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Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury

  1. Solomon H. Snyder*†‡§
  1. The Johns Hopkins University School of Medicine, Departments of *Neuroscience, †Pharmacology and Molecular Sciences, ‡Medicine, and §Psychiatry, 725 North Wolfe Street, Baltimore, MD 21205

  1. Contributed by Solomon H. Snyder

Abstract

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.

Footnotes

    • ↵ To whom reprint requests should be addressed. e-mail: s.snyder{at}jhmi.edu.

  • ABBREVIATIONS

    BR,
    bilirubin;
    BV,
    biliverdin;
    CPR,
    cytochrome p450 reductase;
    EDC,
    1-(ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride);
    GST,
    glutathione S-transferase;
    HO,
    heme oxygenase;
    nNOS,
    neuronal nitric oxide synthase;
    PMA,
    phorbol 12-myristate 13-acetate;
    PPIX,
    protoporphyrin IX;
    PKC,
    protein kinase C;
    HSA,
    human serum albumin;
    HEK,
    human embryonic kidney
    • Accepted December 30, 1998.

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