Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury.
Heme oxygenase (HO) catalyzes the conversion of heme to carbon monoxide, iron, and biliverdin, which is immediately reduced to bilirubin (BR). Two HO active isozymes exist: HO1, an inducible heat shock protein, and HO2, which is constitutive and highly concentrated in neurons. We demonstrate a neuroprotective role for BR formed from HO2. Neurotoxicity elicited by hydrogen peroxide in hippocampal and cortical neuronal cultures is prevented by the phorbol ester, phorbol 12-myristate 13-acetate (PMA) via stimulation of protein kinase C. We observe phosphorylation of HO2 through the protein kinase C pathway with enhancement of HO2 catalytic activity and accumulation of BR in neuronal cultures. The neuroprotective effects of PMA are prevented by the HO inhibitor tin protoporphyrin IX and in cultures from mice with deletion of HO2 gene. Moreover, BR, an antioxidant, is neuroprotective at nanomolar concentrations.
The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
S
S
Doré
M
M
Takahashi
C D
CD
Ferris
R
R
Zakhary
L D
LD
Hester
D
D
Guastella
S H
SH
Snyder
D000818:Animals; D001663:Bilirubin / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology*; D004622:Embryo, Mammalian; D004789:Enzyme Activation; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D018696:Neuroprotective Agents; D018384:Oxidative Stress; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D006861:Hydrogen Peroxide; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D001663:Bilirubin