Document Detail


MCI-186 prevents brain tissue from neuronal damage in cerebral infarction through the activation of intracellular signaling.
MedLine Citation:
PMID:  17628025     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The mechanism by which MCI-186 (3-methyl-1-phenyl-2-prazolin-5-one) exerts protective effects during cerebral infarction, other than its function as a radical scavenger, has not been fully elucidated. Here, we found that MCI-186 stimulates intracellular survival signaling in vivo and in vitro. In a rat infarction model, the infarct area was significantly smaller and the degree of edema was reduced in MCI-186-treated animals. In the MCI-186-treated rats, the number of single stranded (ss) DNA-positive damaged cells in the peri-infarct area was decreased compared with the control, suggesting that MCI-186 protects cerebral tissues from cell damage. To clarify the mechanisms underlying the effect of MCI-186, we also examined the survival-promoting effect of this agent on cultured cortical neurons. In this in vitro system, MCI-186 blocked serum-free induced neuronal cell death. Interestingly, an increase in the activation of both Akt (a component of the PI3 kinase pathway) and ERK (a component of the MAP kinase pathway) was observed in the cortical cultures after MCI-186 exposure. Furthermore, the MCI-186-dependent survival effect in vitro was blocked by U0126, an MEK (an upstream of ERK) inhibitor, and also by LY294002, a PI3 kinase inhibitor. We also observed similar increases in the activation of Akt and ERK in the in vivo model, further suggesting that the antiapoptotic role of MCI-186 is mediated via the PI3 kinase and MAP kinase signaling pathways. We therefore conclude that, in addition to its role as a free radical scavenger, MCI-186 functions as an antiapoptotic factor by enhancing intracellular survival signaling.
Authors:
Madinyet Niyaz; Tadahiro Numakawa; Yoshinori Matsuki; Emi Kumamaru; Naoki Adachi; Hiromi Kitazawa; Hiroshi Kunugi; Motoshige Kudo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of neuroscience research     Volume:  85     ISSN:  0360-4012     ISO Abbreviation:  J. Neurosci. Res.     Publication Date:  2007 Oct 
Date Detail:
Created Date:  2007-09-20     Completed Date:  2008-01-17     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7600111     Medline TA:  J Neurosci Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2933-42     Citation Subset:  IM    
Copyright Information:
2007 Wiley-Liss, Inc.
Affiliation:
Department of Pathology, Tokyo Medical University, Tokyo, Japan.
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MeSH Terms
Descriptor/Qualifier:
1-Phosphatidylinositol 3-Kinase / metabolism
Animals
Animals, Newborn
Antipyrine / analogs & derivatives*,  therapeutic use
Brain Edema / etiology,  prevention & control
Butadienes / pharmacology
Cell Death / drug effects
Cells, Cultured
Cerebral Infarction / drug therapy*,  pathology*
Chromones / pharmacology
Dose-Response Relationship, Drug
Drug Interactions
Enzyme Inhibitors / pharmacology
Free Radical Scavengers / therapeutic use*
Male
Morpholines / pharmacology
Nerve Tissue Proteins / metabolism
Neurons / drug effects*
Nitriles / pharmacology
Oncogene Protein v-akt / metabolism
Rats
Rats, Wistar
Signal Transduction / drug effects*
Time Factors
Chemical
Reg. No./Substance:
0/Butadienes; 0/Chromones; 0/Enzyme Inhibitors; 0/Free Radical Scavengers; 0/Morpholines; 0/Nerve Tissue Proteins; 0/Nitriles; 0/U 0126; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; 60-80-0/Antipyrine; 89-25-8/phenylmethylpyrazolone; EC 2.7.1.137/1-Phosphatidylinositol 3-Kinase; EC 2.7.11.1/Oncogene Protein v-akt

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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