Sedative and hypnotic effects of Perilla frutescens essential oil through GABAergic system pathway

Yu, Zhen; Zheng, Qi; Hu, Peng-Yi; Huang, Xiaoying; Yang, Ming; Ren, Guilin; Li, Jing; Du, Qing; Liu, Shanshan; Zhang, Kenan; Wu, Ling; Zhu, Li; Guo, Yuanyuan; Li, Wenjing; Xiao, Shuai; Shuai, Shuyuan; Zhang, Mingxia

doi:10.1016/j.jep.2020.113627

Cited by 21 publications

(13 citation statements)

References 28 publications

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“…In addition, 5-HT 1A (HTR1A) and 5-HT 2A (HTR2A) have been identified as common targets for the treatment of insomnia, in both clinical and basic studies (Jiang et al, 2016;Ohno et al, 2018;Shao et al, 2020;Lv et al, 2021), as well as prevenient studies of ZSS for the treatment of insomnia (Shen et al, 2020). GABA A Rα1 (GABRA1) and GABA A Rγ2 (GABRG2) are two significant subunits of GABA receptors, and are known to play an important role in the first line treatment of insomnia (Zhong et al, 2020;Lv et al, 2021). Based on our preliminary results, we preferentially selected HTR1A, HTR2A, GABRA1, and GABRG2, as potential therapeutic targets of ZSS for further experimental validation.…”

Section: Go and Kegg Pathway Enrichment Analysismentioning

confidence: 99%

Mechanisms Underlying the Action of Ziziphi Spinosae Semen in the Treatment of Insomnia: A Study Involving Network Pharmacology and Experimental Validation

et al. 2021

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Purpose: This study aimed to investigate the potential mechanisms and related bioactive components of ZSS for the treatment of insomnia.Method: The insomnia model of rat induced by PCPA was established. After oral administration of ZSS extract, the general morphological observation, pentobarbital sodium-induced sleep test and histopathological evaluation were carried out. Network pharmacology, assisted by UHPLC-Q-Exactive-MS/MS analysis, was developed to identify the targets of ZSS in the treatment of insomnia, as well as the corresponding signaling pathways. In addition, we validated the identified targets and pathways by RT-qPCR and immunohistochemical analysis.Results: The pentobarbital sodium-induced sleep test, determination of 5-HT and GABA levles in hypothalamic tissues and HE staining showed that ZSS extract was an effective treatment for insomnia. Network pharmacology analysis identified a total of 19 candidate bioactive ingredients in ZSS extract, along with 433 potentially related targets. Next, we performed protein-protein interaction (PPI), MCODE clustering analysis, GO functional enrichment analysis, KEGG pathway enrichment analysis, and ingredient-target-pathway (I-T-P) sub-networks analysis. These methods allowed us to investigate the synergistic therapeutic effects of crucial pathways, including the serotonergic and GABAergic synapse pathways. Our analyses revealed that palmitic acid, coclaurine, jujuboside A, N-nornuciferine, caaverine, magnoflorine, jujuboside B, and betulinic acid, all played key roles in the regulation of these crucial pathways. Finally, we used the PCPA-induced insomnia in rats to validate the data generated by network pharmacology; these in vivo experiments clearly showed that pathways associated with the serotonergic and GABAergic system were activated in the rats model. Furthermore, ZSS treatment significantly suppressed high levels of HTR1A, GABRA1, and GABRG2 expression in the hypothalamus and reduced the expression levels of HTR2A.Conclusion: Based on the combination of comprehensive network pharmacology and in vivo experiments, we successfully identified the potential pharmacological mechanisms underlying the action of ZSS in the treatment of insomnia. The results provide a theoretical basis for further development and utilization of ZSS, and also provide support for the development of innovative drugs for the treatment of insomnia.

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Section: Go and Kegg Pathway Enrichment Analysismentioning

confidence: 99%

Mechanisms Underlying the Action of Ziziphi Spinosae Semen in the Treatment of Insomnia: A Study Involving Network Pharmacology and Experimental Validation

et al. 2021

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“…Based on the proportional correlation between the frequency of animal locomotor activity and cerebral cortical activity, the locomotor test aims to evaluate the effect of drugs on central excitability by investigating the decrease or increase of autonomous activity of mice using instruments [15] . In the threshold dose of pentobarbital sodium‐induced sleep test, the effect of drugs on the sleep quality of mice is observed by examining the sleep latency and sleep duration of mice treated with a threshold dose of pentobarbital sodium [16] …”

Section: Resultsmentioning

confidence: 99%

“…[15] In the threshold dose of pentobarbital sodium-induced sleep test, the effect of drugs on the sleep quality of mice is observed by examining the sleep latency and sleep duration of mice treated with a threshold dose of pentobarbital sodium. [16] Compared with those in the control group, the number of locomotor activity of mice was significantly downregulated (p < 0.01) by intragastrical administration of ESO (80 mg/kg) and diazepam (DZP, 1.5 mg/kg) (Figure 1A), suggesting that ESO exerts suppressive effects towards the cerebral cortical activity of mice. Meanwhile, the ESO and DZP displayed a significantly positive effect on the sodium pentobarbital-induced sleep of mice, including shortening the sleep latency (p < 0.01, p < 0.001) and prolonging the following sleeping time (p < 0.001) (Figures 1B and 1C).…”

