Article

Gp91phox (NOX2) in classically activated microglia exacerbates traumatic brain injury.

Department of Emergency and Critical Care Medicine, Showa University School of Medicine, Shinagawa-Ku, Tokyo 142-8555, Japan.
Journal of Neuroinflammation (Impact Factor: 4.35). 01/2010; 7:41. DOI: 10.1186/1742-2094-7-41
Source: PubMed

ABSTRACT We hypothesized that gp91phox (NOX2), a subunit of NADPH oxidase, generates superoxide anion (O2-) and has a major causative role in traumatic brain injury (TBI). To evaluate the functional role of gp91phox and reactive oxygen species (ROS) on TBI, we carried out controlled cortical impact in gp91phox knockout mice (gp91phox-/-). We also used a microglial cell line to determine the activated cell phenotype that contributes to gp91phox generation.
Unilateral TBI was induced in gp91phox-/- and wild-type (Wt) mice (C57/B6J) (25-30 g). The expression and roles of gp91phox after TBI were investigated using immunoblotting and staining techniques. Levels of O2- and peroxynitrite were determined in situ in the mouse brain. The activated phenotype in microglia that expressed gp91phox was determined in a microglial cell line, BV-2, in the presence of IFNgamma or IL-4.
Gp91phox expression increased mainly in amoeboid-shaped microglial cells of the ipsilateral hemisphere of Wt mice after TBI. The contusion area, number of TUNEL-positive cells, and amount of O2- and peroxynitrite metabolites produced were less in gp91phox-/- mice than in Wt. In the presence of IFNgamma, BV-2 cells had increased inducible nitric oxide synthase and nitric oxide levels, consistent with a classical activated phenotype, and drastically increased expression of gp91phox.
Classical activated microglia promote ROS formation through gp91phox and have an important role in brain damage following TBI. Modulating gp91phox and gp91phox -derived ROS may provide a new therapeutic strategy in combating post-traumatic brain injury.

1 Bookmark
 · 
171 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A20 (TNFAIP3) is a pleiotropic NFkappaB-dependent gene that terminates NFkappaB activation in response to inflammatory stimuli. The potent anti-inflammatory properties of A20 are well characterized in several organs. However, little is known about its role in the brain. In this study, we investigated the brain phenotype of A20 heterozygous (HT) and knockout (KO) mice.
    Journal of Neuroinflammation 07/2014; 11(1):122. · 4.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose Traumatic brain injury (TBI) is a worldwide health problem with oxidative stress recognized as a major pathogenetic factor. The present experimental study was designed to explore the neuroprotective effect of NADPH oxidase (NOX) inhibitor, apocynin, on mouse TBI. Methods Moderately severe weight-drop impact head injury was induced in adult male mice, randomly divided into four groups: sham, TBI, TBI + vehicle and TBI + apocynin treatment. Apocynin (50 mg/kg) was injected intraperitoneally 30 min before TBI. The expression of NOX2 protein was investigated using immunoblotting techniques 1 and 24 hours after TBI. Neurological score was evaluated 24 hours after TBI. Blood–brain barrier disruption was detected by Evans blue extravasation and cortical apoptosis was analyzed by TUNEL assay. Additionally, we assessed tissue levels of malondialdehyde (MDA). Results NOX2 expression increased rapidly following TBI in male mice, with an early peak at 1h, followed by a second peak at 24 hours. Pre-treatment with the NOX inhibitor, apocynin markedly inhibited NOX2 expression. Apocynin also attenuated MDA levels and TBI-induced blood brain barrier dysfunction. In addition apocynin significantly attenuated TBI-induced neurological deficits and cortical apoptosis. Conclusion Pre-treatment with apocynin effectively attenuates markers of cerebral oxidative stress after TBI, thus supporting the hypothesis that apocynin is a potential neuroprotectant and adjunct therapy for TBI patients.
    Neurochemistry International 01/2014; · 2.66 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A plethora of evidence shows that activated microglia play a critical role in the pathogenesis of the central nervous system (CNS). Toxoplasmic encephalitis (TE) frequently occurs in HIV/AIDS patients. However, knowledge remains limited on the contributions of activated microglia to the pathogenesis of TE.
    Parasites & Vectors 08/2014; 7(1):372. · 3.25 Impact Factor

Full-text (2 Sources)

Download
87 Downloads
Available from
May 22, 2014