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Neuronal trauma model: in search of Thanatos.
Int J Dev Neurosci. 2004 Nov; 22(7):485-96.IJ

Abstract

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.

Authors+Show Affiliations

Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, TX 77555, USA.No affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

15465278

Citation

Cole, Kasie, and J Regino Perez-Polo. "Neuronal Trauma Model: in Search of Thanatos." International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience, vol. 22, no. 7, 2004, pp. 485-96.
Cole K, Perez-Polo JR. Neuronal trauma model: in search of Thanatos. Int J Dev Neurosci. 2004;22(7):485-96.
Cole, K., & Perez-Polo, J. R. (2004). Neuronal trauma model: in search of Thanatos. International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience, 22(7), 485-96.
Cole K, Perez-Polo JR. Neuronal Trauma Model: in Search of Thanatos. Int J Dev Neurosci. 2004;22(7):485-96. PubMed PMID: 15465278.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neuronal trauma model: in search of Thanatos. AU - Cole,Kasie, AU - Perez-Polo,J Regino, PY - 2004/07/07/received PY - 2004/07/12/accepted PY - 2004/10/7/pubmed PY - 2004/12/16/medline PY - 2004/10/7/entrez SP - 485 EP - 96 JF - International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience JO - Int J Dev Neurosci VL - 22 IS - 7 N2 - 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. SN - 0736-5748 UR - https://www.unboundmedicine.com/medline/citation/15465278/Neuronal_trauma_model:_in_search_of_Thanatos_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0736-5748(04)00086-3 DB - PRIME DP - Unbound Medicine ER -