The Journal of Neuroscience, May 13, 2009, 29(19):6186-6195; doi:10.1523/JNEUROSCI.5857-08.2009
Previous Article | Next Article 
Neurobiology of Disease
Neuronal PPAR
Deficiency Increases Susceptibility to Brain Damage after Cerebral Ischemia
Xiurong Zhao,1
Roger Strong,1
Jie Zhang,1
Guanghua Sun,1
Joe Z. Tsien,2
Zhenzhong Cui,3
James C. Grotta,1 and
Jaroslaw Aronowski1
1Stroke Program, Department of Neurology, University of Texas, Houston, Medical School, Houston, Texas 77030, 2Brain and Behavior Discovery Institute, Medical College of Georgia, Augusta, Georgia 30912, and 3Section on Neural Gene Expression, National Institute of Mental Health–National Institutes of Health, Bethesda, Maryland 20892
Correspondence should be addressed to Dr. Jaroslaw Aronowski, Department of Neurology, University of Texas, Houston, Medical School, Houston, TX 77030. Email: J.Aronowski{at}uth.tmc.edu
Peroxisome proliferator-activated receptor gamma (PPAR
) plays a role in regulating a myriad of biological processes in virtually all brain cell types, including neurons. We and others have reported recently that drugs which activate PPAR are effective in reducing damage to brain in distinct models of brain disease, including ischemia. However, the cell type responsible for PPAR-mediated protection has not been established. In response to ischemia, PPAR gene is robustly upregulated in neurons, suggesting that neuronal PPAR may be a primary target for PPAR-agonist-mediated neuroprotection. To understand the contribution of neuronal PPAR to ischemic injury, we generated conditional neuron-specific PPAR knock-out mice (N-PPAR-KO). These mice are viable and appeared to be normal with respect to their gross behavior and brain anatomy. However, neuronal PPAR deficiency caused these mice to experience significantly more brain damage and oxidative stress in response to middle cerebral artery occlusion. The primary cortical neurons harvested from N-PPAR-KO mice, but not astroglia, exposed to ischemia in vitro demonstrated more damage and a reduced expression of numerous key gene products that could explain increased vulnerability, including SOD1 (superoxide dismutase 1), catalase, glutathione S-transferase, uncoupling protein-1, or transcription factor liver X receptor-
. Also, PPAR agonist-based neuroprotective effect was lost in neurons from N-PPAR neurons. Therefore, we conclude that PPAR in neurons play an essential protective function and that PPAR agonists may have utility in neuronal self-defense, in addition to their well established anti-inflammatory effect.
Received Dec. 9, 2008;
revised Feb. 11, 2009;
accepted March 6, 2009.
Correspondence should be addressed to Dr. Jaroslaw Aronowski, Department of Neurology, University of Texas, Houston, Medical School, Houston, TX 77030. Email: J.Aronowski{at}uth.tmc.edu
