Peroxisome-proliferator-activated receptor-gamma (PPARgamma) activation protects neurons from NMDA excitotoxicity.
A growing body of evidence indicates that the transcription factor PPARgamma plays a beneficial role in various neurological diseases. The postulated principal mechanism underlying the beneficial effects of PPARgamma is due to its anti-inflammatory properties. However, PPARgamma 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 PPARgamma. The endogenous PPARgamma ligand, 15d-Delta(12,14)-Prostaglandin J2 (15d-PGJ2), and a selective thiazolidinedione PPARgamma 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 PPARgamma DNA binding activity as it was fully reversed by the pretreatment of neurons with selective PPARgamma antagonists and anti-PPARgamma antibody. It was not due to the blockade of NMDA-receptor-mediated Ca++ entry. Our data demonstrate that PPARgamma activation may represent a potential target for treatment of numerous acute and chronic neurological diseases with pathologies that involve excitotoxic damage.
Zhao
Xiurong
X
Stroke Program, Department of Neurology, University of Texas-Houston Medical School, 6431 Fannin, Rm. 7.044, Houston, TX 77030, USA.
Ou
Zhishuo
Z
Grotta
James C
JC
Waxham
Neal
N
Aronowski
Jaroslaw
J
D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D003952:Diagnostic Imaging / Q000379:methods; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006836:Hydro-Lyases / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology*; D011419:Propidium; D051381:Rats; D017207:Rats, Sprague-Dawley
D000906:Antibodies; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D047495:PPAR gamma; D011419:Propidium; D018698:Glutamic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D006836:Hydro-Lyases; C045581:lactate dehydratase; D002118:Calcium