Section: Eso Displayed Sedative Effects In Micementioning

confidence: 93%

The Ethanol Extract of Syringa oblata Heartwood, a Mongolian Folk Medicine Containing Major Lignans, Exerts Analgesic and Sedative Effects on Mice

Chai

Tai

et al. 2022

Chemistry & Biodiversity

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The heartwood of Syringa oblata Lindl. (SO) is one of Mongolian folk medicines to treat insomnia and pain, while its pharmacological evaluation and underlying mechanism remain unclear. In this study, the sedative effect of ethanol extract of SO (ESO) was evaluated with the locomotor activity test and the threshold dose of pentobarbital sodium-induced sleep test in mice, and the hot plate test, acetic acid-induced writhing test, and formalin test in mice were used to evaluate its analgesic effect. The underlying mechanism of ESO analgesia was explored by RT-PCR and western blot analysis, which is associated with the regulation of the NF-кB signaling pathway. Besides, the main constituents of ESO were characterized by LC/MS data analysis and comparison with isolated pure compounds. The current findings brought evidence for clinical application and further pharmacological and phytochemical studies on SO.

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“…The GABAA receptor is commonly used in the study of insomnia, and the A receptors play further roles as the GABAARα1 receptors ( Liu et al, 2011 ). Studies have shown that the content of GABA can be reduced in the hypothalamus and cerebral cortex, as can the expression of GABAAα1 positive cells in PCPA insomniac rats ( Zhong et al, 2021 ). Shen et al (2020) found that the content of GAD65 can be reduced in the brain of PCPA insomniac rats.…”

Section: Discussionmentioning

confidence: 99%

Effects of the Radix Ginseng and Semen Ziziphi Spinosae drug pair on the GLU/GABA-GLN metabolic cycle and the intestinal microflora of insomniac rats based on the brain–gut axis

et al. 2022

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Introduction: To explore the mechanism of action of appling Radix Ginseng and Semen Ziziphi Spinosae Drug pair (R-S) in the treatment of insomnia by investigating the effect of R-S on GLU/GABA-GLN metabolic cycle and intestinal microflora of rats with insomnia.Methods: Rats were intraperitoneally injected with 4-chloro-DL-phenylalanine (PCPA) to make sleep deprivation (SD) models. The rats were divided into 6 groups, with 8 rats in each group. The general status of the rats was observed and the pentobarbital sodium sleep synergy experiment was performed. The contents of GABA, GLU, GLN, GAD65, and GS in hippocampus of rats were determined by ELISA. The expressions of GABAARα1mRNA, mGluR5mRNA, NR1mRNA and GluR1mRNA in rats’ hippocampal tissue were determined by Realtime PCR. 16SrRNA gene sequencing was used to analyze the intestinal microflora of insomnia rats.Results: In PCPA-induced insomnia rats, the state of insomnia was relieved, the sleep rate was improved, the duration of sleep latency was shortened and the sleep duration was prolonged in each dose group of R-S (p < 0.05, p < 0.01) compared with the model group. The contents of GABA, GLN, GAD65 and GS were increased (p < 0.05, p < 0.01) while GLU content was decreased (p < 0.01) in both medium and high dose groups, especially in the high dose group. The expression of GABAARα1mRNA was increased (p < 0.01), and the expressions of mGluR5mRNA, NR1mRNA and GluR1mRNA were decreased (p < 0.01) in hippocampal tissue of rats in R-S groups, especially in the high dose group. At the same time, the various dose groups of R-S could improve the species diversity, microflora abundance of insomnia rats and regulate the KEGG metabolic pathway related to sleep.Discussion: R-S can improve the sleep of PCPA-induced insomnia rats by regulating GLU/GABA-GLN metabolic cycle and intestinal microflora, which provides experimental basis for appling R-S in the treatment of insomnia.

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Sedative and hypnotic effects of Perilla frutescens essential oil through GABAergic system pathway

Cited by 21 publications

References 28 publications

Mechanisms Underlying the Action of Ziziphi Spinosae Semen in the Treatment of Insomnia: A Study Involving Network Pharmacology and Experimental Validation

Mechanisms Underlying the Action of Ziziphi Spinosae Semen in the Treatment of Insomnia: A Study Involving Network Pharmacology and Experimental Validation

The Ethanol Extract of Syringa oblata Heartwood, a Mongolian Folk Medicine Containing Major Lignans, Exerts Analgesic and Sedative Effects on Mice

Effects of the Radix Ginseng and Semen Ziziphi Spinosae drug pair on the GLU/GABA-GLN metabolic cycle and the intestinal microflora of insomniac rats based on the brain–gut axis

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