Ocular Disorders

TUDCA has been shown to ameliorate a number of retinal disorders. Retinitis pigmentosa (RP) is a genetic disease in which a single point mutation in the rhodopsin-encoding gene (RHO) leads to loss of rod photoreceptor cells via protein misfolding and endoplasmic reticulum stress. The majority of cells in the outer retina are made up of rods, which are metabolically active cells that consume the majority of oxygen delivered to that region of the retina. Once rods die, oxygen consumption is greatly reduced, resulting in a large increase in oxygen in the outer retina. Progressive oxidative damage and death of cones result primarily from the increase of NADPH oxidase and generation of ROS. Other causes of blindness include bright light exposure, retinal detachment, age-related macular degeneration and diabetic retinopathy. Many studies have shown that TUDCA exhibit anti-apoptotic properties in neurodegenerative diseases affecting the retina by reducing photoreceptor apoptosis. TUDCA prevented apoptosis and preserved function and morphology of photoreceptor cells in both genetic and environmental mouse models of human retinal degeneration. These included the Pde6br (rd10) mouse, a genetic model of retinitis pigmentosa, and the environmental model of blindness in the lightinduced retinal degeneration (LIRD) mouse. Electroretinograms (ERGs) were recorded as an outcome measure of retinal function. The results showed that ERG a-wave and b-wave amplitudes were greater in mice treated with TUDCA compared to those treated with vehicle. Retinas of TUDCA-treated mice possessed thicker outer nuclear layers, more photoreceptor cells, and more fully developed photoreceptor outer segments in both mouse models (Figure 3). Overall, signs of apoptosis in rd10 and LIRD mouse models of retinal degeneration were dramatically suppressed with TUDCA treatment. The action of TUDCA in a separate P23H mouse model of RP was shown to preserve cone and rod structure and function, in addition to contacts with their postsynaptic neurons. The number of photoreceptor rows present in the outer nuclear layer (ONL) was observed postnatally to assess the protective action of TUDCA. TUNEL labeling was performed to quantify the degree of photoreceptor cell apoptosis, and the number of TUNEL-positive cells per retinal section was found to be significantly higher in control P23H mice compared to TUDCA-treated mice. TUDCA also prevented the loss of cell dendrites of the retina that establish connections with both rod and cone photoreceptors, including horizontal and bipolar cells. Results from the study also indicated that TUDCA slowed the loss of mitochondria in photoreceptors. In addition to these and other models of retinal disease, TUDCA administration also preserved photoreceptor function after retinal detachment by reducing oxidative stress and caspase activity. A leading cause of vision loss in people over the age of 50 years is age-related macular degeneration (AMD). AMD can be characterized by the development of chorodial neovascularization (CNV), resulting in inflammation, angiogenesis, and apoptosis. A recent study used a laser-induced CNV model to demonstrate the suppressing effects of TUDCA on CNV and vascular endothelial growth factor (VEGF) expression. VEGF is known to be a mediator of CNV in exudative AMD in humans, and anti-VEGF agents suppress CNV and improve vision. Rats treated with systemic TUDCA before and after CNV induction showed less fluorescein leakage from CNV and reduced CNV lesion sizes. VEGF levels of retina in the TUDCA group were significantly lower than in the control group, suggesting that systemic administration of TUDCA was associated with suppression of early VEGF elevation in the retina after laser injury. It also suggested that the inhibition of VEGF up-regulation was associated with the observed reduction in CNV size and vascularity. The development of retinal problems resulting from diabetes is a consequence of endothelial cell (EC) injury due to toxic levels of glucose. In the working-age population, diabetic retinopathy is the most common cause of blindness. Damaged endothelial tight junctions or impaired inner blood-retinal barrier (BRB) result in vascular leakage and retinal barrier. As the disease progresses, ECs undergo apoptosis leading to consequent neovascularization. Activating transcription factor 4 (ATF4), an ER stress-inducible transcription factor, is a key regulator of endothelial inflammation in diabetic retinopathy. High glucose levels, demonstrated through activation of signal transducer and activator of transcription 3 (STAT3) induce ER stress and activate ETF4 in retinal ECs. This results in the increased production of inflammatory factors and retinal vascular leakage commonly seen in diabetic retinopathy. C/EBP homologous protein (CHOP) is a target gene of ATF4, and intermittent exposure to high glucose causes an increase in ATF4 and CHOP expression and inflammatory cytokine expression. Human retinal pericytes (HRP) pretreated with TUDCA followed by incubation with intermittent high glucose showed that VEGF expression was largely abolished. TUDCA also effectively suppressed the induction of CHOP expression by intermittent high glucose. In cultured retinal neural cells induced by exposure to elevated glucose concentration, TUDCA markedly reduced cell death. The release of apoptosis-inducing factor (AIF) from the mitochondria and the accumulation of AIF in the nucleus were partially prevented by TUDCA. After cells exposed to elevated glucose concentration were exposed to TUDCA treatment, decreased levels of biomarkers of oxidative stress such as protein carbonyl groups and ROS production were observed. Retinal neural cell cultures were protected from cell death induced by elevated glucose concentration with TUDCA treatment through decreasing mito-nuclear translocation of AIF. Together, these studies demonstrated that TUDCA can ameliorate cellular damage in a variety of retinal disorders.