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.
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DOI：
10.1038/srep44873
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发表时间：
2017-03-20
影响因子：
4.6
通讯作者：
Yoshimura N
中科院分区：
文献类型：
--
作者：
Hata M;Ikeda HO;Kikkawa C;Iwai S;Muraoka Y;Hasegawa T;Kakizuka A;Yoshimura N
缺血性神经损伤导致几种破坏性疾病，包括脑卒中和缺血性视网膜病变，并且已经提出内质网（ER）应激是这些病症的神经元细胞死亡的潜在机制。我们先前合成了京都大学的物质（KUSs）作为含缬氨肽蛋白（VCP）的调节剂; KUSs抑制VCP ATP酶活性并保护细胞免受不同的细胞死亡诱导损伤。在这里，我们研究了KUS 121在视网膜缺血性损伤大鼠模型中的疗效。通过视网膜电图判断，对缺血性视网膜损伤大鼠全身给予KUS 121可显著抑制视网膜内变薄以及视网膜神经节细胞和无长突细胞的死亡，并显著维持视觉功能。此外，玻璃体内注射KUS 121（其是视网膜疾病的临床优选的药物施用途径）似乎在缺血性视网膜中显示出与全身施用相比相等或更好的神经保护功效。事实上，缺血损伤后ER应激标志物C/EBP同源蛋白（CHOP）的诱导被KUS 121给药显著抑制。我们的研究表明，VCP调制KUS作为一个有前途的新的治疗策略缺血性神经元疾病。
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.