Constituents of bile, bilirubin and TUDCA, protect against oxidative stress-induced retinal degeneration.
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 injection of 5 mg/kg of bilirubin or 500 mg/kg of TUDCA prior to exposure to 5000 lux of white light for 8 h significantly reduced loss of rod and cone function assessed by electroretinograms. Both treatments also reduced light-induced accumulation of superoxide radicals in the outer retina, rod cell death assessed by outer nuclear layer thickness, and disruption of cone inner and outer segments. In rd10+/+ mice, intraperitoneal 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 outer nuclear layer 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 could provide a useful strategy to test the hypothesis that cones die from oxidative damage in patients with retinitis pigmentosa. If proof-of-concept is established, manipulation of bilirubin levels and administration of TUDCA could be tested in interventional trials.
Department of Ophthalmology Johns Hopkins University Baltimore, Maryland, USA.
Brian C
BC
Oveson
Takeshi
T
Iwase
Sean F
SF
Hackett
Sun Young
SY
Lee
Shinichi
S
Usui
Thomas W
TW
Sedlak
Solomon H
SH
Snyder
Peter A
PA
Campochiaro
Jennifer U
JU
Sung
D000818:Animals; D001646:Bile; D001663:Bilirubin / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D012162:Retinal Degeneration / Q000378:metabolism* / Q000517:prevention & control*; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology* / Q000627:therapeutic use
D018696:Neuroprotective Agents; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D001663:Bilirubin