| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 2568285 | Toxicology and Applied Pharmacology | 2015 | 9 Pages |
•There were strong correlations of ERG readouts to in vivo ophthalmic exams, TUNEL assay, and histopathology.•ERG appears to be more sensitive and can detect retinal functional changes at a very early stage of pathogenesis.•ERG can be incorporated into routine exploratory toxicity study to identify compound ocular safety issues.•In drug discovery, ERG is a quick, non-invasive, sensitive and reliable tool in retinal toxicity de-risking.
Retinal ocular toxicity is among the leading causes of drug development attrition in the pharmaceutical industry. Electroretinography (ERG) is a non-invasive functional assay used to assess neuro-retinal physiological integrity by measuring the electrical responses. To directly assess the utility of ERG, a series of studies was conducted following intravitreal and/or iv administration of pan-cyclin-dependent kinase inhibitors: AG-012,986 and AG-024,322 in rats. Both compounds have previously shown to induce retinal toxicity. Retinal injury was evaluated by ERG, histopathology and TUNEL staining. Intravitreal injection of AG-012,986 at ≥ 10 μg/eye resulted in decreases (60%) in ERG b-wave and microscopic changes of mild to moderate retinal degeneration, and at 30 μg/eye led to additional ophthalmic findings. Intravenous administration of AG-012,986 daily at ≥ 5 mg/kg resulted in dose-related decreases (25 to 40%) in b-wave and sporadic to intense positive TUNEL staining. Intravitreal injection of AG-024,322 at 30 μg/eye also resulted in decreases (50 to 60%) in b-wave, mild to marked retinal degeneration and mild vitreous debris. These experiments demonstrate that ERG can be used as a sensitive and reliable functional tool to evaluate retinal toxicity induced by test compounds in rats complementing other classical ocular safety measurements.
