Download PDF
CC BY 4.0 · Chinese medicine and natural products 2024; 04(03): e126-e136
DOI: 10.1055/s-0044-1790290
Original Article

Effect of Suan Zao Ren (Semen Ziziphi Spinosae) Extract on the TXNIP/NLRP3 Pathway in Insomniac Rats

Zijing Xu
1   College of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
,
Wei Xiong
1   College of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
,
Qian Wang
1   College of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
,
Shuyu Li
1   College of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
,
Dexian Jia
1   College of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
› Author Affiliations Funding Research on the Mechanism of Suan Zao Ren's (SZS) Hypnotic Effect Based on TXNIP/NLRP3 Signaling Pathway (2023-ZXFZJJ-JW-071).
› Further Information
Also available at
   Permissions and Reprints

Abstract

Objectives This study aimed to investigate the therapeutic effects of Suan Zao Ren (Semen Ziziphi Spinosae, SZS) extract on insomnia induced by p-chlorophenylalanine (PCPA) in rats and its influence on the thioredoxin-interacting protein (TXNIP)/nucleotide-binding domain Leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3) inflammasome pathway, and to preliminarily explore the mechanism by which SZS extract improves insomnia.

Methods Fifty male Sprague–Dawley (SD) rats were used, with 8 rats in the blank group and 42 rats in the modeling group. The modeling group was induced by intraperitoneal injection of PCPA at a dose of 500 mg·kg−1 for six consecutive days, with daily cage exchange. After 6 days, 40 successfully modeled rats were randomly divided into five groups: the model group (equal volume of distilled water), the positive group (0.75 mg·kg−1), and low-, medium-, and high-dose SZS extract groups (1.5, 3, and 6 g·kg−1, respectively), with 8 rats in each group. Treatments were administered for seven consecutive days. Enzyme-linked immunosorbent assay was used to measure levels of 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (GABA) in the rat cerebral cortex. The thiobarbituric acid (TBA) method was used to determine malondialdehyde (MDA) levels, and the hydroxylamine method was used to determine superoxide dismutase (SOD) levels. The 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) method was used to measure total antioxidant capacity (TAOC) in the cerebral cortex. Pathological changes in the cerebral cortex were observed, and Western blot was used to detect the protein expressions of TXNIP, NLRP3, apoptosis-associated speck-like protein containing a Caspase activation and recruitment domain (CARD), and cysteine–aspartate-specific protease 1 (Caspase-1) in the cerebral cortex.

Results Compared with the blank group, the model group showed a significantly prolonged sleep latency (p < 0.001) and a significantly shortened sleep duration (p < 0.001). There were no changes in serum MDA and SOD levels. MDA levels in the cerebral cortex were significantly increased (p < 0.001), while SOD and TAOC levels were significantly decreased (p < 0.001). The 5-HT level was increased (p < 0.05), and the GABA level was significantly decreased (p < 0.001). SZS extract improved these conditions to varying degrees. Light microscopy showed no significant changes in cortical neurons but transmission electron microscopy revealed intact mitochondrial structures in the blank group, while the model group showed swollen and unclear mitochondria with reduced organelles. After 7 days of treatment, these conditions improved in the SZS extract groups. Compared with the blank group, the expressions of the four proteins in the model group were increased, and the expressions of these proteins were decreased in the SZS extract groups compared with the model group.

Conclusion SZS extract may exert an antioxidant effect to treat insomnia by downregulating the expression of TXNIP/NLRP3 proteins and regulating oxidative stress levels in the cerebral cortex.

Keywords

insomnia - Suan Zao Ren - TXNIP/NLRP3 - oxidative stress - sedative and hypnotic

CRediT Authorship Contribution Statement

Zijing Xu: data curation, formal analysis, validation, visualization, and writing—original draft. Wei Xiong: formal analysis and visualization. Qian Wang: conceptualization, methodology, resources, and writing—review and editing. Shuyu Li: resources and conceptualization. Dexian Jia: funding acquisition, conceptualization, project administration, supervision, and writing—review and editing.




