activities of VCP without apparent inhibition of its cellular functions[17]
In both groups intraperitoneally treated with KUS121 or phosphate-buffered saline (PBS; control group), total retinal thickness increased at day 1 and decreased thereafter (Fig. 1b)
The inner retina [composed of the retinal nerve fiber layer, retinal ganglion cells (RGCs), inner plexiform layer, and inner nuclear layer], which is located under the retinal vessel supply, was primarily impaired by the ischemic insult
Summary
As “VCP modulators” or “ATP regulators” and inhibit the ATPase activities of VCP without apparent inhibition of its cellular functions[17]. These “VCP modulators” have strong neuroprotective effects in vivo on retinal photoreceptor cells and ganglion cells[17,18,19]. These efficacies apparently correlate with their ability to ameliorate ER stress. We investigated the effect of a KUS on the retina after ischemic injury by analyzing the morphology, retinal function, and extents of ER stress and cell death
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