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

A growing body of evidence indicates that the transcription factor PPAR gamma plays a beneficial role in various neurological diseases. The postulated principal mechanism underlying the beneficial effects of PPAR gamma is due to its anti -inflammatory properties. However, PPAR gamma 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 PPAR gamma. The endogenous PPAR-y ligand, 15d-Delta(12) (,14)-Prostaglandin J(2) (15d-PGJ(2)), and a selective thiazolidinedione PPAR gamma agonist, ciglitazone, significantly reduced neuronal death in response to glutamate and NMDA-mediated, but not kainate-mediated toxicity. This neuroprotective effect of 15d-PGJ(2) and ciglitazone was linked to increased PPAR-gamma DNA binding activity as it was fully reversed by the pretreatment of neurons with selective PPAR-y antagonists and anti-PPAR-gamma antibody. It was not due to the blockade of NMDA-receptor-mediated Ca++ entry. Our data demonstrate that PPAR-gamma activation may represent a potential target for treatment of numerous acute and chronic neurological diseases with pathologies that involve excitotoxic damage. (c) 2006 Elsevier B.V. All rights reserved.