{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T13:46:25Z","timestamp":1765547185090,"version":"build-2065373602"},"reference-count":55,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T00:00:00Z","timestamp":1701820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003712","name":"Korea Food Research Institute","doi-asserted-by":"publisher","award":["E0210201-03"],"award-info":[{"award-number":["E0210201-03"]}],"id":[{"id":"10.13039\/501100003712","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Aralia continentalis exhibits various biological activities; however, their sleep-promoting effects have not been previously reported. In this study, we evaluated the hypnotic effects and sleep\u2013wake profiles of A. continentalis root (KS-126) using a pentobarbital-induced sleep-acceleration test and polysomnographic recordings. Additionally, we investigated the molecular mechanism of KS-126 through patch-clamp electrophysiology. Our polysomnographic recordings revealed that KS-126 not only accelerated the onset of non-rapid eye movement sleep (NREMS) but also extends its duration. Considering the temporal dynamics of the sleep\u2013wake stages, during the initial and subsequent periods KS-126 extended NREMS duration and decreased wakefulness, thereby enhancing sleep-promoting effects. Furthermore, the assessment of sleep quality via analysis of electroencephalogram power density indicated that KS-126 did not significantly alter sleep intensity. Finally, we found that KS-126 enhanced GABAA receptor-mediated synaptic responses in primary hippocampal neurons, leading to an increase in the percentage of the GABA current. This effect was not affected by the selective benzodiazepine receptor antagonist flumazenil, but was entirely inhibited by the GABAA receptor antagonist bicuculline. In conclusion, KS-126 extends the duration of NREMS without altering its intensity by prolonging GABAergic synaptic transmission, which modulates GABAA receptor function.<\/jats:p>","DOI":"10.3390\/nu15245020","type":"journal-article","created":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T03:48:41Z","timestamp":1701834521000},"page":"5020","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Aralia continentalis Root Enhances Non-Rapid Eye Movement Sleep by Activating GABAA Receptors"],"prefix":"10.3390","volume":"15","author":[{"given":"Minseok","family":"Yoon","sequence":"first","affiliation":[{"name":"Division of Functional Food Research, Korea Food Research Institute, Wanju-gun 55365, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2386-8414","authenticated-orcid":false,"given":"Dong Wook","family":"Lim","sequence":"additional","affiliation":[{"name":"Division of Functional Food Research, Korea Food Research Institute, Wanju-gun 55365, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonghoon","family":"Jung","sequence":"additional","affiliation":[{"name":"Division of Functional Food Research, Korea Food Research Institute, Wanju-gun 55365, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Young Sung","family":"Jung","sequence":"additional","affiliation":[{"name":"Division of Functional Food Research, Korea Food Research Institute, Wanju-gun 55365, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1039-1434","authenticated-orcid":false,"given":"Changho","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Functional Food Research, Korea Food Research Institute, Wanju-gun 55365, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8448-8837","authenticated-orcid":false,"given":"Min Young","family":"Um","sequence":"additional","affiliation":[{"name":"Division of Functional Food Research, Korea Food Research Institute, Wanju-gun 55365, Republic of Korea"},{"name":"Division of Food Biotechnology, University of Science & Technology, Daejeon 34113, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"zsz279","DOI":"10.1093\/sleep\/zsz279","article-title":"From sleep medicine to medicine during sleep: A new paradigm","volume":"43","author":"Behar","year":"2020","journal-title":"Sleep"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1053\/smrv.2002.0186","article-title":"Epidemiology of insomnia: What we know and what we still need to learn","volume":"6","author":"Ohayon","year":"2002","journal-title":"Sleep Med. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1007\/s11920-013-0418-8","article-title":"Insomnia and its Impact on Physical and Mental Health","volume":"15","author":"Vgontzas","year":"2013","journal-title":"Curr. Psychiatry Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1007\/s11606-007-0251-z","article-title":"The efficacy and safety of drug treatments for chronic insomnia in adults: A meta-analysis of RCTs","volume":"22","author":"Buscemi","year":"2007","journal-title":"J. Gen. