Cytotoxic polyamine-derived amino aldehydes, formed during cerebral ischaemia, damage adjacent tissue (the so-called ‘penumbra') not subject to the initial ischaemic insult. One such product is 3-aminopropanal (3-AP), a potent cytotoxin that accumulates in ischaemic brain, although the precise mechanisms responsible for its formation are still unclear. More relevant to the present investigations, the mechanisms by which such a small aldehydic compound might be cytotoxic are also not known, but we hypothesized that 3-AP, having the structure of a weak lysosomotropic base, might concentrate within lysosomes, making these organelles a probable focus of initial toxicity. Indeed, 3-AP leads to lysosomal rupture of D384 glioma cells, a process which clearly precedes caspase activation and apoptotic cell death. Immunohistochemistry reveals that 3-AP concentrates in the lysosomal compartment and prevention of this accumulation by the lysosomotropic base ammonia, NH3, protects against 3-AP cytotoxicity by increasing lysosomal pH. A thiol compound, N-(2-mercaptopropionyl)glycine, reacts with and neutralizes 3-AP and significantly inhibits cytoxocity. Both amino and aldehyde functions of 3-AP are necessary for toxicity: the amino group confers lysosomotropism and the aldehyde is important for additional, presently unknown, reactions. We conclude that 3-AP exerts its toxic effects by accumulating intralysosomally, causing rupture of these organelles and releasing lysosomal enzymes which initiate caspase activation and apoptosis (or necrosis if the lysosomal rupture is extensive). These results may have implications for the development of new therapeutics designed to lessen secondary damage arising from focal cerebral ischaemia.
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April 2003
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Research Article|
April 15 2003
3-Aminopropanal, formed during cerebral ischaemia, is a potent lysosomotropic neurotoxin
Wei LI;
Wei LI
1
∗Division of Pathology II, Linköping University Hospital, S-581 85 Linköping, Sweden
‡James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, U.S.A.
1To whom correspondence should be addressed (e-mail weili@pat.liu.se).
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Xi-Ming YUAN;
Xi-Ming YUAN
∗Division of Pathology II, Linköping University Hospital, S-581 85 Linköping, Sweden
‡James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, U.S.A.
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Svetlana IVANOVA;
Svetlana IVANOVA
†Laboratory of Biomedical Science, North Shore-LIE Research Institute, Manhasset, NY 11030, U.S.A.
‡James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, U.S.A.
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Kevin J. TRACEY;
Kevin J. TRACEY
†Laboratory of Biomedical Science, North Shore-LIE Research Institute, Manhasset, NY 11030, U.S.A.
‡James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, U.S.A.
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John W. EATON;
John W. EATON
∗Division of Pathology II, Linköping University Hospital, S-581 85 Linköping, Sweden
†Laboratory of Biomedical Science, North Shore-LIE Research Institute, Manhasset, NY 11030, U.S.A.
‡James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, U.S.A.
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Ulf T. BRUNK
Ulf T. BRUNK
∗Division of Pathology II, Linköping University Hospital, S-581 85 Linköping, Sweden
‡James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, U.S.A.
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Publisher: Portland Press Ltd
Received:
September 30 2002
Revision Received:
November 29 2002
Accepted:
January 06 2003
Accepted Manuscript online:
January 06 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 371 (2): 429–436.
Article history
Received:
September 30 2002
Revision Received:
November 29 2002
Accepted:
January 06 2003
Accepted Manuscript online:
January 06 2003
Citation
Wei LI, Xi-Ming YUAN, Svetlana IVANOVA, Kevin J. TRACEY, John W. EATON, Ulf T. BRUNK; 3-Aminopropanal, formed during cerebral ischaemia, is a potent lysosomotropic neurotoxin. Biochem J 15 April 2003; 371 (2): 429–436. doi: https://doi.org/10.1042/bj20021520
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