Neuronal trauma model: In search of Thanatos

Kasie Cole, J. Regino Perez-Polo

    Research output: Contribution to journalArticle

    27 Scopus citations

    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 2O 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 2O 2 exposure blocks the synthesis of poly ADP-ribose and maintains intracellular NAD(P)(H) and ATP levels. H 2O 2 injury is characterized by an immediate, necrotic cell death 2 h after injury and a delayed apoptotic-like death 12-24 h 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 24 h and increases cell survival by ∼25%. This protective effect is accompanied by significantly decreased necrosis and the apoptotic-like death associated with H 2O 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.

    Original languageEnglish (US)
    Pages (from-to)485-496
    Number of pages12
    JournalInternational Journal of Developmental Neuroscience
    Volume22
    Issue number7
    DOIs
    StatePublished - Nov 1 2004

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    Keywords

    • Apoptosis
    • Cell death
    • DNA repair
    • Energy metabolism
    • Oxidative stress

    ASJC Scopus subject areas

    • Developmental Neuroscience
    • Developmental Biology

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