Activation of Akt/FoxO signaling pathway contributes to induction of neuroprotection against transient global cerebral ischemia by hypoxic pre-conditioning in adult rats.
It is well established that pre-conditioning protects neuronal injury against ischemia. However, the molecular mechanisms underlying ischemic tolerance are not completely understood. The purpose of the present study was to investigate the role of Akt/forkhead transcription factor, class O (FoxO) pathway in hypoxic pre-conditioning (HPC) using a newly developed HPC to transient global cerebral ischemia (tGCI) model in adult rats. HPC for 30-120 min significantly reduced cell death in the CA1 subregion after 10 min of tGCI. HPC was effective only when applied 1-4 days before ischemia. The maximum protection was observed with 30 min of hypoxia and 1 day interval between hypoxia and ischemia. The phosphorylated Akt and FoxOs measured by western blot and immunohistochemistry were significantly increased after hypoxia-ischemia except for a transient decrease in the HPC group. Lateral ventricular infusion of LY294002 before HPC blocked the increase in phosphorylated Akt and FoxOs and increased neuronal damage in HPC animals. These results suggest that pre-exposure to hypoxia induces protection against tGCI in adult rats. Activation of Akt results in the inactivation of FoxOs which may mediate ischemic tolerance after HPC.
Zhan
Lixuan
L
Institute of Neurosciences and the Second Affiliated Hospital of Guangzhou Medical College, Guangzhou, China.
Wang
Tao
T
Li
Wen
W
Xu
Zao C
ZC
Sun
Weiwen
W
Xu
En
E
D000818:Animals; D019610:Cytoprotection / Q000502:physiology*; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy*; D019194:Ischemic Preconditioning / Q000379:methods; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D000071161:Forkhead Box Protein O1
D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D051057:Proto-Oncogene Proteins c-akt; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1