Tauroursodeoxycholic Acid (TUDCA) Preserves Photoreceptor Function and Morphology in rd10 Mice at Post–natal Day 30

Abstract

Abstract: : Purpose: Retinitis Pigmentosa (RP) is a progressive neurodegenerative disease resulting in blindness for which no effective treatments currently exist. While RP results from many different mutations, the common outcome is apoptosis of photoreceptors. Recently tauroursodeoxycholic acid (TUDCA), a naturally occurring bile acid, has been shown to have anti–apoptotic properties in a mouse model of RP, rd10. Previously we have shown significant preservation of photoreceptors in rd10 mice treated until post natal day 18 (P18; Boatright et al., 2004, ARVO E–abstract 720). Here we determined if TUDCA could preserve photoreceptors at a more advanced stage of the degenerative process in the rd10 mouse. Methods: Mice were subcutaneously injected every 3 days from P6 to P30. rd10 and wildtype C57BL/6J mice were divided into three treatment groups: TUDCA, vehicle, and untreated. At P30, dark– and light–adapted ERGs were performed to evaluate retinal function. Eyes were then enucleated and processed for histological examination. Photoreceptor cell counts were performed on images of retinal sections. Results: ERG recordings show significant functional preservation in TUDCA–treated rd10 mice. Dark–adapted a–wave amplitudes were 6X larger in TUDCA–treated mice compared to the barely measurable response at P30 in the untreated rd10 mouse. Dark–adapted b–wave amplitudes in TUDCA–treated rd10 mice were significantly larger at every flash intensity, and 3X larger in amplitude compared to untreated rd10 mice at the brightest flash intensity. Additionally, TUDCA–treated mice showed significant preservation of light–adapted a– and b–wave amplitudes. Photoreceptor cell counts revealed highly significant differences between treatment groups. TUDCA–treated rd10 mice had ∼ 5X more photoreceptor nuclei than untreated or vehicle rd10 mice. No effects were noted in ERG recordings or cell counts of wild type mice. Conclusions: The neuropreservation induced by TUDCA can be significantly sustained out to P30 in the rd10 mouse, near the end stage of photoreceptor degeneration in this model. However, TUDCA–treated mice did show some loss of retinal function and photoreceptor numbers compared to the previous data collected at P18. These results show promising possibilities for the use of TUDCA in the treatment of retinitis pigmentosa.

Keywords: apoptosis/cell death • retina • retinitis