Protective effect of an apelin receptor agonist on retinal ganglion cell death induced by retinal ischemia-reperfusion injury in mice

Abstract

Glaucoma is an eye disease that causes blindness through the degeneration of retinal ganglion cells. Glaucoma is typically associated with elevated intraocular pressure, but ocular hypotensive treatment is ineffective in some patients. Therefore, it is necessary to develop a new drug that inhibits retinal ganglion cell death in glaucoma. We have previously reported that APJ, the G protein-coupled receptor for apelin which is the bioactive peptide ligand, is expressed in the retinal ganglion cells in mice and that apelin deficiency in mice facilitates retinal ganglion cell death in a retinal ischemia-reperfusion injury model, a glaucoma model. In this study, we investigated whether ML233, an apelin receptor agonist, inhibited retinal ganglion cell death induced by retinal ischemia-reperfusion injury in mice. Retinal ischemia-reperfusion injury was performed in C57BL/6N mice using the high intraocular pressure method. Retinal ganglion cell death was assessed by counting the number of the cells in the retinal ganglion cell layer of the retinal section stained with hematoxylin and eosin. TUNEL assay was conducted to detect apoptotic cells in the retinal ganglion cell layer. Electroretinography was performed to assess the electro-responses of retinal ganglion cells. An intraperitoneal injection of ML233 (1-5 mg/kg) suppressed the cell death in the retinal ganglion layer in the mouse at 24 h after retinal ischemia-reperfusion injury in a dose-dependent manner. In addition, ML233 inhibited apoptosis in the retinal ganglion layer induced by retinal ischemia-reperfusion injury. Consistent with the retinal histopathological findings, electroretinography showed that ML233 prevented a reduction of electro-responses in the retina after retinal ischemia-reperfusion injury. These results suggest that apelin receptor agonists protect retinal ganglion cells against retinal ischemia reperfusion injury and that the drugs targeting apelin receptor may be a new candidate for treating glaucoma.