| First Author | Zhan S | Year | 2019 |
| Journal | J Cell Mol Med | Volume | 23 |
| Issue | 10 | Pages | 6822-6834 |
| PubMed ID | 31386303 | Mgi Jnum | J:295893 |
| Mgi Id | MGI:6455305 | Doi | 10.1111/jcmm.14566 |
| Citation | Zhan S, et al. (2019) Molecular mechanism of tumour necrosis factor alpha regulates hypocretin (orexin) expression, sleep and behaviour. J Cell Mol Med 23(10):6822-6834 |
| abstractText | Hypocretin 1 and hypocretin 2 (orexin A and B) regulate sleep, wakefulness and emotion. Tumour necrosis factor alpha (TNF-alpha) is an important neuroinflammation mediator. Here, we examined the effects of TNF-alpha treatment on hypocretin expression in vivo and behaviour in mice. TNF-alpha decreased hypocretin 1 and hypocretin 2 expression in a dose-dependent manner in cultured hypothalamic neurons. TNF-alpha decreased mRNA stability of prepro-hypocretin, the single precursor of hypocretin 1 and hypocretin 2. Mice challenged with TNF-alpha demonstrated decreased expression of prepro-hypocretin, hypocretin 1 and hypocretin 2 in hypothalamus. In response to TNF-alpha, prepro-hypocretin mRNA decay was increased in hypothalamus. TNF-alpha neutralizing antibody restored the expression of prepro-hypocretin, hypocretin 1 and hypocretin 2 in vivo in TNF-alpha challenged mice, supporting hypocretin system can be impaired by increased TNF-alpha through decreasing hypocretin expression. Repeated TNF-alpha challenge induced muscle activity during rapid eye movement sleep and sleep fragmentation, but decreased learning, cognition and memory in mice. TNF-alpha neutralizing antibody blocked the effects of TNF-alpha; in contrast, hypocretin receptor antagonist enhanced the effects of TNF-alpha. The data support that TNF-alpha 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. |
