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

Acta Pharmacologica Sinica (2024)Cite this article

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, 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 µM) 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.

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Fig. 1: GV-971 enhanced Ca2+ oscillations in RIN-14B cells.
Fig. 2: GV-971 caused an increase of the vagal afferent nerve activity in the ex vivo jejunum preparation.
Fig. 3: Administration of GV-971 in vivo led to elevations of serum 5-HT and CCK levels and increases in jejunal afferent nerve activity in WT mice.
Fig. 4: Long-term treatment with GV-971 resulted in cognitive improvement and elevations of serum 5-HT and CCK levels and jejunal afferent nerve activity in APP/PS1 mice.
Fig. 5: Sweet taste receptor blocker Lactisole inhibited the effects of GV-971.
Fig. 6: Sweet taste receptor blocker Lactisole inhibited the effects of GV-971 in APP/PS1 mice.
Fig. 7: Schematic diagram of the mechanisms that may underlie the effects of sodium oligomannate (GV-971) on the enteroendocrine-vagal afferent pathways.

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Acknowledgements

We thank Dr. Tian-yu Li for helpful discussions. This work was supported by grants from National Natural Science Foundation of China (32171118, 82370565, 31671049, 31371066), the National Key New Drug Creation Program of China (2018ZX09711002-002-012), the Shanghai Municipal Science and Technology Major Project (184319071000 and 19140903102), and the Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20211102).

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Authors and Affiliations

  1. Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China

    Hua-shan Gong, Mei-mei Wu, Li Dong & Wei-fang Rong

  2. Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Hua-shan Gong, Mei-mei Wu, Li Dong & Wei-fang Rong

  3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Jing-pei Pan, Fei Guo & Yang Li

  4. University of Chinese Academy of Sciences, Beijing, 100049, China

    Jing-pei Pan & Yang Li

  5. National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Yang Li

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HSG, WFR, and YL designed the project. HSG, JPP, MMW, and LD performed experiments and analyzed data. FG assisted with behavioral experiments. HSG, YL, and WFR wrote the manuscript.

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Correspondence to Yang Li or Wei-fang Rong.

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Gong, Hs., Pan, Jp., Guo, F. et al. Sodium oligomannate activates the enteroendocrine-vagal afferent pathways in APP/PS1 mice. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01293-w

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