l-796449 and Inflammation

Topics: Animals; Diabetes Mellitus; Drug Design; Humans; Hyperlipidemias; Hypertension; Inflammation; Ligands; Models, Molecular; Neoplasms; Nuclear Proteins; Obesity; Receptors, Cytoplasmic and Nuclear; Transcription Factors

Some agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma) belonging to the thiazolidinedione (TZD) family, as well as the cyclopentenone prostaglandin 15-dPGJ2, have been shown to cause neuroprotection in animal models of stroke. We have tested whether the TZD-unrelated PPARgamma agonist L-796,449 is neuroprotective after permanent middle cerebral artery occlusion (MCAO) in the rat brain. Our results show that L-796,449 decreases MCAO-induced infarct size and improves neurologic scores. This protection is concomitant to inhibition of MCAO-induced brain expression of inducible NO synthase (iNOS) and the matrix metalloproteinase MMP-9 and to upregulation of the cytoprotective stress protein heme oxygenase-1 (HO-1). Analysis of the NF-kappaB p65 monomer and the NF-kappaB inhibitor IkappaBalpha protein levels as well as gel mobility shift assays indicate that L-796,449 inhibits NF-kappaB signaling, and that it may be recruiting both PPARgamma-dependent and independent pathways. In summary, our results provide new insights for stroke treatment.

Topics: Animals; Benzofurans; Blotting, Western; Brain Ischemia; Caspase 3; Caspases; Cyclooxygenase 2; Disease Models, Animal; Electrophoretic Mobility Shift Assay; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; I-kappa B Proteins; Inflammation; Male; Matrix Metalloproteinase 9; Neuroprotective Agents; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Phenylacetates; PPAR gamma; Prostaglandin-Endoperoxide Synthases; Rats