Neuronal PPARγ deficiency increases susceptibility to brain damage after cerebral ischemia

Xiurong Zhao, Roger Strong, Jie Zhang, Guanghua Sun, Joseph Zhuo Tsien, Zhenzhong Cui, James C. Grotta, Jaroslaw Aronowski

Research output: Contribution to journalArticle

117 Scopus citations

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) 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 PPARγ are effective in reducing damage to brain in distinct models of brain disease, including ischemia. However, the cell type responsible for PPARγ-mediated protection has not been established. In response to ischemia, PPARγ gene is robustly upregulated in neurons, suggesting that neuronal PPARγ may be a primary target for PPARγ-agonist-mediated neuroprotection. To understand the contribution of neuronal PPARγ to ischemic injury, we generated conditional neuron-specific PPARγ knock-out mice (N-PPARγ-KO). These mice are viable and appeared to be normal with respect to their gross behavior and brain anatomy. However, neuronal PPARγ 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-PPARγ-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-α. Also, PPARγ agonist-based neuroprotective effect was lost in neurons from N-PPARγ neurons. Therefore, we conclude that PPARγ in neurons play an essential protective function and that PPARγ agonists may have utility in neuronal self-defense, in addition to their well established anti-inflammatory effect.

Original languageEnglish (US)
Pages (from-to)6186-6195
Number of pages10
JournalJournal of Neuroscience
Volume29
Issue number19
DOIs
Publication statusPublished - May 13 2009

    Fingerprint

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Zhao, X., Strong, R., Zhang, J., Sun, G., Tsien, J. Z., Cui, Z., ... Aronowski, J. (2009). Neuronal PPARγ deficiency increases susceptibility to brain damage after cerebral ischemia. Journal of Neuroscience, 29(19), 6186-6195. https://doi.org/10.1523/JNEUROSCI.5857-08.2009