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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Authors | Wenhu Huang, Walter Collette 3rd, Michelle Twamley, Shirley A Aguirre, Aida Sacaan |
Journal | Toxicology and applied pharmacology
(Toxicol Appl Pharmacol)
Vol. 289
Issue 3
Pg. 525-33
(Dec 15 2015)
ISSN: 1096-0333 [Electronic] United States |
PMID | 26482841
(Publication Type: Journal Article)
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Copyright | Copyright © 2015 Elsevier Inc. All rights reserved. |
Chemical References |
- AG-012986
- Benzamides
- Benzimidazoles
- Indazoles
- N-((5-(3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl)-4-methylpyridin-3-yl)methyl)ethanamine
- Thiazoles
- Cyclin-Dependent Kinases
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Topics |
- Animals
- Benzamides
(administration & dosage, adverse effects)
- Benzimidazoles
(administration & dosage, adverse effects)
- Cyclin-Dependent Kinases
(antagonists & inhibitors, metabolism)
- Drug Discovery
(methods)
- Electroretinography
(methods)
- In Situ Nick-End Labeling
(methods)
- Indazoles
(administration & dosage, adverse effects)
- Intravitreal Injections
(methods)
- Male
- Rats
- Retina
(drug effects, pathology)
- Retinal Degeneration
(pathology)
- Thiazoles
(administration & dosage, adverse effects)
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