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

Publisher: Nature Publishing Group Country of Publication: United States NLM ID: 100956087 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1745-7254 (Electronic) Linking ISSN: 16714083 NLM ISO Abbreviation: Acta Pharmacol Sin Subsets: MEDLINE

Publication: 2009- : New York : Nature Publishing Group
Original Publication: Beijing, China : Science Press, c2000-

Anti-Inflammatory Agents/*therapeutic use ; Astrocytes/*drug effects ; Benzopyrans/*therapeutic use ; Infarction, Middle Cerebral Artery/*drug therapy ; Neuroprotective Agents/*therapeutic use ; PPAR alpha/*agonists ; PPAR gamma/*agonists; Animals ; Anti-Inflammatory Agents/pharmacology ; Astrocytes/immunology ; Astrocytes/pathology ; Benzopyrans/pharmacology ; Cells, Cultured ; Infarction, Middle Cerebral Artery/immunology ; Infarction, Middle Cerebral Artery/pathology ; Male ; NF-kappa B/immunology ; Neuroprotective Agents/pharmacology ; Rats ; Rats, Sprague-Dawley

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.

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0 (Anti-Inflammatory Agents)
0 (Benzopyrans)
0 (NF-kappa B)
0 (Neuroprotective Agents)
0 (PPAR alpha)
0 (PPAR gamma)

Date Created: 20110802 Date Completed: 20120105 Latest Revision: 20211020

20240829

PMC4003300

10.1038/aps.2011.69

21804572