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C. Kendall, S. M. Premji, R. E. Stewart, R. A. Stewart, J. H. Boatright; Ocular Delivery of TUDCA Provides Neuroprotection in a Mouse Model of Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4932. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Tauroursodeoxycholic acid (TUDCA) has been shown to be neuroprotective to the retina in mouse models of retinal degeneration when administered systemically. Local administration however provides benefits of lower dosage and reduced systemic side effects. Before we can inject TUDCA intravitreally in an animal model of retinal degeneration, we must find a dose that would be non-toxic to the retina. In this experiment, we tested several doses of TUDCA injected intravitreally to find the optimal non-toxic dose (Aim 1). After finding the highest non-toxic dose, we injected it intravitreally into a mouse model of light induced retinal degeneration (LIRD) to test for neuroprotective effects similar to systemic administration (Aim 2).
Aim 1: Wild type mice (C57/Bl6 & Balb/c) were intravitreally injected with 1 uL of varying doses of Free Acid TUDCA (0.5, 5, 15, 30, 50 mg/mL of 1xPBS) in one eye, and with sterile 1xPBS in the other. Electroretinograms (ERGs) were taken one and two weeks after the injection to test for retinal function. Aim 2: Albino wild type mice (Balb/c) were intravitreally injected with 1uL of 5mg/mL of TUDCA or 1xPBS in each eye, dark adapted overnight, and exposed to bright light (10,000 lux) or dim light (50 lux) for 7 hours on the following day. ERGs were taken weekly for 25 days after light damage. Mice from both experiments were subsequently sacrificed, and their eyes were enucleated and sectioned for analysis of apoptotic signal using the Dead-end TUNEL fluorometric assay.
Aim 1: According to both the ERGs and the TUNEL assay, the 5mg/mL dose of TUDCA is the highest dose tested in this experiment to be non-toxic to the retina. Doses higher than 5mg/mL showed reduced a-wave and b-wave amplitudes in the ERG waveforms, and increased apoptotic signal that corresponded to reduced outer nuclear layer thickness. Doses of 5 mg/mL and below however showed similar ERG amplitudes to that of the PBS treated eyes, along with similar retinal morphology. Aim 2: Bright-light exposed groups’ ERG data showed higher a-wave and b-wave amplitudes in TUDCA treated eyes, as compared to PBS, 17 days after LIRD. Similarly, TUDCA treated eyes showed reduced apoptotic signal compared to their PBS counterparts according to the TUNEL assay.
A single intravitreal injection of 5mg/mL of TUDCA shows protection from oxidative stress in the wild type mouse retina. Future studies will involve multiple intravitreal injections following light damage.
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