Abstract
Purpose :
Ocular hypertension (OHT), a major glaucoma risk factor, causes mitochondrial dysfunction which results in overt reactive oxygen species (ROS) production, exacerbated retinal ganglion cell (RGC) vulnerability, and neuronal death. MP201 is an oral small molecule prodrug of mitochondrial uncoupler that is brain penetrant with pharmacology that lowers damage by reducing ROS and calcium overload while promoting repair with induction of BDNF production in CNS. Collectively, MP201 protects against neurodegeneration in several disease models, including optic neuritis, but whether this strategy is neuroprotective in glaucoma is unknown. Here, we tested the hypothesis that MP201-induced mitochondrial uncoupling reduces ROS levels and improves RGC survival in experimental glaucoma.
Methods :
The magnetic microbead model was used to induce OHT in mice. MP201 (8 mg/Kg), a slow-release prodrug with first-pass metabolism to an active form, was given by daily oral gavage starting one week post-OHT induction (OHT-1w). Intraocular pressure (IOP) and weight were measured weekly throughout the study to monitor adverse effects. ROS levels in RGCs were measured using MitoSOX and ImageJ software. RGC density was quantified in RBPMS-stained retinas at OHT-3w using a stereological unbiased approach.
Results :
Physical examination and tonometry showed that MP201 treatment did not affect body weight (BW) or IOP relative to vehicle (Two-way ANOVA, N=6 mice/grp, BW: p=0.58, IOP: p=0.60). MitoSOX quantification at OHT-2w, when OHT is stable but before RGC loss, showed substantial ROS levels increase in RGCs compared to sham controls (N=4 mice/grp, ANOVA & Dunnett's **p=0.001). Sustained mitochondrial uncoupling and ROS reduction by MP201 significantly improved RGC survival relative to vehicle (N=6 mice/grp, ANOVA & Dunnett's **p=0.003).
Conclusions :
Our results demonstrate that MP201 reduces ROS levels, increases RGC resilience, and promotes neuronal survival. These findings suggest that mitochondrial uncoupling is beneficial to counter oxidative stress and neurodegeneration in experimental glaucoma.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.