Caspase-3 inhibitor reduces apototic photoreceptor cell death during inherited retinal degeneration in tubby mice.

PURPOSE: The tubby mouse, previously suggested as an animal model for the human Usher Syndrome type I, was used in an analysis of pathophysiological processes leading to the inherited retinal degeneration, also shown in Usher syndrome patients. To evaluate pathogenic mechanisms causing retinal degeneration in tubby mice, we examined the time course of apoptotic photoreceptor cell death. Apoptotic pathways were determined by the inhibition of specific caspases in vivo.
METHODS: Apoptotic cells were identified during retinal differentiation and degeneration by the TUNEL-method. Apoptotic events were confirmed by DNA-laddering. Intravitreal injection of apoptosis inhibitors was applied to reduce apoptotic photoreceptor cell death in tubby mice.
RESULTS: During retinal differentiation there is no apparent difference between tubby and wild type mice in apoptotic events. Between post natal day 16 and 23, apoptosis was detected in the outer nuclear layer of tubby mice retinas, but was absent in control mice. The number of TUNEL-labeled photoreceptor cells peaked at post natal day 19. After this peak of apoptosis, the number of apoptotic photoreceptor cells gradually decreased. While a caspase-1 inhibitor did not reduce the number of apoptotic cells, a specific caspase-3 inhibitor caused a significant decrease of apoptotic photoreceptor cells in the tubby mouse retina.
CONCLUSIONS: Apoptosis is necessary for appropriate differentiation of the retina of tubby and wild type mice. In the fully developed tubby mouse retina, apoptotic photoreceptor cell death leads to retinal degeneration. Apoptosis in the tubby mouse retina is mediated by specific activation of members of the caspase-3 family. Caspase-3 inhibition drastically reduces photoreceptor cell death in the degenerating tubby mouse retina and may be a potential tool for therapeutic strategies of retinal degeneration in human Usher patients.