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The Use of Rat Lens Explant Cultures to Study the Mechanism of Drug-induced Cataractogenesis

Sampath, Shruthi and Mc Lean, Leeanne and Buono-Dalton, Chiara and Richards, Virgile and Moulin, Pierre and Wolf, Armin and Chibout, Salah-Dine and Pognan, Francois and Shangari, Nandita (2011) The Use of Rat Lens Explant Cultures to Study the Mechanism of Drug-induced Cataractogenesis. Toxicological Sciences. ISSN 1096-6080

Abstract

Lens explant cultures were used to assess the mechanism of drug-induced cataractogenic potential of NVS001, a peroxisome proliferator-activated receptor delta (PPAR) agonist, which resulted in cataract in all treated animals during a 13-week rat study. Ciglitazone, a PPARγ agonist and cataractogenic compound, was used as a positive control to validate this model. Rat lenses were extracted and cultured in medium supplemented with antibiotics for 24 h pre-incubation. Lenses showing no signs of damage at the end of the pre-incubation period were randomized into five experimental groups, 1) untreated control, 2) 0.1% DMSO control, 3) 10M NVS001, 4) 10M ciglitazone and 5) 10M acetaminophen (negative control). Lenses were treated every 24 h after pre-incubation for up to 48 h. Samples for viability, histology and gene expression profiling were collected at 4, 24 and 48 h. There was a time-dependent increase in opacity which correlated to a decrease in viability measured by ATP levels in NVS001 and ciglitazone-treated lenses compared to controls. NVS001 and ciglitazone had comparable cataractogenic effects after 48 h with histology showing rupture of the lens capsule, lens fiber degeneration, cortical lens vacuolation, and lens epithelial degeneration. Furthermore, no changes were seen when lenses were treated with acetaminophen. Gene expression analysis supported oxidative and osmotic stress, along with decreases in membrane and epithelial cell integrity as key factors in NVS001-induced cataracts. This study suggests that in vitro lens cultures can be used to assess cataractogenic potential of PPAR-agonists and to sutyd/understand the underlying molecular mechanism of cataractogenesis in rat.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher version cannot be used except for Nucleic Acids Research articles;
Keywords: Lens Cultures, PPAR delta agonist, Cataractogenisis, In-vitro Models
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/4512

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