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T33, a novel peroxisome proliferator-activated receptor |[gamma]|/|[alpha]| agonist, exerts neuroprotective action via its anti-inflammatory activities

renchunxiao 添加于 2011/10/24 15:31:06  1500次阅读 | 0次推荐 | 0个评论

Aim: To examine the neuroprotective effects of T33, a peroxisome proliferator-activated receptor gamma/alpha (PPARγ/α) agonist, in acute ischemic models in vitro and in vivo. Methods: Primary astrocytes subjected to oxygen-glucose deprivation/reperfusion (O/R) and BV-2 cells subjected to hypoxia were used as a model simulating the ischemic core and penumbra, respectively. The mRNA levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured using qPCR. The levels of TNF-α secreted by BV-2 cells were measured using ELISA. Protein levels of cyclooxygenase-2 (COX-2), p65, phosphorylated I-κBα/I-κBα, phosphorylated I-κB kinase (pIKK), phosphorylated eukaryote initiation factor 2α (p-eIF-2α)/eIF-2α and p-p38/p38 were detected using Western blot. PPARγ activity was measured using EMSA. The neuroprotection in vivo was examined in rat middle cerebral artery occlusion (MCAO) model with neurological scoring and TTC staining. Results: Addition of T33 (0.5 μmol/L) increased the level of I-κBα protein in primary astrocytes subjected to O/R, which was due to promoting protein synthesis without affecting degradation. In primary astrocytes subjected to O/R, addition of T33 amplified I-κBα gene transcription and mRNA translation, thus suppressing the nuclear factor-kappa B (NF-κB) pathway and reducing inflammatory mediators (TNF-α, IL-1β, and COX-2). In BV-2 cells subjected to hypoxia, T33 (0.5 μmol/L) reduced TNF-α, COX-2, and p-P38 production, which was antagonized by pre-administration of the specific PPARγ antagonist GW9662 (30 μmol/L). T33 (2 mg/kg, ip) attenuated MCAO-induced inflammatory responses and brain infarction, which was antagonized by pre-administered GW9662 (4 mg/kg, ip). Conclusion: T33 exerted anti-inflammatory effects in the ischemic core and penumbra via PPARγ activation, which contributed to its neuroprotective action

作 者:Ying Wang, Yu-she Yang, Xi-can Tang, Hai-yan Zhang
期刊名称: Acta Pharmacologica Sinica
期卷页: 2011-08-01 第32卷 第9期 1100~1108页
学科领域:医学科学 » 老年医学 » 老年医学
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原文链接:http://www.nature.com/aps/journal/v32/n9/full/aps201169a.html
DOI: doi:10.1038/aps.2011.69
ISBN: 1671-4083
关键词: pharmacology, experimental pharmacology, anticancer pharmacology, cardiovascular pharmacology, pulmonary pharmacology, clinical pharmacology, drug discovery, gastrointestinal and hepatic pharmacology, genitourinary, renal and endocrine pharmacology, immun
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