Constituents of bile, bilirubin and TUDCA, protect against oxidative stress-induced retinal degeneration

Abstract

Two constituents of bile, bilirubin and tauroursodeoxycholic acid (TUDCA), have antioxidant activity. However, bilirubin can also cause damage to some neurons and glial cells, particularly immature neurons. In this study, we tested the effects of bilirubin and TUDCA in two models in which oxidative stress contributes to photoreceptor cell death, prolonged light exposure and rd10+/+ mice. In albino BALB/c mice, intraperitoneal (IP) injection of 5 mg/kg of bilirubin or 500 mg/kg of TUDCA prior to exposure to 5,000 lux of white light for 8 hours significantly reduced loss of rod and cone function assessed by electroretinograms (ERGs). Both treatments also reduced light-induced accumulation of superoxide radicals in the outer retina, rod cell death assessed by outer nuclear layer (ONL) thickness, and disruption of cone inner and outer segments. In rd10+/+ mice, IP injections of 5 or 50 mg/kg of bilirubin or 500 mg/kg of TUDCA every 3 days starting at postnatal day (P) 6, caused significant preservation of cone cell number and cone function at P50. Rods were not protected at P50, but both bilirubin and TUDCA provided modest preservation of ONL thickness and rod function at P30. These data suggest that correlation of serum bilirubin levels with rate of vision loss in patients with retinitis pigmentosa (RP) could provide a useful strategy to test the hypothesis that cones die from oxidative damage in patients with RP. If proof-of-concept is established, manipulation of bilirubin levels and administration of TUDCA could be tested in interventional trials.

Tauroursodeoxycholic acid increases neural stem cell pool and neuronal conversion by regulating mitochondria-cell cycle retrograde signaling

“…These data are in accordance with our previous observation revealing a decrease of mitochondrial mass at early stages of neural differentiation, 15 as well as with other studies reporting the protective effect of TUDCA on mitochondria integrity. 17,21,25 Intriguingly, mitochondrial translocation of p53, already described as a possible protective mechanism of neural differentiation-induced mitochondrial stress 15 and also detected in our differentiation conditions, was not observed in differentiating cells treated with TUDCA. This may be explained by the fact that p53 mitochondrial translocation was only shown to occur after the first signs of differentiationinduced mitochondrial damage.…”

“…[21][22][23]25 In a 3-nitropropionic acid (3-NP) rat model of Huntington's disease, TUDCA prevents mitochondrial outer membrane permeabilization (MOMP), inhibits cytochrome c release, and modulates downstream apoptotic events, such as caspase activation and poly ADP-ribose polymerase (PARP) cleavage. 17 Furthermore, TUDCA was also shown to inhibit bilirubin-and Ab-induced Bax translocation, MOMP and subsequent cytochrome c release, in isolated mitochondria of both neuronal and glial cells.…”

“…15 In addition, we have previously demonstrated that TUDCA is a strong inhibitor of apoptosis by preventing mitochondrial apoptotic signaling, including mitochondrial membrane perturbations and cytochrome c release. 4,25 Therefore, we investigated the potential effect of TUDCA during differentiation-induced mitochondrial stress, as well as its efficacy in regulating NSC differentiation.…”

“…21 TUDCA plays an important neuroprotective role in animal models of acute stroke and Huntington's disease, by regulating mitochondrial apoptosis and oxidative stress, while also improving survival and function of cell transplants in Parkinson disease. [21][22][23][24][25] UDCA has been used also in clinical trials for amyotrophic lateral sclerosis. 26 TUDCA properties in preserving mitochondrial function, together with the key role of mitochondria in regulating NSC fate, provide a new framework to further explore the use of this bile acid in the treatment of neurological disorders with neurogenesis deficit.…”

Effects of Tauroursodeoxycholic Acid and Alpha-Lipoic-Acid on the Visual Response Properties of Cat Retinal Ganglion Cells: An In Vitro Study

“…For example, in animal models, a daily intraperitoneal injection of TUDCA (500 mg/ kg) had anti-inflammatory effects, 28 preserved photoreceptors after retinal detachment, 29 and significantly reduced loss of rod and cone function after exposure to bright light. 30 Similarly, subcutaneous injection of TUDCA (500 mg/kg) was effective in reducing ER stress, preventing apoptosis, and preserving cone function in the Leber congenital amaurosis animal model. 21 Tauroursodeoxycholic acid also rescued ERG b-waves and the outer nuclear layer in an animal model of retinal degeneration.…”