Low dose Hsp90 inhibitor 17AAG protects neural progenitor cells from ischemia induced death
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Stress adaptation effect provides cell protection against ischemia induced apoptosis. Whether this mechanism prevents other types of cell death in stroke is not well studied. This is an important question for regenerative medicine to treat stroke since other types of cell death such as necrosis are also prominent in the stroke brain apart from apoptosis. We report here that treatment with 17-N-Allylamino-17-demethoxygeldanamycin (17AAG), an Hsp90 inhibitor, protected neural progenitor cells (NPCs) against oxygen glucose deprivation (OGD) induced cell death in a dose dependent fashion. Cell death assays indicated that 17AAG not only ameliorated apoptosis, but also necrosis mediated by OGD. This NPC protection was confirmed by exposing cells to oxidative stress, a major stress signal prevalent in the stroke brain. Mechanistic studies demonstrated that 17AAG activated PI3K/Akt and MAPK cell protective pathways. More interestingly, these two pathways were activated in vivo by 17AAG and 17AAG treatment reduced infarct volume in a middle cerebral artery occlusion (MCAO) stroke model. These data suggest that 17AAG protects cells against major cell death pathways and thus might be used as a pharmacological conditioning agent for regenerative medicine for stroke.
KeywordsStress adaptation Hormesis Hsp90 17AAG Stroke Regenerative and reparative medicine Ischemia
neural progenitor cells
oxygen glucose deprivation
Remote ischemic preconditioning
middle cerebral artery occlusion
We are grateful to Dr. Weiguo Li, Dr. Quanguang Zhang, Dr. Jianghe Yuan, and Dong Han for technical assistance. We thank Dr. Lin Mei for institutional support. This project is partly supported by a Scientist Training Program award from Medical College of Georgia and partly by a Scientist Development Grant award from American Heart Association to GW.
Conflict of interest
The authors declare no conflict of interest.
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