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1177\/0269881113503509","article-title":"Benzodiazepines: Risks and benefits. A reconsideration","volume":"27","author":"Baldwin","year":"2013","journal-title":"J. Psychopharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1016\/j.sleep.2008.10.009","article-title":"The use of natural products for sleep: A common practice?","volume":"10","author":"Belanger","year":"2009","journal-title":"Sleep Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1002\/ptr.6019","article-title":"Phlorotannin supplement decreases wake after sleep onset in adults with self-reported sleep disturbance: A randomized, controlled, double-blind clinical and polysomnographic study","volume":"32","author":"Um","year":"2018","journal-title":"Phytother. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1080\/14786410701192827","article-title":"Comparison of the sedative and hypnotic effects of flavonoids, saponins, and polysaccharides extracted from Semen Ziziphus jujube","volume":"21","author":"Jiang","year":"2007","journal-title":"Nat. Prod. Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Wang, M.Y., Liu, J.L., Sun, W., Li, N., Yu, Z.P., Zhu, K., Gao, J.Q., Wang, C.M., Sun, J.H., and Chen, J.G. (2019). Schisantherin A Exerts Sedative and Hypnotic Effects Through Regulating GABA and its Receptor in Mice and Rats. Nat. Prod. Commun., 14.","DOI":"10.1177\/1934578X19858165"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/j.foodchem.2011.08.040","article-title":"Phlorotannins of the edible brown seaweed Ecklonia cava Kjellman induce sleep via positive allosteric modulation of gamma-aminobutyric acid type A-benzodiazepine receptor: A novel neurological activity of seaweed polyphenols","volume":"132","author":"Cho","year":"2012","journal-title":"Food Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2825","DOI":"10.1007\/s00213-014-3445-1","article-title":"Marine polyphenol phlorotannins promote non-rapid eye movement sleep in mice via the benzodiazepine site of the GABA(A) receptor","volume":"231","author":"Cho","year":"2014","journal-title":"Psychopharmacology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.cbi.2012.06.003","article-title":"Pimaric acid from Aralia cordata has an inhibitory effect on TNF-alpha-induced MMP-9 production and HASMC migration via down-regulated NF-kappa B and AP-1","volume":"199","author":"Suh","year":"2012","journal-title":"Chem.-Biol. Interact."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/s12272-010-0403-2","article-title":"The Analgesic and Anti-inflammatory Effects of 7-Oxosandaracopimaric Acid Isolated from the Roots of Aralia cordata","volume":"33","author":"Kim","year":"2010","journal-title":"Arch. Pharm. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1007\/s12272-009-1615-1","article-title":"Anti-ischemic activities of Aralia cordata and its active component, oleanolic acid","volume":"32","author":"Cho","year":"2009","journal-title":"Arch. Pharm. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.jep.2009.07.010","article-title":"Therapeutic effect of Aralia cordata extracts on cartilage protection in collagenase-induced inflammatory arthritis rabbit model","volume":"125","author":"Park","year":"2009","journal-title":"J. Ethnopharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1248\/bpb.29.1423","article-title":"Effect of Aralia cordata extracts on cartilage protection and apoptosis inhibition","volume":"29","author":"Baek","year":"2006","journal-title":"Biol. Pharm. Bull."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ali, H., Khan, A., Ali, J., Ullah, H., Khan, A., Ali, H., Irshad, N., and Khan, S. (2020). Attenuation of LPS-induced acute lung injury by continentalic acid in rodents through inhibition of inflammatory mediators correlates with increased Nrf2 protein expression. BMC Pharmacol. Toxicol., 21.","DOI":"10.1186\/s40360-020-00458-7"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/S1537-1891(03)00028-4","article-title":"Anti-inflammatory effect of kaurenoic acid, a diterpene from Copaifera langsdorffii on acetic acid-induced colitis in rats","volume":"39","author":"Paiva","year":"2002","journal-title":"Vasc. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Jeon, B.E., Kwon, C.S., Lee, J.E., Moon, K., Cha, J., Park, I., Koh, S., Yoon, M., Kim, S.W., and Kim, J.N. (2021). Anticancer Activity of Continentalic Acid in B-Cell Lymphoma. Molecules, 26.","DOI":"10.3390\/molecules26226845"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"745","DOI":"10.4103\/pm.pm_344_20","article-title":"Simultaneous determination of two diterpenoids, continentalic acid and kaurenoic acid, in the water extract of Aralia continentalis and their wound-healing activity","volume":"16","author":"Yoo","year":"2020","journal-title":"Pharmacogn. Mag."},{"key":"ref_21","first-page":"99","article-title":"Anticonvulsant Effects of Kaurenoic Acid Isolated from the Root Bark of Annona Senegalensis","volume":"115","author":"Okoye","year":"2014","journal-title":"Basic. Clin. