Pharmacological and genetic inhibition of NADPH oxidase does not reduce brain damage in different models of perinatal brain injury in newborn mice
Background: Inflammation and reactive oxygen species (ROS) are important in the development of perinatal brain injury. The ROS-generating enzyme NADPH oxidase (Nox2) is present in inflammatory cells and contributes to brain injury in adult animal models. Hypothesis: NADPH oxidase contributes to ROS...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2008-07-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996108000727 |
| _version_ | 1818616194603679744 |
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| author | Christina Doverhag Matthias Keller Anna Karlsson Maj Hedtjarn Ulf Nilsson Edith Kapeller Gergely Sarkozy Lars Klimaschewski Christian Humpel Henrik Hagberg Georg Simbruner Pierre Gressens Karin Savman |
| author_facet | Christina Doverhag Matthias Keller Anna Karlsson Maj Hedtjarn Ulf Nilsson Edith Kapeller Gergely Sarkozy Lars Klimaschewski Christian Humpel Henrik Hagberg Georg Simbruner Pierre Gressens Karin Savman |
| author_sort | Christina Doverhag |
| collection | DOAJ |
| description | Background: Inflammation and reactive oxygen species (ROS) are important in the development of perinatal brain injury. The ROS-generating enzyme NADPH oxidase (Nox2) is present in inflammatory cells and contributes to brain injury in adult animal models. Hypothesis: NADPH oxidase contributes to ROS formation and development of injury in the immature brain and inhibition of NADPH oxidase attenuates perinatal brain injury. Methods: We used animal models of term hypoxia–ischemia (HI) (P9 mice) as well as ibotenate-induced excitotoxic injury (P5 mice) mimicking features of periventricular leukomalacia in preterm infants. In vitro microglia cell cultures were used to investigate NADPH oxidase-dependent ROS formation. In vivo we determined the impact 1) of HI on NADPH oxidase gene expression 2) of genetic (gp91-phox/Nox2 knock-out) and 3) of pharmacological NADPH oxidase inhibition on HI-induced injury and NMDA receptor-mediated excitotoxic injury, respectively. Endpoints were ROS formation, oxidative stress, apoptosis, inflammation and extent of injury. Results: Hypoxia–ischemia increased NADPH oxidase subunits mRNA expression in total brain tissue in vivo. In vitro ibotenate increased NADPH oxidase-dependent formation of reactive oxygen species in microglia. In vivo the inhibition of NADPH oxidase did not reduce the extent of brain injury in any of the animal models. In contrast, the injury was increased by inhibition of NADPH oxidase and genetic inhibition was associated with an increased level of galectin-3 and IL-1β. Conclusion: NADPH oxidase is upregulated after hypoxia–ischemia and activated microglia cells are a possible source of Nox2-derived ROS. In contrast to findings in adult brain, NADPH oxidase does not significantly contribute to the pathogenesis of perinatal brain injury. Results obtained in adult animals cannot be transferred to newborns and inhibition of NADPH oxidase should not be used in attempts to attenuate injury. |
| first_indexed | 2024-12-16T16:45:56Z |
| format | Article |
| id | doaj.art-694fd5b29433410db0612a4fa6e8aa2d |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-16T16:45:56Z |
| publishDate | 2008-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-694fd5b29433410db0612a4fa6e8aa2d2022-12-21T22:24:10ZengElsevierNeurobiology of Disease1095-953X2008-07-01311133144Pharmacological and genetic inhibition of NADPH oxidase does not reduce brain damage in different models of perinatal brain injury in newborn miceChristina Doverhag0Matthias Keller1Anna Karlsson2Maj Hedtjarn3Ulf Nilsson4Edith Kapeller5Gergely Sarkozy6Lars Klimaschewski7Christian Humpel8Henrik Hagberg9Georg Simbruner10Pierre Gressens11Karin Savman12Perinatal Center, Department of Physiology and Neuroscience and Department of Pediatrics, Sahlgrenska Academy, Göteborg University, SwedenDepartment of Pediatrics IV, Neonatology, Neuropediatrics and Metabolic Diseases, Medical University, Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria; Corresponding author. Fax: +43 512 504 27766.Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, Göteborg University, SwedenPerinatal Center, Department of Physiology and Neuroscience and Department of Pediatrics, Sahlgrenska Academy, Göteborg University, SwedenDepartment of Nephrology, Sahlgrenska Academy, Göteborg University, SwedenDepartment of Pediatrics IV, Neonatology, Neuropediatrics and Metabolic Diseases, Medical University, Innsbruck, Anichstrasse 35, 6020 Innsbruck, AustriaDepartment of Pediatrics IV, Neonatology, Neuropediatrics and Metabolic Diseases, Medical University, Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria; 2nd Department of Pediatrics, Semmelweis University Budapest, HungaryDivision of Neuroanatomy, Department of Anatomy and Histology, Medical University Innsbruck, AustriaLaboratory of Psychiatry and Experimental Alzheimer's Research, Department of Psychiatry, Medical University Innsbruck, AustriaPerinatal Center, Department of Physiology and Neuroscience and Department of Pediatrics, Sahlgrenska Academy, Göteborg University, SwedenDepartment of Pediatrics IV, Neonatology, Neuropediatrics and Metabolic Diseases, Medical University, Innsbruck, Anichstrasse 35, 6020 Innsbruck, AustriaInserm, U676, 48 Blvd Serurier, F-75019 Paris, France; Université Paris 7, Faculté de Médecine Denis Diderot, 16 rue Huchard, F-75018 Paris, FrancePerinatal Center, Department of Physiology and Neuroscience and Department of Pediatrics, Sahlgrenska Academy, Göteborg University, SwedenBackground: Inflammation and reactive oxygen species (ROS) are important in the development of perinatal brain injury. The ROS-generating enzyme NADPH oxidase (Nox2) is present in inflammatory cells and contributes to brain injury in adult animal models. Hypothesis: NADPH oxidase contributes to ROS formation and development of injury in the immature brain and inhibition of NADPH oxidase attenuates perinatal brain injury. Methods: We used animal models of term hypoxia–ischemia (HI) (P9 mice) as well as ibotenate-induced excitotoxic injury (P5 mice) mimicking features of periventricular leukomalacia in preterm infants. In vitro microglia cell cultures were used to investigate NADPH oxidase-dependent ROS formation. In vivo we determined the impact 1) of HI on NADPH oxidase gene expression 2) of genetic (gp91-phox/Nox2 knock-out) and 3) of pharmacological NADPH oxidase inhibition on HI-induced injury and NMDA receptor-mediated excitotoxic injury, respectively. Endpoints were ROS formation, oxidative stress, apoptosis, inflammation and extent of injury. Results: Hypoxia–ischemia increased NADPH oxidase subunits mRNA expression in total brain tissue in vivo. In vitro ibotenate increased NADPH oxidase-dependent formation of reactive oxygen species in microglia. In vivo the inhibition of NADPH oxidase did not reduce the extent of brain injury in any of the animal models. In contrast, the injury was increased by inhibition of NADPH oxidase and genetic inhibition was associated with an increased level of galectin-3 and IL-1β. Conclusion: NADPH oxidase is upregulated after hypoxia–ischemia and activated microglia cells are a possible source of Nox2-derived ROS. In contrast to findings in adult brain, NADPH oxidase does not significantly contribute to the pathogenesis of perinatal brain injury. Results obtained in adult animals cannot be transferred to newborns and inhibition of NADPH oxidase should not be used in attempts to attenuate injury.http://www.sciencedirect.com/science/article/pii/S0969996108000727Brain injuryNewbornHypoxia–ischemiaExcitoxicityNADPH oxidase |
| spellingShingle | Christina Doverhag Matthias Keller Anna Karlsson Maj Hedtjarn Ulf Nilsson Edith Kapeller Gergely Sarkozy Lars Klimaschewski Christian Humpel Henrik Hagberg Georg Simbruner Pierre Gressens Karin Savman Pharmacological and genetic inhibition of NADPH oxidase does not reduce brain damage in different models of perinatal brain injury in newborn mice Neurobiology of Disease Brain injury Newborn Hypoxia–ischemia Excitoxicity NADPH oxidase |
| title | Pharmacological and genetic inhibition of NADPH oxidase does not reduce brain damage in different models of perinatal brain injury in newborn mice |
| title_full | Pharmacological and genetic inhibition of NADPH oxidase does not reduce brain damage in different models of perinatal brain injury in newborn mice |
| title_fullStr | Pharmacological and genetic inhibition of NADPH oxidase does not reduce brain damage in different models of perinatal brain injury in newborn mice |
| title_full_unstemmed | Pharmacological and genetic inhibition of NADPH oxidase does not reduce brain damage in different models of perinatal brain injury in newborn mice |
| title_short | Pharmacological and genetic inhibition of NADPH oxidase does not reduce brain damage in different models of perinatal brain injury in newborn mice |
| title_sort | pharmacological and genetic inhibition of nadph oxidase does not reduce brain damage in different models of perinatal brain injury in newborn mice |
| topic | Brain injury Newborn Hypoxia–ischemia Excitoxicity NADPH oxidase |
| url | http://www.sciencedirect.com/science/article/pii/S0969996108000727 |
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