Abstract
The purpose of this study is to test the hypothesis that the mammalian target of rapamycin (mTOR) signaling pathway might mediate neuroprotection in a mouse model of septic encephalopathy and also to identify the role of autophagy. Mice were subjected to cecal ligation and puncture (CLP) or a sham operation, and all 50 mice were randomly assigned to five groups: sham, CLP+ saline, CLP+ rapamycin (1, 5, 10 mg/kg) groups. Two weeks after the operation, Morris water maze was conducted for behavioral test; Nissl staining was used for observing glia infiltration; immunohistochemical staining and biochemical measures in hippocampi were performed to detect mTOR targets and autophagy indicators. Immunochemistry revealed significant loss of neurons and increased glia infiltration in hippocampus after CLP operation. Inhibition of mTOR by rapamycin rescued cognitive deficits caused by sepsis (p < 0.05). Rapamycin did not affect total mTOR targets, while phosphorylated mTOR targets (p-mTOR-Ser2448, p-p70S6k-Thr389, p-AKT-S473) decreased (p < 0.05) and autophagy indicators (LC3-II, Atg5, Atg7) were increased, and P62 was decreased in rapamycin-treated CLP mice compared with the untreated (p < 0.05) in hippocampus. Rapamycin improves learning after sepsis through enhancing autophagy and may be a potentially effective therapeutic agent for the treatment of sepsis-induced cognitive impairment.
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Abbreviations
- mTOR:
-
Mammalian target of rapamycin
- CLP:
-
Cecal ligation and puncture
- KM mice:
-
Kunming mice
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Acknowledgements
The authors thank Ms. Lihong Wan for administrative assistance. We are also grateful to Mr. Shikun Miao for their help with excellent animal care. This work was supported by National Natural Science Foundation of China (Nos. 81301659 and 81401077).
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Liu, W., Guo, J., Mu, J. et al. Rapamycin Protects Sepsis-Induced Cognitive Impairment in Mouse Hippocampus by Enhancing Autophagy. Cell Mol Neurobiol 37, 1195–1205 (2017). https://doi.org/10.1007/s10571-016-0449-x
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DOI: https://doi.org/10.1007/s10571-016-0449-x