Nelumbo nucifera promotes non-rapid eye movement sleep by regulating GABAergic receptors in rat model (2024)

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Article preview Journal of Ethnopharmacology Abstract Ethnopharmacological relevance Aim of the study Materials and methods Results Conclusion Graphical abstract Introduction Section snippets Plant material and preparation of extracts Analysis of GABA, tryptophan, quinidine, and neferine Chemical composition of lotus extract Discussion Conclusion Author's contributions Declaration of competing interest Acknowledgments References (34) Curr. Biol. Food Chem. Phytomedicine Eur. Neuropsychopharmacol Sleep Med. Rev. Neuropharmacology Trends Neurosci. Methods J. Ethnopharmacol. J. Pharmaceut. Biomed. Anal. Involvement of 5-HT1A receptors in homeostatic and stress-induced adaptive regulations of paradoxical sleep: studies in 5-HT1A knock-out mice J. Neurosci. Sleep and circadian rhythm disturbance in bipolar disorder Psychol. Med. Interactions between traditional Chinese medicines and Western therapeutics Curr. Opin. Drug Disc. Neuropharmacological screening of ethanolic extract of Nelumbo nucifera Gaertner seeds IJRPB Low tryptophan and protein in the diet during development increase the susceptibility to convulsions in adult rats Neurochem. Res. Neurobehavioral effects and biomarkers of sleep loss in healthy adults Curr. Neurol. Neurosci. Rep. Cited by (5) Sleep-promoting activity of lotus (Nelumbo nucifera) rhizome water extract via GABA<inf>A</inf> receptors Effects of green lettuce leaf extract on sleep disturbance control in oxidative stress-induced invertebrate and vertebrate models Quercetin-3-o-glucuronide in the ethanol extract of lotus leaf (Nelumbo nucifera) enhances sleep quantity and quality in a rodent model via a gabaergic mechanism Effect of Black Pepper (Piper nigrum) Extract on Caffeine-Induced Sleep Disruption and Excitation in Mice Recommended articles (6)
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Journal of Ethnopharmacology

Volume 267,

1 March 2021

, 113511

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Abstract

Ethnopharmacological relevance

Nelumbo nucifera are used in folk medicine for anti-depressant, anti-convulsant, neuroprotective, and many other purposes.

Aim of the study

The present work evaluated the sleep potentiating effects of water extract from lotus seed in rat, and the neuropharmacological mechanisms underlying these effects.

Materials and methods

Pentobarbital-induced sleep test and electroencephalogram (EEG) analysis were applied to investigate sleep latency, duration, total sleeping time and sleep quality of Lotus extract. In addition, real-time PCR and HPLC analysis were applied to analyze the signaling pathway.

Results

We found that the amounts of the possible active compounds GABA (2.33mg/g) and L-tryptophan (2.00mg/g) were higher than quinidine (0.55mg/g) and neferine (0.16mg/g) in lotus seed extract. High dose (160mg/kg) administration of lotus extract led to a tendency towards decreased sleep latency time and an increase in sleep duration time compared to the control group in a pentobarbital-induced sleep model (p<0.05). After high dose administration, total sleep and NREM were significantly increased compared to control, while wake time and REM were significantly decreased. Lotus extract-treated rats showed significantly reduced wake time and increased sleep time in a caffeine-induced model of arousal. The transcription level of GABAA receptor, GABAB receptor, and serotonin receptor tended to increase with dose, and lotus extract showed a strong dose-dependent binding capacity to the GABAA receptor.

Conclusion

The above results strongly suggest that GABA contained in lotus seed extract acts as a sleep potentiating compound, and that sleep-potentiating activity involves GABAA receptor binding.

Introduction

Sleep disorders are common in modern society and are associated with considerable economic costs along with psychological and social disruption, which can lead to reduced quality of life (Ong et al., 2017). Sleep disorders have long been treated with herbal medicines (Bardley et al., 2017). Indeed, herbal supplements and complementary and alternative medicine (CAM) therapies have widespread use among people suffering from psychological disorders, including sleep disorder. Thus, interest in more effective and safe herbal medicines has increased in recent years. In CAM practice, several herbal medicines and supplements have been applied to treat sleep disorders or anxiety (Palmieri et al., 2017; Sarris and Mcintyre, 2017). Although these herbal remedies are often considered effective and well-tolerated, there is a lack of research into their pharmacological mechanisms.

