eprintid: 10405
rev_number: 69
eprint_status: archive
userid: 598
dir: disk0/00/01/04/05
datestamp: 2008-11-05 11:44:25
lastmod: 2015-07-23 09:35:15
status_changed: 2008-11-05 11:44:25
type: article
metadata_visibility: show
item_issues_count: 0
creators_name: Abramov, A.Y.
creators_name: Jacobson, J.
creators_name: Wientjes, F.
creators_name: Hothersall, J.
creators_name: Canevari, L.
creators_name: Duchen, M.R.
creators_id: AABRA58
creators_id: JJACO94
creators_id: 
creators_id: JSHOT73
creators_id: LCANE26
creators_id: MRDUC42
title: Expression and modulation of an NADPH oxidase in mammalian astrocytes
ispublished: pub
subjects: 25700
subjects: 10000
subjects: 3900
divisions: F84
keywords: NADPH oxidase, intracellular calcium, free radicals, oxidative stress, alzheimer's disease, amyloid β peptide
note: Published by the Society of Neuroscience
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abstract: Amyloid β peptides generate oxidative stress in hippocampal astrocytes through a mechanism sensitive to inhibitors of the NADPH oxidase [diphenylene iodonium (DPI) and apocynin]. Seeking evidence for the expression and function of the enzyme in primary hippocampal astrocytes, we confirmed the expression of the subunits of the phagocyte NADPH oxidase by Western blot analysis and by immunofluorescence and coexpression with the astrocyte-specific marker glial fibrillary acidic protein both in cultures and in vivo. Functional assays using lucigenin luminescence, dihydroethidine, or dicarboxyfluorescein fluorescence to measure the production of reactive oxygen species (ROS) demonstrated DPI and apocynin-sensitive ROS generation in response to the phorbol ester PMA and to raised [Ca2+]c after application of ionomycin or P2u receptor activation. Stimulation by PMA but not Ca2+ was inhibited by the protein kinase C (PKC) inhibitors staurosporine and hispidin. Responses were absent in transgenic mice lacking gp91phox. Expression of gp91phox and p67phox was increased in reactive astrocytes, which showed increased rates of both resting and stimulated ROS generation. NADPH oxidase activity was modulated by intracellular pH, suppressed by intracellular alkalinization, and enhanced by acidification. The protonophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone suppressed basal ROS generation but markedly increased PMA-stimulated ROS generation. This was independent of mitochondrial ROS production, because it was unaffected by mitochondrial depolarization with rotenone and oligomycin. Thus, the NADPH oxidase is expressed in astrocytes and is functional, activated by PKC and intracellular calcium, modulated by pHi, and upregulated by astrocyte activation. The astrocytic NADPH oxidase is likely to play important roles in CNS physiology and pathology.
date: 2005-10-05
official_url: http://dx.doi.org/10.1523/JNEUROSCI.1632-05.2005
vfaculties: VFBRS
rae2008: 14
oa_status: green
language: eng
primo: open
primo_central: open_green
doi: 10.1523/JNEUROSCI.1632-05.2005
lyricists_name: Abramov, A
lyricists_name: Transfer, MM
lyricists_id: AABRA58
lyricists_id: JJACO94
full_text_status: public
publication: Journal of Neuroscience
volume: 25
number: 40
pagerange: 9176-9184
refereed: TRUE
issn: 0270-6474
citation:        Abramov, A.Y.;    Jacobson, J.;    Wientjes, F.;    Hothersall, J.;    Canevari, L.;    Duchen, M.R.;      (2005)    Expression and modulation of an NADPH oxidase in mammalian astrocytes.                   Journal of Neuroscience , 25  (40)   pp. 9176-9184.    10.1523/JNEUROSCI.1632-05.2005 <https://doi.org/10.1523/JNEUROSCI.1632-05.2005>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10405/1/10405.pdf