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The Journal of Neuroscience, May 1, 2003, 23(9):3689
Heme Oxygenase-2 Protects against Lipid Peroxidation-Mediated
Cell Loss and Impaired Motor Recovery after Traumatic Brain Injury
Edward F.
Chang1,
Ronald J.
Wong2,
Hendrik J.
Vreman2,
Takuji
Igarashi1,
Ethel
Galo1,
Frank R.
Sharp3,
David K.
Stevenson2, and
Linda J.
Noble-Haeusslein1
1 Department of Neurosurgery, University of California,
San Francisco, San Francisco, California 94143, 2 Department of Pediatrics, Stanford University School of
Medicine, Stanford, California 94305, and 3 Department of
Neurology and the Neuroscience Program, University of Cincinnati,
Cincinnati, Ohio 45267
After traumatic brain injury (TBI), substantial extracellular heme
is released from hemoproteins during hemorrhage and cell injury. Heme
oxygenase (HO) isozymes are thought to detoxify the pro-oxidant heme to
the potent antioxidant, bilirubin. HO-1, the inducible isozyme, is
expressed in glial populations after injury and may play a protective
role. However, the role of HO-2, the predominant and constitutively
expressed isozyme in the brain, remains unclear after TBI. We used a
controlled cortical impact injury model to determine the extent and
mechanism of damage between HO-2 knock-out (KO) ( /) and wild-type
(WT) (+/+) mice. The specific cellular and temporal expressions of HO-2
and HO-1 were characterized by immunocytochemistry and Western blots.
HO-2 was immunolocalized in neurons both before and after TBI, whereas
HO-1 was highly upregulated in glia only after TBI. HO activity
determined by gas chromatography using brain sonicates from injured
HO-2 KO mice was significantly less than that of HO-2 wild
types, despite the induction of HO-1 expression after TBI. Cell
loss was significantly greater in KO mice in areas including the
cortex, the CA3 region of hippocampus, and the lateral dorsal thalamus.
Furthermore, motor recovery after injury, as measured by the rotarod
assay and an inclined beam-walking task, was compromised in the KO
mice. Finally, brain tissue from injured HO-2 KO mice exhibited
decreased ability to reduce oxidative stress, as measured with an
Fe2+/ascorbic acid-mediated carbon monoxide
generation assay for lipid peroxidation susceptibility. These findings
demonstrate that HO-2 expression protects neurons against TBI by
reducing lipid peroxidation via the catabolism of free heme.
Key words:
heme oxygenase-2; traumatic brain injury; lipid
peroxidation; oxidative stress; controlled cortical impact; heme-oxygenase-1
Copyright © 2003 Society for Neuroscience 0270-6474/03/2393689-08$05.00/0
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