The nonthiazolidinedione PPARγ agonist L-796,449 is neuroprotective in experimental stroke

Some agonists of the peroxisome proliferator-activated receptor gamma (PPAR gamma) belonging to the thiazolidinedione (TZD) family, as well as the cyclopentenone prostaglandin 15-dPGJ(2), have been shown to cause neuroprotection in animal models of stroke. We have tested whether the TZD-unrelated PPAR gamma 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-kappa B p65 monomer and the NF-kappa B inhibitor I kappa B alpha protein levels as well as gel mobility shift assays indicate that L-796,449 inhibits NF-kappa B signaling, and that it may be recruiting both PPAR gamma-dependent and independent pathways. In summary, our results provide new insights for stroke treatment.