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Molecular mechanism of tumour necrosis factor alpha regulates hypocretin (orexin) expression, sleep and behaviour

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机构： [1]Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China [2]Beijing Key Laboratory of Neuromodulation, Beijing, China [3]Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA [4]Neurology, University of Alabama at Birmingham, Birmingham, AL, USA

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关键词： Alzheimer hypocretin orexin Parkinson rapid eye movement sleep behaviour disorder TNF

摘要：

Hypocretin 1 and hypocretin 2 (orexin A and B) regulate sleep, wakefulness and emotion. Tumour necrosis factor alpha (TNF-α) is an important neuroinflammation mediator. Here, we examined the effects of TNF-α treatment on hypocretin expression in vivo and behaviour in mice. TNF-α decreased hypocretin 1 and hypocretin 2 expression in a dose-dependent manner in cultured hypothalamic neurons. TNF-α decreased mRNA stability of prepro-hypocretin, the single precursor of hypocretin 1 and hypocretin 2. Mice challenged with TNF-α demonstrated decreased expression of prepro-hypocretin, hypocretin 1 and hypocretin 2 in hypothalamus. In response to TNF-α, prepro-hypocretin mRNA decay was increased in hypothalamus. TNF-α neutralizing antibody restored the expression of prepro-hypocretin, hypocretin 1 and hypocretin 2 in vivo in TNF-α challenged mice, supporting hypocretin system can be impaired by increased TNF-α through decreasing hypocretin expression. Repeated TNF-α challenge induced muscle activity during rapid eye movement sleep and sleep fragmentation, but decreased learning, cognition and memory in mice. TNF-α neutralizing antibody blocked the effects of TNF-α; in contrast, hypocretin receptor antagonist enhanced the effects of TNF-α. The data support that TNF-α is involved in the regulation of hypocretin expression, sleep and cognition. The findings shed some lights on the role of neuroinflammation in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. © 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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出版当年[2018]版：

大类 | 2 区医学

小类 | 2 区医学：研究与实验 3 区细胞生物学

最新[2023]版：

大类 | 2 区

医学

小类 | 2 区医学：研究与实验 3 区细胞生物学

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出版当年[2017]版：

Q1 MEDICINE, RESEARCH & EXPERIMENTAL Q2 CELL BIOLOGY

最新[2023]版：

Q2 CELL BIOLOGY Q2 MEDICINE, RESEARCH & EXPERIMENTAL

影响因子： 4.3 最新[2023版] 5.1 最新五年平均 4.302 出版当年[2017版] 4.252 出版当年五年平均 4.499 出版前一年[2016版] 4.658 出版后一年[2018版]

第一作者：

第一作者机构： [1]Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China [2]Beijing Key Laboratory of Neuromodulation, Beijing, China

通讯作者：

通讯机构： [1]Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China [2]Beijing Key Laboratory of Neuromodulation, Beijing, China [3]Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

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