Interaction between inducible nitric oxide synthase and poly(ADP-ribose) polymerase in focal ischemic brain injury

被引:69
作者
Park, EM
Cho, S
Frys, K
Racchumi, G
Zhou, P
Anrather, J
Iadecola, C
机构
[1] Cornell Univ, Weill Med Coll, Div Neurobiol, Dept Neurol & Neurosci, New York, NY 10021 USA
[2] Ewha Womans Univ, Coll Med, Dept Pharmacol, Seoul, South Korea
关键词
adhesion molecules; inflammation; neuroprotection; polymerase chain reaction; real time;
D O I
10.1161/01.STR.0000147042.53659.6c
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Background and Purpose-Overactivation of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) contributes to ischemic brain injury. Because PARP upregulates proinflammatory genes, we investigated whether inducible nitric oxide synthase (iNOS), a gene involved in the deleterious effects of postischemic inflammation, participates in the mechanisms by which PARP activation contributes to cerebral ischemic injury. Methods-The middle cerebral artery (MCA) was occluded in mice for 20 minutes using an intravascular filament, and injury volume was measured 72 hours later in Nissl-stained brain sections. mRNA expression was assessed in the postischemic brain by the quantitative "real-time" polymerase chain reaction. Results-The PARP inhibitor PJ34 reduced infarct volume and attenuated postischemic iNOS mRNA upregulation by 72%. To determine whether iNOS contributes to the toxicity of PARP, the iNOS inhibitor aminoguanidine was co-administered with PARP inhibitors. Unexpectedly, co-administration of PARP and iNOS inhibitors, or treatment of iNOS-null mice with PARP inhibitors, abrogated the protective effect afforded by iNOS or PARP inhibition alone. The loss of neuroprotection was associated with upregulation of the inflammatory genes iNOS, intercellular adhesion molecule-1, and gp91(phox). Conclusions-The results suggest that iNOS expression contributes to the deleterious effects exerted by PARP activation in cerebral ischemia. However, iNOS activity is required for the protective effect of PARP inhibition and, conversely, PARP activity must be present for iNOS inhibition to be effective. The findings unveil a previously unrecognized deleterious interaction between iNOS and PARP that is relevant to the development of combination therapies for ischemic stroke.
引用
收藏
页码:2896 / 2901
页数:6
相关论文
共 28 条
[1]  
Abdelkarim GE, 2001, INT J MOL MED, V7, P255
[2]   Poly(ADP-ribose) polymerase-1 activity promotes NF-κB-driven transcription and microglial activation:: implication for neurodegenerative disorders [J].
Chiarugi, A ;
Moskowitz, MA .
JOURNAL OF NEUROCHEMISTRY, 2003, 85 (02) :306-317
[3]   Cell biology: PARP-1 - A perpetrator of apoptotic cell death? [J].
Chiarugi, A ;
Moskowitz, MA .
SCIENCE, 2002, 297 (5579) :200-201
[4]   Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia [J].
Eliasson, MJL ;
Sampei, K ;
Mandir, AS ;
Hurn, PD ;
Traystman, RJ ;
Bao, J ;
Pieper, A ;
Wang, ZQ ;
Dawson, TM ;
Snyder, SH ;
Dawson, VL .
NATURE MEDICINE, 1997, 3 (10) :1089-1095
[5]   Ischemic brain injury is mediated by the activation of poly(ADP-ribose)polymerase [J].
Endres, M ;
Wang, ZQ ;
Namura, S ;
Waeber, C ;
Moskowitz, MA .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 1997, 17 (11) :1143-1151
[6]   Toward wisdom from failure - Lessons from neuroprotective stroke trials and new therapeutic directions [J].
Gladstone, DJ ;
Black, SE ;
Hakim, AM .
STROKE, 2002, 33 (08) :2123-2136
[7]   Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion [J].
Ha, HC ;
Snyder, SH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (24) :13978-13982
[8]   The functional role of poly(ADP-ribose)polymerase 1 as novel coactivator of NF-κB in inflammatory disorders [J].
Hassa, PO ;
Hottiger, MO .
CELLULAR AND MOLECULAR LIFE SCIENCES, 2002, 59 (09) :1534-1553
[9]   Cerebral ischemia and inflammation [J].
Iadecola, C ;
Alexander, M .
CURRENT OPINION IN NEUROLOGY, 2001, 14 (01) :89-94
[10]  
Iadecola C, 1997, J NEUROSCI, V17, P9157