Application of electroretinography (ERG) in early drug development for assessing retinal toxicity in rats.
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.
Drug Safety Research and Development, Pfizer Global Research and Development, San Diego, CA 92121, USA. Electronic address: wenhu.huang@pfizer.com.
Wenhu
W
Huang
Drug Safety Research and Development, Pfizer Global Research and Development, San Diego, CA 92121, USA.
Walter
W
Collette
Drug Safety Research and Development, Pfizer Global Research and Development, San Diego, CA 92121, USA.
Michelle
M
Twamley
Drug Safety Research and Development, Pfizer Global Research and Development, San Diego, CA 92121, USA.
Shirley A
SA
Aguirre
Drug Safety Research and Development, Pfizer Global Research and Development, San Diego, CA 92121, USA.
Aida
A
Sacaan
D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D004596:Electroretinography / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D007191:Indazoles / Q000008:administration & dosage / Q000009:adverse effects*; D058449:Intravitreal Injections / Q000379:methods; D008297:Male; D051381:Rats; D012160:Retina / Q000187:drug effects* / Q000473:pathology*; D012162:Retinal Degeneration / Q000473:pathology; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects*
C512484:AG-012986; D001549:Benzamides; D001562:Benzimidazoles; D007191:Indazoles; C533671:N-((5-(3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl)-4-methylpyridin-3-yl)methyl)ethanamine; D013844:Thiazoles; D018844:Cyclin-Dependent Kinases
Electroretinography; Pan-cyclin dependent kinase inhibitors; Rats; Retina; Toxicity