Peroxynitrite-induced oligodendrocyte toxicity is not dependent on poly(ADP-ribose) polymerase activation

被引:36
作者
Scott, GS
Virág, L
Szabó, C
Hooper, DC
机构
[1] Thomas Jefferson Univ, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA
[2] Inotek Corp, Beverly, MA USA
[3] Univ Debrecen, Dept Med Chem, Debrecen, Hungary
关键词
free radicals; necrosis; demyelination; multiple sclerosis; spinal cord; injury;
D O I
10.1002/glia.10137
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Oligodendrocyte loss is a characteristic feature of several CNS disorders, including multiple sclerosis (MS) and spinal cord injury. However, the mechanisms responsible for oligodendrocyte destruction remain undefined. As recent studies have implicated peroxynitrite in the pathogenesis of both spinal cord injury and MS, we have examined whether peroxynitrite may mediate at least some of the oligodendrocyte damage and demyelination observed in these conditions. Primary rat oligodendrocytes were exposed to authentic peroxynitrite in vitro and assessed for cytotoxicity. Mitochondrial function, measured by the reduction of MTT to formazan, and mitochondrial membrane potential were used as indicators of cell viability. Cell death was quantitated by measuring either the release of lactate dehydrogenase from, or the uptake of propidium iodide into, damaged and dying cells. Peroxynitrite dose-dependently reduced the viability of primary oligodendrocytes and induced cell death. Furthermore, peroxynitrite significantly increased DNA strand breakage and the activity of poly(ADP-ribose) polymerase (PARP) in oligodendrocyte cultures. To identify whether PARP activation plays a role in peroxynitrite-induced oligodendrocyte toxicity, we examined the effects of the PARP inhibitors 3-aminobenzamide (3AB) and 5-iodo-6-amino-1,2-benzopyrone (INH2BP) on mitochondrial function and cell death in oligodendrocytes. The presence of 3AB and INH2BP did not protect oligodendrocytes from peroxynitrite-induced cytotoxicity. However, both compounds significantly reduced PARP activity in these cells. Primary oligodendrocytes generated from PARP-deficient mice were also highly susceptible to peroxynitrite-induced cell death. Therefore, our results show that peroxynitrite exerts cytotoxic effects on oligodendrocytes in vitro independently of PARP activation.
引用
收藏
页码:105 / 116
页数:12
相关论文
共 89 条
[1]   Induction of the mitochondrial permeability transition by protease activity in rats: A mechanism of hepatocyte necrosis [J].
Aguilar, HI ;
Botla, R ;
Arora, AS ;
Bronk, SF ;
Gores, GJ .
GASTROENTEROLOGY, 1996, 110 (02) :558-566
[2]   Activation of the inducible form of nitric oxide synthase in the brains of patients with multiple sclerosis [J].
Bagasra, O ;
Michaels, FH ;
Zheng, YM ;
Bobroski, LE ;
Spitsin, SV ;
Fu, ZF ;
Tawadros, R ;
Koprowski, H .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (26) :12041-12045
[3]   APPARENT HYDROXYL RADICAL PRODUCTION BY PEROXYNITRITE - IMPLICATIONS FOR ENDOTHELIAL INJURY FROM NITRIC-OXIDE AND SUPEROXIDE [J].
BECKMAN, JS ;
BECKMAN, TW ;
CHEN, J ;
MARSHALL, PA ;
FREEMAN, BA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (04) :1620-1624
[4]  
BECKMAN JS, 1994, METHOD ENZYMOL, V233, P229
[5]  
Blight A R, 1985, Cent Nerv Syst Trauma, V2, P299
[6]  
Boczkowski J, 2001, BIOL SIGNAL RECEPT, V10, P66
[7]  
BOLANOS JP, 1994, J NEUROCHEM, V63, P910
[8]  
BOLANOS JP, 1995, J NEUROCHEM, V64, P1965
[9]   Lipid constituents in oligodendroglial cells alter susceptibility to H2O2-induced apoptotic cell death via ERK activation [J].
Brand, A ;
Gil, S ;
Seger, R ;
Yavin, E .
JOURNAL OF NEUROCHEMISTRY, 2001, 76 (03) :910-918
[10]  
BRAUGHLER JM, 1992, J NEUROTRAUM, V9, pS1