上海交通大学Wei-fang Rong等研究人员合作发现，低聚甘露酸钠可激活APP/PS1小鼠的肠内分泌-迷走神经传入通路。相关论文于2024年5月3日在线发表于国际学术期刊《中国药理学报》。

研究人员表示，肠内分泌细胞（EEC）和迷走神经传入神经元构成了肠道的功能性感觉单元，它们与自下而上地调节大脑功能有关。低聚甘露酸钠（GV-971）已被证明能改善阿尔茨海默病（AD）小鼠模型的认知功能，最近在中国被批准用于治疗AD患者。

研究人员探讨了肠内分泌-迷走神经传入通路的激活是否参与了GV-971的治疗作用。研究人员发现，肠内分泌细胞系RIN-14B在TRPA1介导的钙离子进入作用下表现出自发性钙振荡；灌注GV-971（50、100 mg/L）浓度依赖性地增强了肠内分泌细胞的钙振荡。在体外小鼠空肠制备中，腔内灌注GV-971（500 mg/L）可显著提高迷走传入神经的自发放电率和膨胀诱导放电率。在野生型小鼠体内注射GV-971（100 mg/kg每天，连续注射7天）可明显提高血清素和CCK水平，并增强空肠传入神经的活性。在7个月大的APP/PS1小鼠中，连续12周服用GV-971可明显提高空肠传入神经活性，并改善行为测试中的认知缺陷。

甜味受体抑制剂Lactisole（0.5 mM）和TRPA1通道阻断剂HC-030031（10 µM）可消除GV-971对RIN-14B细胞钙振荡以及空肠传入神经活动的影响。在APP/PS1小鼠中，联合给药Lactisole（30 mg/kg每天，静脉注射12周）可减轻GV-971对血清素和CCK水平、迷走神经传入发射和认知行为的影响。研究人员认为，GV-971可直接或间接激活甜味受体和TRPA1，从而增强肠内分泌细胞中的钙离子进入，导致CCK和5-HT释放增加，迷走神经传入活动随之增加。GV-971可能会激活 EEC-迷走神经传入通路，从而调节认知功能。

附：英文原文

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

Author: Gong, Hua-shan, Pan, Jing-pei, Guo, Fei, Wu, Mei-mei, Dong, Li, Li, Yang, Rong, Wei-fang

Issue&Volume: 2024-05-03

Abstract: 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, 100mg/L) concentration-dependently enhanced the calcium oscillations in EECs. In ex vivo murine jejunum preparation, intraluminal infusion of GV-971 (500mg/L) significantly increased the spontaneous and distension-induced discharge rate of the vagal afferent nerves. In wild-type mice, administration of GV-971 (100mg·kg1·d1, 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 (0.5mM) and the TRPA1 channel blocker HC-030031 (10μM) 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 (30mg·kg1·d1, 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.

DOI: 10.1038/s41401-024-01293-w

Source: https://www.nature.com/articles/s41401-024-01293-w