3-Aminopropanal, formed during cerebral ischaemia, is a potent lysosomotropic neurotoxin

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Li, WeiLinköpings universitet,Hälsouniversitetet,Institutionen för medicin och hälsa (author)

3-Aminopropanal, formed during cerebral ischaemia, is a potent lysosomotropic neurotoxin

Article/chapterEnglish2003

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2003
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LIBRIS-ID:oai:DiVA.org:liu-46662
https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-46662URI
https://doi.org/10.1042/BJ20021520DOI

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Language:English
Summary in:English

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

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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.

Subject headings and genre

3-Aminopropanal
Amine oxidase
Apoptosis
Cerebral ischaemia
Lysosome
MEDICINE
MEDICIN

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Yuan, XimingLinköpings universitet,Hälsouniversitetet,Institutionen för klinisk och experimentell medicin(Swepub:liu)ximyu81 (author)
Ivanova, S.Laboratory of Biomedical Science, North Shore-LIE Research Institute, Manhasset, NY 11030, United States (author)
Tracey, K.J.Laboratory of Biomedical Science, North Shore-LIE Research Institute, Manhasset, NY 11030, United States (author)
Eaton, John WallaceÖstergötlands Läns Landsting,Linköpings universitet,Hälsouniversitetet,Experimentell patologi,Klinisk patologi och klinisk genetik(Swepub:liu)johea42 (author)
Brunk, UlfLinköpings universitet,Hälsouniversitetet,Farmakologi(Swepub:liu)ulfbr20 (author)
Linköpings universitetHälsouniversitetet (creator_code:org_t)

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In:Biochemical Journal371:2, s. 429-4360264-60211470-8728

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By the author/editor: Li, Wei; Yuan, Ximing; Ivanova, S.; Tracey, K.J.; Eaton, John Wall ...; Brunk, Ulf

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