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The Hypnotic Effect of Spinosin Is Mediated by Adenosine A<sub>2A</sub> Receptors in Male Mice.

Overview

Authors: Jianping Zhang1, Haimin Zhang1, Wenrui Zhao1, Lin Li2, Lisheng Chu2
ORCID iDs: Lisheng Chu
  1. Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; (J.Z.); (H.Z.); (W.Z.)
  2. Department of Physiology, School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
Institutions: Zhejiang Chinese Medical University (China)
Journal: Nutrients, volume 18, issue 11, article 1785
Dates: received 22 April 2026; accepted 29 May 2026; published online 1 June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.3390/nu18111785 · PMID 42280428 · PMCID PMC13258738 · OpenAlex W7163075063
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: mouse (organism), sleep disorders (population), cellular / molecular (subfield)
Methods: Statistics, Preprocessing, Physiology & signal measures
Keywords: spinosin, caffeine, adenosine A2A receptor, sleep, wakefulness
MeSH: Hypnotics and Sedatives*, Receptor, Adenosine A2A*, Animals, Caffeine, Diazepam, Flavonoids, gamma-Aminobutyric Acid, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Docking Simulation, Orexins, Sleep, Sleep Initiation and Maintenance Disorders (* major topic)
Topic: Ziziphus Jujuba Studies and Applications (Food Science, Agricultural and Biological Sciences), according to OpenAlex
Funding: National Natural Science Foundation of China (82074146); Zhejiang Province Natural Science Foundation (ZCLMS25H2901)
Citations: not cited yet (Europe PMC); 78 references in the paper

Abstract

Background/Objectives: Insomnia is a prevalent clinical sleep disorder, with existing hypnotic therapies limited by safety concerns. There is an urgent clinical need for new safe, effective sleep-promoting candidates derived from natural products. Spinosin is one of the main active components of Semen Ziziphi Spinosae that exerts sedative and hypnotic effects. The adenosine receptor (AR) has been reported as a potential therapeutic target for insomnia; however, the hypnotic effect of spinosin through the A2AR remains to be elucidated. Methods: In the study, the involvement of A2ARs in spinosin’s hypnotic effect was investigated using caffeine and further elucidated in A2AR-knockout (KO) mice. Diazepam was used as a positive control drug to validate the experimental model and evaluate the hypnotic effect of spinosin. Molecular docking and molecular dynamics (MDs) simulations were performed to validate the interaction of spinosin with the A2AR. Results: The hypnotic effects of spinosin were effectively antagonized by caffeine. Compared with A2AR-wild-type (WT) mice, spinosin-induced non-rapid eye movement (NREM) sleep and locomotor activity diminution were significantly reduced in A2AR-KO mice. Spinosin significantly increased the activity of γ-aminobutyric acid (GABA)ergic medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and significantly decreased the activity of orexin neurons in the lateral hypothalamus (LH), as revealed by c-Fos immunostaining. These effects were significantly reversed by caffeine pretreatment or in A2AR-KO mice. Finally, the results of molecular docking showed that spinosin had a good binding potential with the A2AR. MD simulations further demonstrated that spinosin had strong binding stability with the A2AR. Conclusions: Our findings strongly suggest that spinosin exerts the hypnotic effects through the A2AR, and thus may have therapeutic potential for insomnia. Our identification of spinosin’s direct molecular target supports its translational potential as a novel natural-origin candidate for clinical insomnia drug development.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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Data Availability Statement

The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 5 keywords, 15 MeSH terms, 2 funders, 78 references.

Cite

This paper

Zhang, J., Zhang, H., Zhao, W., Li, L., & Chu, L. (2026). The Hypnotic Effect of Spinosin Is Mediated by Adenosine A<sub>2A</sub> Receptors in Male Mice. Nutrients, 18(11), 1785. https://doi.org/10.3390/nu18111785

BibTeX

@article{zhang2026hypnotic,
author = {Zhang, Jianping and Zhang, Haimin and Zhao, Wenrui and Li, Lin and Chu, Lisheng},
title = {{The Hypnotic Effect of Spinosin Is Mediated by Adenosine A\<sub\>2A\</sub\> Receptors in Male Mice}},
journal = {Nutrients},
year = {2026},
month = jun,
volume = {18},
number = {11},
pages = {1785},
publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},
issn = {2072-6643},
doi = {10.3390/nu18111785},
url = {https://doi.org/10.3390/nu18111785},
pmid = {42280428},
pmcid = {PMC13258738}
}

RIS

TY - JOUR
AU - Zhang, Jianping
AU - Zhang, Haimin
AU - Zhao, Wenrui
AU - Li, Lin
AU - Chu, Lisheng
TI - The Hypnotic Effect of Spinosin Is Mediated by Adenosine A<sub>2A</sub> Receptors in Male Mice
T2 - Nutrients
J2 - Nutrients
PY - 2026
DA - 2026/06/01
VL - 18
IS - 11
SP - 1785
SN - 2072-6643
PB - Multidisciplinary Digital Publishing Institute (MDPI)
DO - 10.3390/nu18111785
UR - https://doi.org/10.3390/nu18111785
LA - en
ER -

CSL-JSON

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