Biliverdin reductase, a major physiologic cytoprotectant, suppresses experimental autoimmune encephalomyelitis.
Oxidative stress plays an important role in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Bilirubin is regarded today as a potent antioxidant. Recent studies show that the potent antioxidant actions of bilirubin reflect an amplification mechanism whereby biliverdin reductase (BVR) physiologically regenerates bilirubin in a catalytic cycle. We hypothesized that BVR might prove to be a new effective target for the treatment of free radical-mediated diseases. In this study, we demonstrated that treatment with BVR ameliorated both clinical and pathological signs of EAE more efficiently than treatments with traditional antioxidant enzymes. In vitro, interference with cellular BVR activity by siRNA elicited greater increases in reactive oxygen species and cell death than interference with the activities of other antioxidant enzymes. Further studies showed that BVR surpasses other enzymes by the multifactorial functions of its only end product, bilirubin, including anti-complement activity, and an activity that inhibits antibody-dependent cell-mediated cytotoxicity of lymphocytes. Since BVR regenerates bilirubin in a redox cycle without significantly increasing the concentration of bilirubin, our results suggest that BVR may represent a novel strategy for the treatment of multiple sclerosis and other oxidative stress-mediated diseases.
Brain Research Center, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5. yingru@interchange.ubc.ca
Yingru
Y
Liu
Jie
J
Liu
Wolfram
W
Tetzlaff
Donald W
DW
Paty
Max S
MS
Cynader
D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000975:Antioxidants / Q000378:metabolism; D001663:Bilirubin / Q000494:pharmacology; D019610:Cytoprotection / Q000502:physiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000517:prevention & control*; D004790:Enzyme Induction; D005978:Glutathione / Q000494:pharmacology; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008297:Male; D009187:Myelitis / Q000473:pathology / Q000517:prevention & control; D009447:Neuroblastoma; D018384:Oxidative Stress / Q000187:drug effects; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D005978:Glutathione; D001663:Bilirubin