Beneficial effects of sulindac in focal cerebral ischemia: A positive role in Wnt/β-catenin pathway

Abstract Background Accumulated evidences have established that inflammatory damage plays an important role in cerebral ischemic pathogenesis and may represent a target for treatment. Sulindac is well known as a nonsteroidal anti-inflammatory drug. However, little is known regarding the effect of su...

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Published in:Brain research 2012-10, Vol.1482, p.71-80
Main Authors: Xing, Yinxue, Zhang, Xiangjian, Zhao, Kang, Cui, Lili, Wang, Lina, Dong, Lipeng, Li, Yanhua, Liu, Zongjie, Wang, Chaohui, Zhang, Xiaolin, Zhu, Chunhua, Qiao, Huimin, Ji, Ye, Cao, Xiaoyun
Format: Article
Language:English
Subjects:
Analysis of Variance
Animals
Anti-Inflammatory Agents, Non-Steroidal - administration & dosage
Bax
Bcl-2
bcl-2-Associated X Protein - genetics
bcl-2-Associated X Protein - metabolism
beta Catenin - genetics
beta Catenin - metabolism
Biological and medical sciences
brain
Brain Edema - drug therapy
Brain Edema - etiology
Brain Infarction - drug therapy
Brain Infarction - etiology
Brain Ischemia - complications
Brain Ischemia - drug therapy
Cerebral ischemia
Claudin-5
Disease Models, Animal
Drug Administration Schedule
Gene Expression Regulation - drug effects
Gene Expression Regulation - genetics
immunohistochemistry
Indexing in process
infarction
ischemia
Male
Medical sciences
Nervous System Diseases - etiology
Nervous System Diseases - prevention & control
Neurology
nonsteroidal anti-inflammatory agents
pathogenesis
protective effect
Proto-Oncogene Proteins c-bcl-2 - genetics
Proto-Oncogene Proteins c-bcl-2 - metabolism
Rats
Rats, Sprague-Dawley
reverse transcriptase polymerase chain reaction
signal transduction
Statistics, Nonparametric
Sulindac
Sulindac - administration & dosage
Vascular diseases and vascular malformations of the nervous system
water content
Western blotting
Wnt Signaling Pathway - drug effects
Wnt Signaling Pathway - genetics
Wnt/β-catenin signaling
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Summary:Abstract Background Accumulated evidences have established that inflammatory damage plays an important role in cerebral ischemic pathogenesis and may represent a target for treatment. Sulindac is well known as a nonsteroidal anti-inflammatory drug. However, little is known regarding the effect of sulindac in acute cerebral ischemia. Here, we designed this study to investigate the potential protective effects of sulindac in focal cerebral ischemia and the mechanisms underlying in vivo. Methods Focal cerebral ischemia was induced in male Sprague-Dawley rats by permanent middle cerebral artery occlusion (pMCAO). Sulindac was administrated at dose of 4, 10, or 20 mg/kg at 30 min before the operation. Neurological deficit scores, brain water content and infarct volumes were measured at 24 h after pMCAO. Immunohistochemistry, western blot and reverse transcription-polymerase chain reaction were used for examining the mediators involved in Wnt/β-catenin signaling pathway, including the positive regulators dishevelled (Dvl) and β-catenin, the negative regulators adenomatous polyposis coli (APC), and P-β-catenin, as well as the downstream targets Bcl-2, Bax and claudin-5. Results Compared with Vehicle group, 20 mg/kg sulindac reduced neurological deficits, brain water content and infarct volumes. The same dose of sulindac upregulated the expression of Dvl, β-catenin, Bcl2 and claudin-5, and downregulated APC, P-β-catenin and Bax compared with Vehicle group. Conclusions These results showed that sulindac had a significant beneficial effect in cerebral ischemia; this effect may be correlated with the activation of the Wnt/β-catenin signaling.
ISSN:0006-8993
1872-6240
DOI:10.1016/j.brainres.2012.08.057