Lotus (Nelumbo nucifera Gaertn.) is a perennial aquatic herbal plant that has long been widely used in Oriental medicine. Almost all parts of lotus, such as flowers, leaves, leaf stalks, seeds, and rhizomes, are utilized for broad purposes. For example, lotus leaves are used both in traditional cuisine and in herbal medicine. In southeastern Asia, the lotus seed and lotus root are popular foods, and lotus leaf in particular is a common ingredient in traditional Korean foods (Ryu et al., 2017). In particular, the embryo, part of the lotus seeds, is used in a traditional Chinese drug called ‘Lian Zi Xin’, which mainly helps to treat neurological disorders, insomnia, high fever and cardiovascular diseases (Chen et al., 2007).

In Chinese traditional medicine, lotus seeds have been reported to exhibit effective anti-depressant effects on the central nervous system (CNS), such as sedation (Sugimoto et al., 2008). Our previous study revealed that the hot water extract of lotus seed played an active role in sleep promotion through GABAergic system in the Drosophila melanogaster model (Jo et al., 2018). In addition, in the study of Chowdary S (2013), neuropharmacological activity of ethanol extract of Nelumbo nucifera Gaertner seeds was evaluated in mice and rats. Nelumbo nucifera seeds increase phenobarbitone-induced sleep time and have confirmed anxiolytic action through light-dark model transitions and elevated zero maze test. The major active ingredients present in the seeds are alkaloids, such as neferine and quinidine (Sugimoto et al., 2008; Li et al., 1990). In addition, many studies have shown that flavonoids found in lotus have diverse neuropharmacological activities, including sedative, anticonvulsant, antidepressive, and neuroprotective effects (Hinton et al., 2017; Liu et al., 2015). However, the sleep potentiating activity of lotus derivatives and related putative mechanisms of action have not yet been reported.

The present work was undertaken to evaluate the sleep potentiating effects of a single and 7-day multiple oral dose of water extract from lotus rhizome in rat. Additionally, possible neuropharmacological effects on the GABAergic and monoaminergic systems were investigated to clarify the mechanism of pharmacological activity.

Section snippets

Plant material and preparation of extracts

N. nucifera seed (100g) was extracted with 700mL distilled water at 80°C for 2h. This process was repeated for 1h with fresh distilled water, and the combined aqueous extracts were then filtered, concentrated by vaporization under reduced pressure at 60°C in a rotary evaporator (R-100, BUCHI Labortechnik AG, Flawil, Switzerland), freeze-dried, and stored at 4°C.

Analysis of GABA, tryptophan, quinidine, and neferine

GABA, tryptophan, quinidine, and neferine from Nelumbo nucifera seeds water extract (NNE) were analyzed by HPLC. GABA was detected

Chemical composition of lotus extract

Water extraction was used to remove lipid soluble compounds and to obtain hydrophilic functional compounds, such as certain alkaloids and polar phenolic content, from lotus seed. Total sugar, polyphenols, and flavonoids contents of lotus extract were 501.18, 99.44, and 7.16mg/g of extract, respectively (Data were not showed). Table 1 shows the content of the expected active compounds with GABA, L-tryptophan, quinidine and neferine being the expected active compounds. Among the suspected active

Discussion

Recently, the demand for traditional Chinese herbal medicine, and dietary supplements (particularly supplements used for medicinal or therapeutic purposes) has dramatically increased in Asian, North American, and European countries (Chan et al., 2010). Although adequate symptomatic relief is achieved with currently available drugs, these drugs have limited benefits and side effects that negatively affect the quality of life of users. Thus, in recent years, there has been growing attention

Conclusion

The above results strongly suggest that GABA is one of the lotus seed sleep-potentiating compounds, as further indicated by lotus seed sleep-potentiating activity being mediated through GABAA receptor binding. However, the extract dose-dependently increased expression of GABAA-R2, GABAB-R1, and 5-HT1A receptor mRNA, and thus sleep enhancement may operate through receptors in addition to the GABAA receptor. Therefore, mechanisms involving binding with receptors other than the GABAA receptor

Author's contributions

Conceptualization: HJS. Data curation: KJ. Formal analysis: KJ, SK. Methodology: KJ, KBH. Software: KBH. Validation: KJ. Investigation: HJS. Writing - original draft: KJ, HJS. Writing - review & editing: JK, SK, KBH, HJS. All authors read and approved the final manuscript.

Declaration of competing interest

The authors declare no conflicts of interest.

Acknowledgments

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2018R1D1A1B07046771).

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    Nelumbo nucifera promotes non-rapid eye movement sleep by regulating GABAergic receptors in rat model (2024)
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