Application of electroretinography (ERG) in early drug development for assessing retinal toxicity in rats

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Abstract

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.

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