Up-regulation of heme oxygenase-1 protects against cold injury-induced brain damage: a laboratory-based study.
Heme oxygenase-1 (HO-1), a kind of stress protein, is critical for the protection against ischemic stroke and cerebrovascular endothelium damage. However, the effects of HO-1 on trauma-induced brain injury are still unknown. Hence, we attempted to use a cold injury-induced brain trauma (CIBT) model in mice, which provides for a well-established approach for assessing brain edema and blood-brain barrier breakdown. Additionally, we explored cultured mouse brain endothelial cells (bEnd.3) to investigate the protective effects of HO-1. HO-1 was induced by infection with a recombinant adenovirus carrying the human HO-1 gene or an inducer of HO-1 activity, cobalt protoporphyrin IX (CoPP). The recombinant adenovirus (3.5 x 10(7) PFU/mouse, i.v.) or CoPP (10 mg/kg, i.v.) significantly increased HO-1 protein expression and HO-1 enzyme activity in the cerebral cortex of the mice. We found that overexpression of HO-1 protected against cold injury-induced secondary damage and behavioral impairment. Up-regulation of HO-1 decreased brain edema and neutrophil infiltration induced by cold injury. These HO-1-dependent protecting effects were abrogated by pretreatment with the HO-1 inhibitor, zinc protoporphyrin IX (ZnPP; 3 mg/kg, i.v.). HO-1 expression in the cerebral endothelium was observed by immunofluorescent staining. CoPP-induced (1 muM, 24 h) HO-1 protein expression was determined by western blotting in bEnd.3 cells. Enhanced HO-1 also protected against cold injury-induced cell loss and damage, which were respectively determined by GAPDH leakage into the cell medium and XTT assay in bEnd.3 cells. In summary, HO-1 overexpression appears to offer an effective neuroprotection against cold-induced secondary brain injury.
Shih
Ruey-Horng
RH
Department of Pharmacology, Chang Gung University, Tao-Yuan, Taiwan.
Cheng
Shin-Ei
SE
Tung
Wei-Hsuan
WH
Yang
Chuen-Mao
CM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001812:Blood-Brain Barrier / Q000502:physiology; D015153:Blotting, Western; D001925:Brain Damage, Chronic / Q000473:pathology / Q000517:prevention & control*; D001929:Brain Edema / Q000473:pathology; D002470:Cell Survival; D003080:Cold Temperature / Q000009:adverse effects*; D004396:Coloring Agents; D042783:Endothelial Cells / Q000473:pathology; D005455:Fluorescent Antibody Technique; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020556:Neutrophil Infiltration; D013778:Tetrazolium Salts; D013844:Thiazoles; D015854:Up-Regulation / Q000502:physiology
D004396:Coloring Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D051547:Heme Oxygenase-1; C022616:thiazolyl blue