Journal
NEUROSCIENCE
Volume 419, Issue -, Pages 83-99Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2019.09.020
Keywords
Dexamethasone; Autophagy; Sepsis; Neurons; mTOR; Apoptosis
Categories
Funding
- National Key R&D Programme of China [2017YFA0104201, 2017YFA0104200]
- National Science Foundation of China [81330016, 81630038, 81771634, 81971433, 81971428, 81842011]
- Science and Technology Bureau of Chengdu City [2015-HM01-00424-SF]
- Ministry of Education of China [IRT0935]
- Science and Technology Project of Sichuan Province [2016TD0002]
- National Key Project of Neonatal Children [1311200003303]
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Studies have shown that a certain dose of dexamethasone can improve the survival rate of patients with sepsis, and in sepsis associated encephalopathy (SAE), autophagy plays a regulatory role in brain function. Here, we proved for the first time that small-dose dexamethasone (SdDex) can regulate the autophagy of cerebral cortex neurons in SAE rats and plays a protective role. Cortical neurons were cultured in vitro in a septic microenvironment and a sepsis rat model was established. The small-dose dexamethasone (SdDex) or high-dose dexamethasone (HdDex) was used to intervene in neurons or SAE rats. Through fluorescence microscopy and western blot analysis, the expressions of microtubule-associated protein 1 light chain 3 (LC3), p62/sequestosomel (p62/SQSTMI), mammalian target of rapamycin (mTOR) signaling pathway related proteins, and apoptosis-related proteins were detected. The results show that compared with those in SAE rats, the cortical pathological changes in SAE rats treated with SdDex were improved, and damaged substances were encapsulated and degraded by autophagosomes in neurons. Additionally, similar to neurons in vitro, cortical autophagy was further activated and the mTOR signaling pathway was inhibited. After HdDex treatment, the mTOR signaling pathway in cortex is inhibited, but further activation of autophagy is not obvious, the cortical pathological changes were further worsened and the ultrastructure of neurons was disturbed. Furthermore, the HdDex group exhibited the most obvious apoptosis. SdDex can regulate autophagy of cortical neurons by inhibiting the mTOR signaling pathway and plays a protective role. Brain damage induced by HdDex may be related to the activation of apoptosis. (C) 2019 The Author(s). Published by Elsevier Ltd on behalf of IBRO.
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