Neuronal PPARgamma deficiency increases susceptibility to brain damage after cerebral ischemia.

Abstract

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

• Authors: Xiurong Zhao, Roger Strong, Jie Zhang, Guanghua Sun, Joe Z Tsien, Zhenzhong Cui, James C Grotta, Jaroslaw Aronowski
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 29 Issue 19 Pg. 6186-95 (May 13 2009) ISSN: 1529-2401 [Electronic] United States
• PMID: 19439596 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Neuroprotective Agents
• PPAR gamma
• RNA, Messenger
• Thiazolidinediones
• Rosiglitazone

Topics

• Animals
• Astrocytes (physiology)
• Brain (drug effects, physiopathology)
• Cells, Cultured
• Coculture Techniques
• Female
• Gene Expression
• Infarction, Middle Cerebral Artery (drug therapy, physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neuroglia (drug effects, physiology)
• Neurons (drug effects, physiology)
• Neuroprotective Agents (pharmacology)
• Oxidative Stress (drug effects, physiology)
• PPAR gamma (agonists, genetics, physiology)
• RNA, Messenger (genetics, metabolism)
• Rosiglitazone
• Thiazolidinediones (pharmacology)