Peroxisome-proliferator-activated receptor-gamma (PPARγ) activation protects neurons from NMDA excitotoxicity

A growing body of evidence indicates that the transcription factor PPARγ plays a beneficial role in various neurological diseases. The postulated principal mechanism underlying the beneficial effects of PPARγ is due to its anti-inflammatory properties. However, PPARγ exists in neurons where it may provide additional effects that regulate neuronal vulnerability. In the present study, we employed in vitro and in vivo models of excitotoxic neuronal injury to test hypothesis on the neuroprotective role of PPARγ. The endogenous PPARγ ligand, 15d-Δ12,14-Prostaglandin J2 (15d-PGJ2), and a selective thiazolidinedione PPARγ agonist, ciglitazone, significantly reduced neuronal death in response to glutamate and NMDA-mediated, but not kainate-mediated toxicity. This neuroprotective effect of 15d-PGJ2 and ciglitazone was linked to increased PPARγ DNA binding activity as it was fully reversed by the pretreatment of neurons with selective PPARγ antagonists and anti-PPARγ antibody. It was not due to the blockade of NMDA-receptor-mediated Ca++ entry. Our data demonstrate that PPARγ activation may represent a potential target for treatment of numerous acute and chronic neurological diseases with pathologies that involve excitotoxic damage.