Pharmacological and genetic inhibition of NADPH oxidase does not reduce brain damage in different models of perinatal brain injury in newborn mice

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Pharmacological and genetic inhibition of NADPH oxidase does not reduce brain damage in different models of perinatal brain injury in newborn mice

Doverhag, Christina, 1979 (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology

Keller, M. (author)

Karlsson, Anna, 1967 (author): Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research

Hedtjärn, Maj, 1973 (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology

Nilsson, Ulf, 1957 (author): Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory

Kapeller, E. (author)

Sarkozy, G. (author)

Klimaschewski, L. (author)

Humpel, C. (author)

Hagberg, Henrik, 1955 (author): Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper,Institute of Clinical Sciences

Simbruner, G. (author)

Gressens, P. (author)

Sävman, Karin, 1960 (author): Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper,Institute of Clinical Sciences

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Elsevier BV, 2008
2008
English.
In: Neurobiology of Disease. - : Elsevier BV. - 1095-953X .- 0969-9961. ; 31:1, s. 133-44

Related links:: https://gup.ub.gu.se...; show more...; https://doi.org/10.1...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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-1beta. 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.

Keyword

Animals
Animals
Newborn
Apoptosis/physiology
Brain Injuries/*enzymology/etiology/pathology
Excitatory Amino Acid Agonists/toxicity
Female
Gene Expression
Hypoxia-Ischemia
Brain/complications/*enzymology/pathology
Ibotenic Acid/toxicity
Immunohistochemistry
Inflammation/metabolism/pathology
Male
Mice
Mice
Knockout
Microglia/metabolism
NADPH Oxidase/genetics/*metabolism
Oxidative Stress/physiology
RNA
Messenger/analysis
Reactive Oxygen Species/*metabolism

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By the author/editor: Doverhag, Christ ...; Keller, M.; Karlsson, Anna, ...; Hedtjärn, Maj, 1 ...; Nilsson, Ulf, 19 ...; Kapeller, E.; show more...; Sarkozy, G.; Klimaschewski, L ...; Humpel, C.; Hagberg, Henrik, ...; Simbruner, G.; Gressens, P.; Sävman, Karin, 1 ...; show less...

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