title: Heme Oxygenase-1 Protects Neurons from Ischemic Damage by Upregulating Expression of Cu,Zn-Superoxide Dismutase, Catalase, and Brain-Derived Neurotrophic Factor in the Rabbit Spinal Cord.
abstract: In the present study, we investigated the protective effects of heme oxygenase (HO-1) against ischemic damage in motor neurons of the rabbit spinal cord. A PEP-1-HO-1 fusion protein was made to and confirmed the effective the penetration of HO-1 into spinal cord neurons at 8 h after treatment. Transient spinal cord ischemia was induced by occlusion of the abdominal aorta for 15 min. Vehicle (glycerol) or 0.375 mg/kg PEP-1-HO-1 was administered intraperitoneally to rabbits immediately after ischemia/reperfusion. Animals were sacrificed 15 min after reperfusion to measure lactate levels; 24 h after reperfusion to measure caspase 3 and myeloperoxidase levels, lipid peroxidation, and the activity of Cu,Zn-superoxide dismutase (SOD1) and catalase (CAT); or 72 h after reperfusion to assess neuronal survival and measure the levels of brain-derived neurotrophic factor (BDNF) in spinal cord homogenates. Administration of PEP-1-HO-1 did not significantly alter arterial blood gases (PaCO2 and PaO2), pH, or blood glucose levels before ischemia, 10 min after occlusion, or 10 min after reperfusion. Mean arterial pressure was selectively reduced 10 min after occlusion. Administration of PEP-1-HO-1 improved the rabbit Tarlov scores, and increased neuronal survival, as assessed by NeuN immunohistochemical staining 72 h after ischemia/reperfusion. In addition, administration of PEP-1-HO-1 significantly ameliorated lactate accumulation 15 min after reperfusion, and the increases in caspase 3, myeloperoxidase, and lipid peroxidation 24 h after reperfusion. PEP-1-HO-1 administration significantly mitigated the decrease in SOD1 and CAT 24 h after reperfusion, and reversed the decrease in BDNF levels in spinal cord homogenates 72 h after ischemia/reperfusion. These results suggest that PEP-1-HO-1 can protect against neuronal damage after transient spinal cord ischemia by limiting early lactic acidosis and increasing SOD1, CAT, and BDNF levels.
authors.affiliation: Department of Anatomy and Cell Biology, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Hyo Young
authors.initials: HY
authors.lastname: Jung
authors.affiliation: Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Kangneung-Wonju National University, Gangneung, 210-702, South Korea.
authors.forename: Dae Won
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Kangneung-Wonju National University, Gangneung, 210-702, South Korea.
authors.forename: Hee Sun
authors.initials: HS
authors.lastname: Yim
authors.affiliation: Department of Anatomy and Cell Biology, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Yoo
authors.affiliation: Department of Anatomy and Cell Biology, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Jong Whi
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, 200-701, South Korea.
authors.forename: Moo-Ho
authors.initials: MH
authors.lastname: Won
authors.affiliation: Department of Anatomy and Cell Biology, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Yeo Sung
authors.initials: YS
authors.lastname: Yoon
authors.affiliation: Department of Biomedical Sciences, Research Institute for Bioscience and Biotechnology, Hallym University, Chuncheon, 200-702, South Korea. sychoi@hallym.ac.kr.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Anatomy and Cell Biology, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 151-742, South Korea. vetmed2@snu.ac.kr.
authors.forename: In Koo
authors.initials: IK
authors.lastname: Hwang
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000494:pharmacology*; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013116:Spinal Cord / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D011993:Recombinant Fusion Proteins; D019344:Lactic Acid; D002374:Catalase; D051547:Heme Oxygenase-1; C561500:PEP-1-heme oxygenase-1 fusion protein; D013482:Superoxide Dismutase
keywords: Anti-inflammation; Antioxidants; Brain-derived neurotrophic factor; Heme oxygenase-1; Lactate; Neuroprotection; Transient spinal cord ischemia