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

被引：57

作者：

Doverhag, Christina ^{[2
]}

Keller, Matthias ^{[1
]}

Karlsson, Anna ^{[3
]}

Hedtjarn, Maj

Nilsson, Ulf ^{[4
]}

Kapeller, Edith ^{[1
]}

Sarkozy, Gergely ^{[1
,9
]}

Klimaschewski, Lars ^{[7
]}

Humpel, Christian ^{[8
]}

Hagberg, Henrik ^{[2
]}

Simbruner, Georg ^{[1
]}

Gressens, Pierre ^{[5
,6
]}

Savman, Karin ^{[2
]}

机构：

[1] Med Univ, Dept Pediat Neonatol Neuropediatr & Metab Dis 4, Innsbruck, Austria

[2] Univ Gothenburg, Sahlgrenska Acad, Dept Physiol & Neurosci, Perinatal Ctr, Gothenburg, Sweden

[3] Univ Gothenburg, Sahlgrenska Acad, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden

[4] Univ Gothenburg, Sahlgrenska Acad, Dept Nephrol, Gothenburg, Sweden

[5] Inserm, U676, F-75019 Paris, France

[6] Univ Paris 07, Fac Med Denis Diderot, F-75018 Paris, France

[7] Med Univ Innsbruck, Dept Anat & Histol, Div Neuroanat, Innsbruck, Austria

[8] Med Univ Innsbruck, Dept Psychiat, Lab Psychiat & Expt Alzheimers Res, Innsbruck, Austria

[9] Semmelweis Univ, Dept Pediat 2, H-1085 Budapest, Hungary

来源：

NEUROBIOLOGY OF DISEASE | 2008年 / 31卷 / 01期

基金：

英国医学研究理事会;

关键词：

brain injury; newborn; hypoxia-ischemia; excitoxicity; NADPH oxidase;

D O I：

10.1016/j.nbd.2008.04.003

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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) (139 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-1 beta. 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. (C) 2008 Elsevier Inc. All rights reserved.

引用

页码：133 / 144

页数：12

共 63 条

[61] The influence of age on apoptotic and other mechanisms of cell death after cerebral hypoxia-ischemia [J].

Zhu, C ;

Wang, X ;

Xu, F ;

Bahr, BA ;

Shibata, M ;

Uchiyama, Y ;

Hagberg, H ;

Blomgren, K .

CELL DEATH AND DIFFERENTIATION, 2005, 12 (02) :162-176

[62] Nitrosylation precedes caspase-3 activation and translocation of apoptosis-inducing factor in neonatal rat cerebral hypoxia-ischaemia [J].

Zhu, CL ;

Wang, XY ;

Qiu, L ;

Peeters-Scholte, C ;

Hagberg, H ;

Blomgren, K .

JOURNAL OF NEUROCHEMISTRY, 2004, 90 (02) :462-471

[63]

[No title captured], DOI DOI 10.1016/0891-5849(90)90115-Y

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