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

Abstract

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 m RNA levels of tumor necrosis factor-α (TNF-α) and interleukin-1Β (IL-1Β) were measured using q PCR. The levels of TNF-α secreted by BV-2 cells were measured using ELISA. Protein levels of cyclooxygenase-2 (COX-2), p65, phosphorylated I-Bα/I-Bα, phosphorylated I-B kinase (p IKK), phosphorylated eukaryote initiation factor 2α (p-e IF-2α)/e IF-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 mol/L) increased the level of I-Bα 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-Bα gene transcription and m RNA translation, thus suppressing the nuclear factor-kappa B (NF-B) pathway and reducing inflammatory mediators (TNF-α, IL-1Β, and COX-2). In BV-2 cells subjected to hypoxia, T33 (0.5 mol/L) reduced TNF-α, COX-2, and p-P38 production, which was antagonized by pre-administration of the specific PPARγ antagonist GW9662 (30 mol/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. © 2011 CPS and SIMM. All rights reserved.