期刊
EXPERIMENTAL NEUROLOGY
卷 279, 期 -, 页码 223-231出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2016.03.011
关键词
Brain damage; Hypoxia-ischemia; MLKL; Neonate; Neuron
资金
- Major State Basic Research Development Program [2013CB967404]
- National Science Foundation of China [81330016, 81270724]
- Ministry of Education of China [313037, IRT0935]
- State Commission of Science Technology of China [2012BAI04B04]
- Science and Technology Bureau of Sichuan province [2014SZ0149]
- Ministry of Health of China [1311200003303]
Mixed lineage kinase domain-like protein (MLKL) is a critical molecule mediating cell necroptosis. However, its role in brain injury remains obscure. We first investigated the functions and mechanisms of MLKL in mediating neuronal damage in developing brain after hypoxia-ischemia. Neuronal necroptosis was induced by oxygen glucose deprivation (OGD) plus caspase inhibitor zVAD treatment (OGD/zVAD). We found that two important necroptosis related proteins, receptor-interacting protein 1 and 3 (RIP1, RIP3) were upregulated. Furthermore, the interaction of RIP1-RIP3 with MLKL increased. Inhibition of MLKL through siRNA diminished RIP1-RIP3-MLKL interaction and attenuated neuronal death induced by OGD/zVAD. The translocation of oligomerized MLKL to the neuronal membrane leading to the injury of cellular membrane is the possible new mechanism of neuronal necroptosis. Animal experiment with neonatal rats further proved that MLKL inhibition attenuated brain damage induced by hypoxia-ischemia. These findings suggest that MLKL is a target to attenuate brain damage in developing brain. (C) 2016 Elsevier Inc All rights reserved.
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