Neuroprotective effects of PEP-1-carbonyl reductase 1 against oxidative-stress-induced ischemic neuronal cell damage |
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| Institution: | 1. Department of Hepatobiliary-Splenic Surgery, General Surgery, Shengjing Hospital, China Medical University, Shenyang 110004, China;2. Intensive Care Unit, Heze Municipal Hospital, Heze, Shandong 274000, China;1. Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney, Sydney, NSW, 2006, Australia;2. Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan;3. Department of Medicine, David Geffen School of Medicine, Los Angeles, CA, 90095, USA;4. Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia;5. Membrane Transport Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia;6. School of Medicine and Pharmacology, Harry Perkins Institute of Medical Research, The University of Western Australia, Fiona Stanley Hospital, Murdoch, WA, 6150, Australia;7. Department of Gastroenterology, Fiona Stanley Hospital, Bull Creek, WA, 6149, Australia;8. School of Veterinary Sciences, Murdoch University, Murdoch, WA, 6150, Australia;9. Curtin Health Innovation Research Institute and School of Biomedical Sciences, Curtin University, Perth, WA, 6102, Australia;10. Ingham Institute for Applied Medical Research, Sydney, NSW, Australia;11. Discipline of Pathology and Molecular Medicine Research Group, School of Medicine, University of Western Sydney, Sydney, NSW, Australia;12. Department of Anatomical Pathology, Liverpool Hospital, Sydney, NSW, Australia;1. Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan;2. Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan;3. School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway, Selangor, Malaysia;4. Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan;5. Department of Molecular Cell Pharmacology, Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan;6. Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan;7. Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan;8. Faculty of Pharmaceutical Sciences, DDS Research Institute, Sojo University, 1-22-4 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan |
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| Abstract: | Human carbonyl reductase 1 (CBR1) is a member of the NADPH-dependent short-chain dehydrogenase/reductase superfamily that is known to play an important role in neuronal cell survival via its antioxidant function. Oxidative stress is one of the major causes of degenerative disorders including ischemia. However, the role CBR1 plays with regard to ischemic injury is as yet poorly understood. Protein transduction domains such as PEP-1 are well known and now commonly used to deliver therapeutic proteins into cells. In this study, we prepared PEP-1–CBR1 protein and examined whether it protects against oxidative-stress-induced neuronal cell damage. PEP-1–CBR1 protein was efficiently transduced into hippocampal neuronal HT-22 cells and protected against hydrogen peroxide (H2O2)-induced neuronal cell death. Transduced PEP-1–CBR1 protein drastically inhibited H2O2-induced reactive oxygen species production, the oxidation of intracellular macromolecules, and the activation of mitogen-activated protein kinases, as well as cellular apoptosis. Furthermore, we demonstrated that transduced PEP-1–CBR1 protein markedly protected against neuronal cell death in the CA1 region of the hippocampus resulting from ischemic injury in an animal model. In addition, PEP-1–CBR1 protein drastically reduced activation of glial cells and lipid peroxidation in an animal model. These results indicate that PEP-1–CBR1 protein significantly protects against oxidative-stress-induced neuronal cell death in vitro and in vivo. Therefore, we suggest that PEP-1–CBR1 protein may be a therapeutic agent for the treatment of ischemic injuries as well as oxidative-stress-induced cell damage and death. |
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| Keywords: | Apoptosis Ischemic injury Oxidative stress PEP-1–CBR1 Protein therapy Free radicals |
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