Kikkawa Chinami, Ikeda Hanako Ohashi, Hata Masayuki, Iwai Sachiko, Tsujikawa Akitaka
Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, 606-8507, Japan.
Product Development Division, Santen Pharmaceutical Co., Ltd, Nara, Japan.
Sci Rep. 2025 Apr 27;15(1):14721. doi: 10.1038/s41598-025-99287-z.
Ischemic optic neuropathy is a leading cause of sudden vision loss, particularly in elderly individuals, with no available effective treatments. Ischemia-induced irreversible damage to optic nerve fibers highlights the need for novel therapies with neuroprotective potential. Therefore, we investigated the effects of modulating valosin-containing proteins by regulating their intracellular ATPase activity in a rat model of anterior ischemic optic neuropathy. Intravitreal injection of KUS121 (Kyoto University Substance 121), a valosin-containing protein modulator, significantly reduced retinal thinning, retinal ganglion cell death, and optic nerve fiber loss. Morphological and histopathological analyses showed that KUS121 treatment prevented the disorganization, swelling, and loss of myelin. Notably, KUS121 demonstrated strong neuroprotective effects even when administered immediately after the induction of ischemic optic neuropathy. Mechanistically, the neuroprotective effect of KUS121 can be attributed to the suppression of endoplasmic reticulum stress, as evidenced by reduced expression of the C/EBP homologous protein, a marker of endoplasmic reticulum stress, following ischemic injury. Conclusively, KUS121 is promising as a therapeutic option for ischemic optic neuropathy and other ischemia-related neurodegenerative conditions.
缺血性视神经病变是导致突然视力丧失的主要原因，尤其是在老年人中，且目前尚无有效的治疗方法。缺血对视神经纤维造成的不可逆损伤凸显了开发具有神经保护潜力的新疗法的必要性。因此，我们在大鼠前部缺血性视神经病变模型中，研究了通过调节含缬酪肽蛋白的细胞内ATP酶活性来调控该蛋白的作用效果。玻璃体内注射含缬酪肽蛋白调节剂KUS121（京都大学物质121）可显著减轻视网膜变薄、视网膜神经节细胞死亡和视神经纤维损失。形态学和组织病理学分析表明，KUS121治疗可防止髓鞘的紊乱、肿胀和损失。值得注意的是，即使在缺血性视神经病变诱导后立即给药，KUS121也表现出强大的神经保护作用。从机制上讲，KUS121的神经保护作用可归因于对内质网应激的抑制，缺血损伤后内质网应激标志物C/EBP同源蛋白的表达降低证明了这一点。总之，KUS121有望成为治疗缺血性视神经病变和其他缺血相关神经退行性疾病的一种治疗选择。
