PMID- 21803432
OWN - NLM
STAT- MEDLINE
DCOM- 20111122
LR  - 20121115
IS  - 1872-8421 (Electronic)
IS  - 0165-5728 (Linking)
VI  - 238
IP  - 1-2
DP  - 2011 Sep 15
TI  - Inhibition of prostaglandin E2 EP3 receptors improves stroke injury via 
      anti-inflammatory and anti-apoptotic mechanisms.
PG  - 34-43
LID - 10.1016/j.jneuroim.2011.06.014 [doi]
AB  - Although deletion of EP3 receptors is known to ameliorate stroke injury in 
      experimental stroke models, the underlying mechanisms and the effects of 
      EP3-specific antagonists remain poorly understood. Here we demonstrate the 
      protective effect of postischemic treatment with an EP3 antagonist, ONO-AE3-240, 
      through anti-inflammatory and anti-apoptotic effects. In transient focal ischemia 
      models, peritoneal injection of an EP3 antagonist after occlusion-reperfusion 
      reduced infarction, edema and neurological dysfunctions to almost the same levels 
      of those in EP3 knockout (KO) mice. Furthermore, neuronal apoptosis in the 
      ischemic cortex investigated by terminal dUTP nick-end labeling (TUNEL) and 
      caspase-3 immunostaining were ameliorated in EP3 antagonist-treated mice or EP3 
      KO mice as compared with vehicle-treated mice or wild-type (WT) mice, 
      respectively. There were no significant differences between ONO-AE3-240-injected 
      or EP3 KO mice and vehicle-injected or WT mice, respectively, in mean arterial 
      blood pressure, cerebral blood flow or body temperature. The 
      double-immunostaining showed that EP3 receptor-positive cells were also positive 
      for CD-11b and partially for Neu-N, the marker for microglia and neurons. 
      Deletion of EP3 receptors also reduced damage of the blood-brain barrier, 
      activation of microglia and infiltration of neutrophils into the ischemic cortex. 
      These results suggest that EP3 receptors are involved in stroke injury through 
      the enhancement of inflammatory and apoptotic reactions in the ischemic cortex. 
      Thus, EP3 antagonists may be valuable for the treatment of human stroke.
CI  - Copyright (c) 2011 Elsevier B.V. All rights reserved.
FAU - Ikeda-Matsuo, Yuri
AU  - Ikeda-Matsuo Y
AD  - Laboratory of Pharmacology, School of Pharmaceutical Sciences, Kitasato 
      University, Tokyo, Japan. matsuoy@pharm.kitasato-u.ac.jp
FAU - Tanji, Hayato
AU  - Tanji H
FAU - Narumiya, Shuh
AU  - Narumiya S
FAU - Sasaki, Yasuharu
AU  - Sasaki Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110730
PL  - Netherlands
TA  - J Neuroimmunol
JT  - Journal of neuroimmunology
JID - 8109498
RN  - 0 (Aif1 protein, rat)
RN  - 0 (Anilides)
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Benzoates)
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Membrane Proteins)
RN  - 0 (Microfilament Proteins)
RN  - 0 (OCLN protein, human)
RN  - 0 (ONO-AE3-240)
RN  - 0 (Occludin)
RN  - 0 (Ocln protein, mouse)
RN  - 0 (Ocln protein, rat)
RN  - 0 (Ptger3 protein, mouse)
RN  - 0 (Receptors, Prostaglandin E, EP3 Subtype)
SB  - IM
MH  - Anilides/pharmacology/therapeutic use
MH  - Animals
MH  - Anti-Inflammatory Agents/pharmacology/*therapeutic use
MH  - Apoptosis/drug effects/genetics/*physiology
MH  - Benzoates/pharmacology/therapeutic use
MH  - Blood Pressure/drug effects
MH  - Blood-Brain Barrier/physiopathology
MH  - Body Temperature
MH  - Brain Infarction/etiology/genetics/prevention & control
MH  - Calcium-Binding Proteins/metabolism
MH  - Cerebral Cortex/pathology
MH  - Cerebrovascular Circulation/drug effects
MH  - Disease Models, Animal
MH  - Immunoglobulin G/metabolism
MH  - In Situ Nick-End Labeling
MH  - Infarction, Middle Cerebral Artery/complications/drug 
      therapy/*genetics/*pathology
MH  - Inflammation/etiology/genetics/prevention & control
MH  - Membrane Proteins/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Microfilament Proteins/metabolism
MH  - Microglia/drug effects/metabolism/pathology
MH  - Nervous System Diseases/drug therapy/etiology
MH  - Neurons/drug effects/metabolism
MH  - Neutrophils/metabolism/pathology
MH  - Occludin
MH  - Receptors, Prostaglandin E, EP3 Subtype/antagonists & 
      inhibitors/deficiency/*metabolism
MH  - Time Factors
EDAT- 2011/08/02 06:00
MHDA- 2011/12/13 00:00
CRDT- 2011/08/02 06:00
PHST- 2009/09/25 00:00 [received]
PHST- 2011/06/22 00:00 [revised]
PHST- 2011/06/24 00:00 [accepted]
PHST- 2011/08/02 06:00 [entrez]
PHST- 2011/08/02 06:00 [pubmed]
PHST- 2011/12/13 00:00 [medline]
AID - S0165-5728(11)00174-3 [pii]
AID - 10.1016/j.jneuroim.2011.06.014 [doi]
PST - ppublish
SO  - J Neuroimmunol. 2011 Sep 15;238(1-2):34-43. doi: 10.1016/j.jneuroim.2011.06.014. 
      Epub 2011 Jul 30.