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2025

FASEB J. 2025 Mar 31;39(6):e70465. doi: 10.1096/fj.202402642R.

Retinoid X receptor agonist 9CDHRA mitigates retinal ganglion cell apoptosis and neuroinflammation in a mouse model of glaucoma

Devaraj Basavarajappa, Nitin Chitranshi, Seyed Shahab Oddin Mirshahvaladi, Veer B Gupta, Viswanthram Palanivel, Gabriella E Parrilla, Akanksha Salkar, Mehdi Mirzaei, András M Komáromy, Wojciech Krezel, Stuart L Graham, Vivek Gupta

Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia. School of Medicine, Deakin University, Geelong, Victoria, Australia. Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, USA. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut de la Santé et de la Recherche Médicale (U1258), Centre National de la Recherche Scientifique (UMR7104), Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Illkirch, France.

Service type: Stock strains

Abstract

Glaucoma, a leading cause of irreversible blindness, is characterized by the progressive loss of retinal ganglion cells (RGCs) and optic nerve damage, often associated with elevated intraocular pressure (IOP). Retinoid X receptors (RXRs) are ligand-activated transcription factors crucial for neuroprotection, as they regulate gene expression to promote neuronal survival via several biochemical networks and reduce neuroinflammation. This study investigated the therapeutic potential of 9-cis-13,14-dihydroretinoic acid (9CDHRA), an endogenous retinoid RXR agonist, in mitigating RGC degeneration in a high-IOP-induced experimental model of glaucoma. We administered 9CDHRA to glaucomatous mice eyes via intravitreal injections and assessed its effects on endoplasmic reticulum (ER) stress markers, glial cell activation, and RGC survival. Our findings demonstrated that 9CDHRA treatment significantly protected inner retinal function and retinal laminar structure in high-IOP glaucoma. The treatment reduced ER stress markers, increased protein lysine acetylation, and diminished glial cell activation, leading to a significant decrease in apoptotic cells under glaucomatous conditions. These results suggest that 9CDHRA exerts neuroprotective effects by modulating key pathogenic pathways in glaucoma, highlighting its potential as a novel therapeutic strategy for preserving vision in glaucoma. Keywords: 9CDHRA; ER stress; apoptosis; glaucoma; glial cell; intraocular pressure; neuroinflammation; neuroprotection; retinoid X receptors.

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