Hata Masayuki, Ikeda Hanako Ohashi
Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Neuroprotective Treatment Project for Ocular Diseases, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
Neural Regen Res. 2017 Aug;12(8):1252-1255. doi: 10.4103/1673-5374.213540.
Retinal ischemia causes several vision-threatening diseases, including diabetic retinopathy, retinal artery occlusion, and retinal vein occlusion. Intracellular adenosine triphosphate (ATP) depletion and subsequent induced endoplasmic reticulum (ER) stress are proposed to be the underlying mechanisms of ischemic retinal cell death. Recently, we found that a naphthalene derivative can inhibit ATPase activity of valosin-containing protein, universally expressed within various types of cells, including retinal neural cells, with strong cytoprotective activity. Based on the chemical structure, we developed novel valosin-containing protein modulators, Kyoto University Substances (KUSs), that not only inhibit intracellular ATP depletion, but also ameliorate ER stress. Suppressing ER stress by KUSs is associated with neural cell survival in animal models of several neurodegenerative diseases, such as glaucoma and retinal degeneration. Given that a major pathology of ischemic retinal diseases, other than intracellular ATP depletion, is ER stress-induced cell death, KUSs may provide a novel strategy for cell protection in ischemic conditions. Hence, we investigated the efficacy of KUS121 in a rat model of retinal ischemic injury. Intravitreal injections of KUS121, which is clinically preferable route of drug administration in retinal diseases, significantly suppressed inner retinal thinning and retinal cell death, and maintained visual functions. Valosin-containing protein modulation by KUS is a promising novel therapeutic strategy for ischemic retinal diseases.
视网膜缺血会引发多种威胁视力的疾病，包括糖尿病性视网膜病变、视网膜动脉阻塞和视网膜静脉阻塞。细胞内三磷酸腺苷（ATP）耗竭以及随后诱导的内质网（ER）应激被认为是缺血性视网膜细胞死亡的潜在机制。最近，我们发现一种萘衍生物可以抑制含缬酪肽蛋白的ATP酶活性，该蛋白在包括视网膜神经细胞在内的各种类型细胞中普遍表达，具有很强的细胞保护活性。基于其化学结构，我们开发了新型含缬酪肽蛋白调节剂——京都大学物质（KUSs），它不仅能抑制细胞内ATP耗竭，还能改善内质网应激。在青光眼和视网膜变性等几种神经退行性疾病的动物模型中，KUSs抑制内质网应激与神经细胞存活相关。鉴于缺血性视网膜疾病的主要病理除了细胞内ATP耗竭外，还有内质网应激诱导的细胞死亡，KUSs可能为缺血情况下的细胞保护提供一种新策略。因此，我们在大鼠视网膜缺血损伤模型中研究了KUS121的疗效。玻璃体内注射KUS121（这是视网膜疾病临床上首选的给药途径）可显著抑制视网膜内层变薄和视网膜细胞死亡，并维持视觉功能。通过KUS调节含缬酪肽蛋白是一种有前景的缺血性视网膜疾病新型治疗策略。
