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.
© 2025. The Author(s).