Abstract
Purpose :
Our prior work links mitochondrial dysfunction and oxidative stress to retinal ganglion cell death in glaucoma models. Angiotensin receptor blockers (ARBs) show neuroprotective effects in neurodegenerative disorders. This study explores irbesartan, an ARB, for its therapeutic potential in mitigating mitochondrial dysfunction and enhancing survivability in mice through ex vivo retinal explant and in vivo optic nerve crush experiments.
Methods :
Ex vivo retinal explant experiments, as previously described, involved daily 10μM irbesartan administration. Mitochondrial location and viability were assessed using 100nM mitotracker red CMXROS dye. Published experiments showed a neuroprotective effect (RBPMS staining) with irbesartan, reducing mitochondrial superoxide formation (DHE stain). In parallel in vivo optic nerve crush experiments, 10μM irbesartan eye drops were administered twice daily. Postmortem assessments, 7 days post-unilateral optic nerve crush in anesthetized mice (n=9), included mitochondrial survival and superoxide formation, with the contralateral eye as a control.
Results :
Ex vivo experiments showed active mitochondrial axonal staining with irbesartan treatment using mitotracker red CMXROS dye. A concurrent decrease in mitochondrial superoxide formation was observed, consistent with the neuroprotective effect (p<0.05). In parallel in vivo experiments, irbesartan eye drops led to a 1.5- and 1.8-fold (p <0.05) increase in surviving RGCs on day 7, compared to vehicle treatment, using RBPMS staining. There was also a decrease in superoxide production detected by DHE staining (p<0.05), indicating targeted increase in mitochondrial survival at the optic nerve site.
Conclusions :
Our findings suggest that ARBs like irbesartan hold therapeutic potential in degenerative eye conditions like glaucoma. Increased mitochondrial viability and decreased mitochondrial superoxide formation highlight irbesartan eye drops as a candidate for further exploration in clinical settings. This emphasizes its role in preserving retinal health and mitigating degenerative processes linked to mitochondrial dysfunction. These insights contribute to understanding ARBs as neuroprotective agents in ocular pathology, offering new avenues for developing targeted therapeutic strategies in retinal degeneration.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.