TY - JOUR
T1 - Role of superoxide in poly(ADP-ribose) polymerase upregulation after transient cerebral ischemia
AU - Narasimhan, Purnima
AU - Fujimura, Miki
AU - Noshita, Nobuo
AU - Chan, Pak H.
N1 - Funding Information:
This study was supported by NIH grants P50 NS 14534, NS 25372, NS 36147, NS 38653 and by an American Heart Association Bugher Foundation Award. PHC is a recipient of the Jacob Javits Neuroscience Investigator Award. The authors thank Cheryl Christensen for editorial assistance and Elizabeth Hoyte for figure preparation.
PY - 2003/5/12
Y1 - 2003/5/12
N2 - Oxidative stress plays a pivotal role in ischemic-reperfusion cell injury. Oxygen-derived free radicals trigger DNA strand damage, which is responsible for the activation of poly(ADP-ribose) polymerase (PARP). Recent studies have shown that peroxynitrite is the primary mediator of DNA damage and, hence, PARP activation after ischemia. PARP activation depletes NAD and ATP pools, ultimately resulting in necrotic cell death by loss of energy stores. Our study shows that PARP is upregulated as early as 15 min after 1 h of transient focal cerebral ischemia and remains for 8 h. We also examined the role of superoxide in PARP induction using copper/zinc-superoxide dismutase transgenic mice. Immunohistochemical and Western blotting data showed that there was no increased induction in PARP expression in these mice, suggesting that one of the mechanisms by which ischemic injury is attenuated in these mice might be by the inhibition of PARP induction. Furthermore, double staining of ischemic tissue with a PARP antibody and terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end labeling (TUNEL) indicated that most cells that are positive for TUNEL do not stain for the PARP antibody, confirming recent reports that PARP activation is involved in necrotic cell death rather than apoptosis during ischemic-reperfusion injury.
AB - Oxidative stress plays a pivotal role in ischemic-reperfusion cell injury. Oxygen-derived free radicals trigger DNA strand damage, which is responsible for the activation of poly(ADP-ribose) polymerase (PARP). Recent studies have shown that peroxynitrite is the primary mediator of DNA damage and, hence, PARP activation after ischemia. PARP activation depletes NAD and ATP pools, ultimately resulting in necrotic cell death by loss of energy stores. Our study shows that PARP is upregulated as early as 15 min after 1 h of transient focal cerebral ischemia and remains for 8 h. We also examined the role of superoxide in PARP induction using copper/zinc-superoxide dismutase transgenic mice. Immunohistochemical and Western blotting data showed that there was no increased induction in PARP expression in these mice, suggesting that one of the mechanisms by which ischemic injury is attenuated in these mice might be by the inhibition of PARP induction. Furthermore, double staining of ischemic tissue with a PARP antibody and terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end labeling (TUNEL) indicated that most cells that are positive for TUNEL do not stain for the PARP antibody, confirming recent reports that PARP activation is involved in necrotic cell death rather than apoptosis during ischemic-reperfusion injury.
KW - Cell death
KW - Cerebral ischemia
KW - Cytochrome c
KW - Poly(ADP-ribose) polymerase induction
KW - SOD1
KW - Superoxide
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U2 - 10.1016/S0169-328X(03)00062-7
DO - 10.1016/S0169-328X(03)00062-7
M3 - Article
C2 - 12750003
AN - SCOPUS:0038582584
SN - 0006-8993
VL - 113
SP - 28
EP - 36
JO - Molecular Brain Research
JF - Molecular Brain Research
IS - 1-2
ER -