Publication History

Received: 21 April 2024

Accepted: 29 June 2024

Article published online:
30 September 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Lucey BP, Hicks TJ, McLeland JS. et al. Effect of sleep on overnight cerebrospinal fluid amyloid β kinetics. Ann Neurol 2018; 83 (01) 197-204
    CrossrefPubMedSearch in Google Scholar
  • 2 Siriwardena AN, Apekey T, Tilling M, Dyas JV, Middleton H, Ørner R. General practitioners' preferences for managing insomnia and opportunities for reducing hypnotic prescribing. J Eval Clin Pract 2010; 16 (04) 731-737
    CrossrefPubMedSearch in Google Scholar
  • 3 Glass J, Lanctôt KL, Herrmann N, Sproule BA, Busto UE. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ 2005; 331 (7526): 1169
    CrossrefPubMedSearch in Google Scholar
  • 4 Lin ST, Qu ST. Clinical efficacy of integrated traditional Chinese and Western medicine in treating insomnia. Chin J Mod Drug App 2017; 11 (23) 129-130
    Search in Google Scholar
  • 5 Cunnington D, Junge MF, Fernando AT. Insomnia: prevalence, consequences and effective treatment. Med J Aust 2013; 199 (08) S36-S40
    PubMedSearch in Google Scholar
  • 6 De Crescenzo F, D'Alò GL, Ostinelli EG. et al. Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis. Lancet 2022; 400 (10347): 170-184
    CrossrefPubMedSearch in Google Scholar
  • 7 DeMartinis NA, Kamath J, Winokur A. New approaches for the treatment of sleep disorders. Adv Pharmacol 2009; 57: 187-235
    CrossrefPubMedSearch in Google Scholar
  • 8 Hood SD, Norman A, Hince DA, Melichar JK, Hulse GK. Benzodiazepine dependence and its treatment with low dose flumazenil. Br J Clin Pharmacol 2014; 77 (02) 285-294
    CrossrefPubMedSearch in Google Scholar
  • 9 Kales A, Scharf MB, Kales JD, Soldatos CR. Rebound insomnia. A potential hazard following withdrawal of certain benzodiazepines. JAMA 1979; 241 (16) 1692-1695
    CrossrefPubMedSearch in Google Scholar
  • 10 Zhang QQ, Liu P, Zhao JL. et al. Based on data mining, the medication rules for treating insomnia in the Dictionary of Traditional Chinese Medicine Formulas . World Sci Technol Modern Tradit Chin Med 2019; 21 (05) 923-930
    Search in Google Scholar
  • 11 Gulec M, Ozkol H, Selvi Y. et al. Oxidative stress in patients with primary insomnia. Prog Neuropsychopharmacol Biol Psychiatry 2012; 37 (02) 247-251
    CrossrefPubMedSearch in Google Scholar
  • 12 Liang B, Li YH, Kong H. Serum paraoxonase, arylesterase activities and oxidative status in patients with insomnia. Eur Rev Med Pharmacol Sci 2013; 17 (18) 2517-2522
    PubMedSearch in Google Scholar
  • 13 Singh A, Kukreti R, Saso L, Kukreti S. Oxidative stress: a key modulator in neurodegenerative diseases. Molecules 2019; 24 (08) 1583
    CrossrefPubMedSearch in Google Scholar
  • 14 Li HJ, Gao Y, Liu P. et al. Research progress on insomnia animal models. Zhongguo Yaolixue Tongbao 2007; 23 (04) 437-440
    Search in Google Scholar
  • 15 Liang CW, Cao Y, Li J. et al. Milk-derived sleep-inducing peptides with extracts of semen ziziphi spinosae and bulbus lilii improve sleep in rat models of insomnia. Mod Food Sci Techn 2021; 37 (09) 1-7
    Search in Google Scholar
  • 16 Si Y, Wang L, Lan J. et al. Lilium davidii extract alleviates p–chlorophenylalanine–induced insomnia in rats through modification of the hypothalamic-related neurotransmitters, melatonin and homeostasis of the hypothalamic-pituitary-adrenal axis. Pharm Biol 2020; 58 (01) 915-924
    CrossrefPubMedSearch in Google Scholar
  • 17 Wei XR, Zheng XN, Pei Y. et al. An improved method for the preparation of para-chlorobenzalanine suspension in a rat model of insomnia. J Hunan Univ Chin Med 2018; 38 (09) 986-989
    Search in Google Scholar
  • 18 Peng ZP, Liu WK, Guo Y. et al. A preliminary discussion on Professor Tong Xiaolin's medication strategy due to illness. World J Integr Tradit Wes Med 2012; 7 (05) 377-379
    Search in Google Scholar
  • 19 He QR, Li Y, Deng WZ. et al. Thioredoxin-interacting protein promotes renal fibrosis in mice by inducing oxidative stress. Acta Acad Med Mil Tert 2018; 40 (22) 2061-2067
    Search in Google Scholar
  • 20 Domingues A, Jolibois J, Marquet de Rougé P, Nivet-Antoine V. The emerging role of TXNIP in ischemic and cardiovascular diseases; A novel marker and therapeutic target. Int J Mol Sci 2021; 22 (04) 1693
    CrossrefPubMedSearch in Google Scholar