T33, a novel peroxisome proliferator-activated receptor γ/α agonist, exerts neuroprotective action via its anti-inflammatory activities

• Published in: Acta pharmacologica Sinica 2011-09, Vol.32 (9), p.1100-1108
• Main Authors: Wang, Ying, Yang, Yu-she, Tang, Xi-can, Zhang, Hai-yan
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Antiinflammatory agents; Astrocytes; Astrocytes - drug effects; Astrocytes - immunology; Astrocytes - pathology; Benzopyrans - pharmacology; Benzopyrans - therapeutic use; Biomedical and Life Sciences; Biomedicine; Cells, Cultured; Cerebral blood flow; Cerebral infarction; Cyclooxygenase-2; Glucose; Hypoxia; Immunology; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - immunology; Infarction, Middle Cerebral Artery - pathology; Inflammation; Initiation factor eIF-2; Interleukin 1; Internal Medicine; Ischemia; Male; Medical Microbiology; mRNA水平; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; NF- Kappa B protein; NF-kappa B - immunology; Original; original-article; Peroxisome proliferator-activated receptors; Pharmacology/Toxicology; PPAR alpha - agonists; PPAR gamma - agonists; Protein biosynthesis; Rats; Rats, Sprague-Dawley; Translation; Tumor necrosis factor- alpha; Vaccine; Western blotting; 抗炎作用; 星形胶质细胞; 激动剂; 神经保护; 肿瘤坏死因子; 蛋白质合成; 过氧化物酶体增殖物激活受体
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2011.69

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 lev- els of cyclooxygenase-2 （COX-2）, p65, phosphorylated I-KBa/I-KBa, phosphorylated I-KB kinase （plKK）, phosphorylated eukaryote initia- tion factor 2α （p-elF-2α）/elF-2α and p-p38/p38 were detected using Western blot. PPARy 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 pro- moting 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 media- tors （TNF-α, IL-1β, and COX-2）. In BV-2 cells subjected to hypoxia, T33 （0.5 pmol/L） reduced TNF-α, COX-2, and p-P38 production, which was antagonized by pre-administration of the specific PPARy antagonist GW9662 （30 pmol/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 PPARy activation, which contributed to its neuroprotective action.