Abstract
Purpose :
Oxidative stress is frequently associated with retinal diseases. Small molecule drugs with anti-oxidative activity may offer therapeutical potential and affordable cost to end users. Our previous work applying chemical screen, cellular imaging, and ocular pharmacokinetic analysis has identified certain marketed drugs that protect against oxidative stress in retinal cells and are able to cross blood-retina barrier reaching bioavailability in the retina after systemic administration. The purpose of this presentation is to perform in vivo anti-oxidative testing of an investigational drug (CM20) clinically used to treat hypertension.
Methods :
Adult albino BALB/c mice were given a bolus intraperitoneal injection at a therapeutic dose of the drug (20 mg/kg) dissolved in solvent (10% DMSO + 90% corn oil). After dosing, animals were either kept in dim light environment or were subject to eye exposure to a damaging level of intense bright light. Expression of anti-oxidant and mitochondrial genes including Mt1, Hmox1, Nqo1, Prdx1, SOD1, SOD2, TFAM, Nrf1, PGC-1a in the retinas was detected at 24 hours by quantitative RT-PCR in animals kept under dim light environment. Oxidative stress maker (8-OHdG) and retinal structure were examined by immunofluorescence and histology, respectively, in animals after eye exposure to intense bright light. Retinal function was examined by ERG.
Results :
Expression of metallothionein 1 (Mt1) and mitochondrial superoxide dismutase 2 (SOD2) was significantly upregulated in the retinas at 24 hours after drug dosing in animals kept under dim light environment. Fluorescent signal of oxidative stress marker (8-OHdG) was significantly lower in the retinas of drug-treated animals as compared to that of solvent-treated animals after eye exposure to intense bright light. Drug-treated animals showed better structural protection to the outer nuclear layer (ONL), in contrast to the more severe degeneration in ONL such as thinning and formation of infoldings and rosette-like structures in solvent-treated animals. Treatment with the drug had no harmful effect on retinal function.
Conclusions :
Systemic treatment with the investigative drug stimulated expression of endogenous anti-oxidant genes in the retina and protected the structure of ONL against photo-oxidative stress. Further studies in therapeutic testing and development of a topical delivery system would be desired.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.