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Sodium oligomannate activates the enteroendocrine-vagal afferent pathways in APP/PS1 mice

文献类型：期刊论文

作者Gong, Hua-shan4,5; Pan, Jing-pei2,3; Guo, Fei3; Wu, Mei-mei4,5; Dong, Li4,5; Li, Yang1,2,3; Rong, Wei-fang4,5
刊名ACTA PHARMACOLOGICA SINICA
出版日期2024-05-03
页码11
关键词sodium oligomannate gut-brain axis enteroendocrine cells vagus nerve sweet taste receptor TRPA1 channel
ISSN号1671-4083
DOI10.1038/s41401-024-01293-w
通讯作者Li, Yang(liyang@simm.ac.cn) ; Rong, Wei-fang(weifangrong@shsmu.edu.cn)
英文摘要Enteroendocrine cells (EECs) and vagal afferent neurons constitute functional sensory units of the gut, which have been implicated in bottom-up modulation of brain functions. Sodium oligomannate (GV-971) has been shown to improve cognitive functions in murine models of Alzheimer's disease (AD) and recently approved for the treatment of AD patients in China. In this study, we explored whether activation of the EECs-vagal afferent pathways was involved in the therapeutic effects of GV-971. We found that an enteroendocrine cell line RIN-14B displayed spontaneous calcium oscillations due to TRPA1-mediated calcium entry; perfusion of GV-971 (50, 100 mg/L) concentration-dependently enhanced the calcium oscillations in EECs. In ex vivo murine jejunum preparation, intraluminal infusion of GV-971 (500 mg/L) significantly increased the spontaneous and distension-induced discharge rate of the vagal afferent nerves. In wild-type mice, administration of GV-971 (100 mg kg-1 d-1, i.g. for 7 days) significantly elevated serum serotonin and CCK levels and increased jejunal afferent nerve activity. In 7-month-old APP/PS1 mice, administration of GV-971 for 12 weeks significantly increased jejunal afferent nerve activity and improved the cognitive deficits in behavioral tests. Sweet taste receptor inhibitor Lactisole (0.5 mM) and the TRPA1 channel blocker HC-030031 (10 mu M) negated the effects of GV-971 on calcium oscillations in RIN-14B cells as well as on jejunal afferent nerve activity. In APP/PS1 mice, co-administration of Lactisole (30 mg kg-1 d-1, i.g. for 12 weeks) attenuated the effects of GV-971 on serum serotonin and CCK levels, vagal afferent firing, and cognitive behaviors. We conclude that GV-971 activates sweet taste receptors and TRPA1, either directly or indirectly, to enhance calcium entry in enteroendocrine cells, resulting in increased CCK and 5-HT release and consequent increase of vagal afferent activity. GV-971 might activate the EECs-vagal afferent pathways to modulate cognitive functions.
WOS关键词VAGUS NERVE-STIMULATION ; ALZHEIMERS-DISEASE ; TASTE RECEPTOR ; GUT ; CELLS ; SWEET ; EXPRESSION ; TRPA1 ; MODEL ; PLASTICITY
资助项目National Natural Science Foundation of China[32171118] ; National Natural Science Foundation of China[82370565] ; National Natural Science Foundation of China[31671049] ; National Natural Science Foundation of China[31371066] ; National Key New Drug Creation Program of China[2018ZX09711002-002-012] ; Shanghai Municipal Science and Technology Major Project[184319071000] ; Shanghai Municipal Science and Technology Major Project[19140903102] ; Innovative Research Team of High-level Local Universities in Shanghai[SHSMU-ZDCX20211102]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001214079700002
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/310873]  
专题新药研究国家重点实验室
通讯作者Li, Yang; Rong, Wei-fang
作者单位1.Fudan Univ, Huashan Hosp, Natl Clin Res Ctr Aging & Med, Shanghai 200040, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Shanghai Jiao Tong Univ, Sch Med, Dept Anat & Physiol, Shanghai 200025, Peoples R China
5.Shanghai Jiao Tong Univ, Shanghai Songjiang Dist Cent Hosp, Songjiang Res Inst, Sch Med, Shanghai 201600, Peoples R China
推荐引用方式
GB/T 7714		 Gong, Hua-shan,Pan, Jing-pei,Guo, Fei,et al. Sodium oligomannate activates the enteroendocrine-vagal afferent pathways in APP/PS1 mice[J]. ACTA PHARMACOLOGICA SINICA,2024:11.
APA Gong, Hua-shan.,Pan, Jing-pei.,Guo, Fei.,Wu, Mei-mei.,Dong, Li.,...&Rong, Wei-fang.(2024).Sodium oligomannate activates the enteroendocrine-vagal afferent pathways in APP/PS1 mice.ACTA PHARMACOLOGICA SINICA,11.
MLA Gong, Hua-shan,et al."Sodium oligomannate activates the enteroendocrine-vagal afferent pathways in APP/PS1 mice".ACTA PHARMACOLOGICA SINICA (2024):11.

入库方式： OAI收割

来源：上海药物研究所

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