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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

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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.

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Acknowledgments

This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2013R1A1A2059364) and also supported by Priority Research Centers Program grant from the National Research Foundation (NRF-2009-0093812) funded by the Ministry of Science, ICT & Future Planning in the Republic of Korea.

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    Authors and Affiliations

    1. Department of Anatomy and Cell Biology, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 151-742, South Korea

      Hyo Young Jung, Dae Young Yoo, Jong Whi Kim, Yeo Sung Yoon & In Koo Hwang

    2. Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Kangneung-Wonju National University, Gangneung, 210-702, South Korea

      Dae Won Kim & Hee Sun Yim

    3. Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, 200-701, South Korea

      Moo-Ho Won

    4. Department of Biomedical Sciences, Research Institute for Bioscience and Biotechnology, Hallym University, Chuncheon, 200-702, South Korea

      Soo Young Choi

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    Dae Young Yoo and Dae Won Kim have contributed equally to this article.

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    Jung, H.Y., Kim, D.W., Yim, H.S. et al. 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. Neurochem Res 41, 869–879 (2016). https://doi.org/10.1007/s11064-015-1764-1

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