Background: Brief transient global cerebral ischemia (bTGCI) displays ischemic preconditioning (IPC) and confers neuroprotection against subsequent severer ischemic insults by ischemic tolerance: its impact in subsequent severer ischemic insults under obese condition has not been fully addressed. We studied effects of obesity on neuronal damage/death in the hippocampus after bTGCI and its related mechanisms. Methods: Gerbils were maintained on high-fat diet (HFD) or normal diet (ND) for 12 weeks and subjected to bTGCI (2-min TGCI). 
Results: HFD gerbils were heavier and had higher blood glucose, serum total cholesterol and triglycerides levels. Massive loss of pyramidal neurons occurred in the CA1 filed of HFD animals 5 days after bTGCI, even though bTGCI showed neuroprotection in ND animals. The HFD group showed further increased levels of oxidative stress indicators (4-hydroxynonenal and dihydroethidium) and proinflammatory cytokines (tumor necrosis factor-alpha and interukin-1 beta) as well as microglia activation during pre- and/or post-ischemic phases. In addition, severely increased levels of mammalian target of rapamycin (mTOR) and phosphorylated-mTOR were observed in the CA1 field of the HFD group. On the other hand, the inhibition of mTOR activation by rapamycin (an allosteric mTOR inhibitor) significantly attenuated the HFD-induced neuronal death, showing the reduction of HFD-induced increases of oxidative stress indicators and proinflammatory cytokines as well as microglia activation. 
Conclusion: In brief, bTGCI evoked neuronal death under obese condition, which might be closely associated with abnormal increase of mTOR activation-mediated severe oxidative stress and neuroinflammation during pre- and/or post-ischemic phases.

4 - Ischemic Preconditioning does not Display Neuroprotection in High-fat Diet-induced Obese Gerbils but Rather Elicits Neuronal Death Through Increase of Abnormal mTOR Activation-mediated Oxidative Stress and Neuroinflammation