Neuronal PPARγ Deficiency Increases Susceptibility to Brain Damage after Cerebral Ischemia

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