| Neuronal trauma model: in search of Thanatos. | |
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MedLine Citation:
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PMID: 15465278 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Trauma to the nervous system triggers responses that include oxidative stress due to the generation of reactive oxygen species (ROS). DNA is a major macromolecular target of ROS, and ROS-induced DNA strand breaks activate poly(ADP-ribose)polymerase-1 (PARP-1). Upon activation PARP-1 uses NAD(+) as a substrate to catalyze the transfer of ADP-ribose subunits to a host of nuclear proteins. In the face of extensive DNA strand breaks, PARP-1 activation can lead to depletion of intracellular NAD(P)(H) pools, large decreases in ATP, that threaten cell survival. Accordingly, inhibition of PARP-1 activity after acute oxidative injury has been shown to increase cell survival. When NGF-differentiated PC12 cells, an in vitro neuronal model, are exposed to H(2)O(2) there is increased synthesis of poly ADP-ribose and decreases in intracellular NAD(P)(H) and ATP. Addition of the chemical PARP inhibitor 3-aminobenzamide (AB) prior to H(2)O(2) exposure blocks the synthesis of poly ADP-ribose and maintains intracellular NAD(P)(H) and ATP levels. H(2)O(2) injury is characterized by an immediate, necrotic cell death 2h after injury and a delayed apoptotic-like death 12-24h after injury. This apoptotic-like death is characterized by apoptotic membrane changes and apoptotic DNA fragmentation but is not associated with measurable caspase-3 activity. AB delays cell death beyond 24h and increases cell survival by approximately 25%. This protective effect is accompanied by significantly decreased necrosis and the apoptotic-like death associated with H(2)O(2) exposure. AB also restores caspase-3 which can be attributed to the activation of the upstream activator of caspase-3, caspase-9. Thus, the maintenance of intracellular ATP levels associated with PARP-1 inhibition shifts cell death from necrosis to apoptosis and from apoptosis to cell survival. Furthermore, the shift from necrosis to apoptosis may be explained, in part, by an energy-dependent activation of caspase-9. |
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Authors:
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Kasie Cole; J Regino Perez-Polo |
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Publication Detail:
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Type: Journal Article; Review |
Journal Detail:
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Title: International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience Volume: 22 ISSN: 0736-5748 ISO Abbreviation: Int. J. Dev. Neurosci. Publication Date: 2004 Nov |
Date Detail:
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Created Date: 2004-10-06 Completed Date: 2004-12-15 Revised Date: 2005-11-16 |
Medline Journal Info:
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Nlm Unique ID: 8401784 Medline TA: Int J Dev Neurosci Country: England |
Other Details:
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Languages: eng Pagination: 485-96 Citation Subset: IM |
Affiliation:
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Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, TX 77555, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis* Benzamides / pharmacology DNA Damage* Disease Models, Animal Energy Metabolism / drug effects Humans Neurons / drug effects, metabolism*, pathology Poly(ADP-ribose) Polymerases / antagonists & inhibitors, metabolism* Reactive Oxygen Species / metabolism* Trauma, Nervous System / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Benzamides; 0/Reactive Oxygen Species; 3544-24-9/3-aminobenzamide; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 2.4.2.30/poly(ADP-ribose)polymerase-1, mouse |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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