Selective Blockade of PGE2 EP1 Receptor Protects Brain against Experimental Ischemia and Excitotoxicity, and Hippocampal Slice Cultures against Oxygen-Glucose Deprivation

被引:43
作者
Ahmad, Abdullah Shafique [1 ]
Kim, Yun Tai [1 ]
Ahmad, Muzamil [1 ]
Maruyama, Takayuki [2 ]
Dore, Sylvain [1 ]
机构
[1] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA
[2] Ono Pharmaceut Co Ltd, Discovery Res Inst, Osaka, Japan
基金
美国国家卫生研究院;
关键词
Antagonism; Hippocampal slice cultures; Middle cerebral artery occlusion; ONO-8713; Oxygen glucose deprivation; Prostaglandin;
D O I
10.1007/BF03033858
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Cyclooxygenase-2 (COX-2) enzyme increases abnormally during excitotoxicity and cerebral ischemia and promotes neurotoxicity. Although COX-2 inhibitors could be beneficial, they have significant side effects. We and others have shown that the EP1 receptor is important in mediating PGE(2) toxicity. Here, we tested the hypothesis that pretreatment with a highly selective EP1 receptor antagonist, ONO-8713, would improve stroke outcome and that post-treatment would attenuate NMDA-induced acute excitotoxicity and protect organotypic brain slices from oxygen-glucose deprivation (OGD)-induced toxicity. Male C57BL/6 mice were injected intracerebroventricularly with ONO-8713 before being subjected to 90-min middle cerebral artery occlusion (MCAO) and 96-h reperfusion. Significant reduction in infarct size was observed in groups given 0.1 (25.9 +/- 4.7%) and 1.0 nmol (27.7 +/- 2.8%) ONO-8713 as compared with the vehicle-treated control group. To determine the effects of ONO-8713 post-treatment on NMDA-induced excitotoxicity, mice were given a unilateral intrastriatal NMDA injection followed by one intraperitoneal injection of 10 mu g/kg ONO-8713, 1 and 6 h later. Significant attenuation of brain damage (26.6 +/- 4.9%) was observed at 48 h in the ONO-8713-treated group. Finally, brain slice cultures were protected (25.5 +/- 2.9%) by the addition of ONO-8713 to the medium after OGD. These findings support the notion that the EP1 receptor propagates neurotoxicity and that selective blockade could be considered as a potential preventive and/or therapeutic tool against ischemic/hypoxic neurological conditions.
引用
收藏
页码:343 / 351
页数:9
相关论文
共 37 条
[1]   The neuroprotective effect of prostaglandin E2 EP1 receptor inhibition has a wide therapeutic window, is sustained in time and is not sexually dimorphic [J].
Abe, Takato ;
Kunz, Alexander ;
Shimamura, Munehisa ;
Zhou, Ping ;
Anrather, Josef ;
Iadecola, Costantino .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2009, 29 (01) :66-72
[2]  
Adams J, 1996, J NEUROCHEM, V66, P6
[3]   Stimulation of prostaglandin EP2 receptors prevents NMDA-induced excitotoxicity [J].
Ahmad, Abdullah Shafique ;
Zhuang, Hean ;
Echeverria, Valentina ;
Dore, Sylvain .
JOURNAL OF NEUROTRAUMA, 2006, 23 (12) :1895-1903
[4]   Prostaglandin EP1 receptor contributes to excitotoxicity and focal ischemic brain damage [J].
Ahmad, AS ;
Saleem, S ;
Doré, S .
TOXICOLOGICAL SCIENCES, 2006, 89 (01) :265-270
[5]   1-HydroxyPGE1 reduces infarction volume in mouse transient cerebral ischemia [J].
Ahmad, M ;
Saleem, S ;
Zhuang, H ;
Ahmad, AS ;
Echeverria, V ;
Sapirstein, A ;
Doré, S .
EUROPEAN JOURNAL OF NEUROSCIENCE, 2006, 23 (01) :35-42
[6]   Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial [J].
Baron, John A. ;
Sandler, Robert S. ;
Bresalier, Robert S. ;
Lanas, Angel ;
Morton, Dion G. ;
Riddell, Robert ;
Iverson, Erik R. ;
DeMets, David L. .
LANCET, 2008, 372 (9651) :1756-1764
[7]   Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial [J].
Bresalier, RS ;
Sandler, RS ;
Quan, H ;
Bolognese, JA ;
Oxenius, B ;
Horgan, K ;
Lines, C ;
Riddell, R ;
Morton, D ;
Lanas, A ;
Konstam, MA ;
Baron, JA .
NEW ENGLAND JOURNAL OF MEDICINE, 2005, 352 (11) :1092-1102
[8]   Neuronal overexpression of cyclooxygenase-2 increases cerebral infarction [J].
Doré, S ;
Otsuka, T ;
Mito, T ;
Sugo, N ;
Hand, T ;
Wu, LJ ;
Hurn, PD ;
Traystman, RJ ;
Andreasson, K .
ANNALS OF NEUROLOGY, 2003, 54 (02) :155-162
[9]   Stimulation of PGE2 receptors EP2 and EP4 protects cultured neurons against oxidative stress and cell death following β-amyloid exposure [J].
Echeverria, V ;
Clerman, A ;
Doré, S .
EUROPEAN JOURNAL OF NEUROSCIENCE, 2005, 22 (09) :2199-2206
[10]   The effect of oxidative stress on Ca2+ release and capacitative Ca2+entry in vascular endothelial cells [J].
Florea, Stela M. ;
Blatter, Lothar A. .
CELL CALCIUM, 2008, 43 (04) :405-415