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1007\/s10068-017-0107-1","article-title":"Sleep-inducing effect of lettuce (Lactuca sativa) varieties on pentobarbital-induced sleep","volume":"26","author":"Kim","year":"2017","journal-title":"Food Sci. Biotechnol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"314","DOI":"10.4062\/biomolther.2014.045","article-title":"Pachymic Acid Enhances Pentobarbital-Induced Sleeping Behaviors via GABAA-ergic Systems in Mice","volume":"22","author":"Shah","year":"2014","journal-title":"Biomol. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"105","DOI":"10.4062\/biomolther.2016.035","article-title":"Rosmarinic Acid Potentiates Pentobarbital-Induced Sleep Behaviors and Non-Rapid Eye Movement (NREM) Sleep through the Activation of GABA(A)-ergic Systems","volume":"25","author":"Kwon","year":"2017","journal-title":"Biomol. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.neulet.2012.07.068","article-title":"Ferulic acid potentiates pentobarbital-induced sleep via the serotonergic system","volume":"525","author":"Tu","year":"2012","journal-title":"Neurosci. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e2100100","DOI":"10.1002\/mnfr.202100100","article-title":"A Novel Potent Sleep-Promoting Effect of Turmeric: Turmeric Increases Non-Rapid Eye Movement Sleep in Mice Via Histamine H1Receptor Blockade","volume":"65","author":"Um","year":"2021","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lee, B., Hong, R., Lim, P., Cho, D., Yeom, M., Lee, S., Kang, K.S., Lee, S.C., Shim, I., and Lee, H. (2019). The ethanolic extract of Aralia continentalis ameliorates cognitive deficits via modifications of BDNF expression and anti-inflammatory effects in a rat model of post-traumatic stress disorder. BMC Complement. Altern. Med., 19.","DOI":"10.1186\/s12906-018-2417-0"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Yang, D.K., Lee, S.-J., Adam, G.O., and Kim, S.-J. (2020). Aralia continentalis kitagawa extract attenuates the fatigue induced by exhaustive exercise through inhibition of oxidative stress. Antioxidants, 9.","DOI":"10.3390\/antiox9050379"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nbd.2018.04.012","article-title":"Sleep dysfunction following neonatal ischemic seizures are differential by neonatal age of insult as determined by qEEG in a mouse model","volume":"116","author":"Kang","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e80206","DOI":"10.7554\/eLife.80206","article-title":"Non-rapid eye movement sleep determines resilience to social stress","volume":"11","author":"Bush","year":"2022","journal-title":"Elife"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1080\/1028415X.2019.1681089","article-title":"Dieckol is a natural positive allosteric modulator of GABAA-benzodiazepine receptors and enhances inhibitory synaptic activity in cultured neurons","volume":"24","author":"Kwon","year":"2021","journal-title":"Nutr. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.smrv.2014.12.003","article-title":"Herbal medicine for insomnia: A systematic review and meta-analysis","volume":"24","author":"Leach","year":"2015","journal-title":"Sleep Med. Rev."},{"key":"ref_33","first-page":"401","article-title":"Potentiating Effects of Lactuca sativa on Pentobarbital-Induced Sleep","volume":"12","author":"Ghorbani","year":"2013","journal-title":"Iran. J. Pharm. Res."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Yoon, M., and Cho, S. (2018). Triphlorethol A, a Dietary Polyphenol from Seaweed, Decreases Sleep Latency and Increases Non-Rapid Eye Movement Sleep in Mice. Mar. Drugs, 16.","DOI":"10.3390\/md16050139"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1002\/mnfr.201100181","article-title":"Crocin promotes non-rapid eye movement sleep in mice","volume":"56","author":"Masaki","year":"2012","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1111\/j.1460-9568.2009.06716.x","article-title":"Role of GABAA receptors in the physiology and pharmacology of sleep","volume":"29","year":"2009","journal-title":"Eur. J. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1152\/jn.1997.77.3.1624","article-title":"Muscimol and midazolam do not potentiate each other\u2019s effects on sleep EEG in the rat","volume":"77","author":"Lancel","year":"1997","journal-title":"J. Neurophysiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6464","DOI":"10.1073\/pnas.111055398","article-title":"Diazepam-induced changes in sleep: Role of the alpha 1 GABA(A) receptor subtype","volume":"98","author":"Tobler","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1097\/00001756-200410050-00031","article-title":"Sleep EEG changes after zolpidem in mice","volume":"15","author":"Kopp","year":"2004","journal-title":"Neuroreport"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3674","DOI":"10.1073\/pnas.0306975101","article-title":"Modulation of rhythmic brain activity by diazepam: GABA(A) receptor subtype and state specificity","volume":"101","author":"Kopp","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.neuropharm.2004.03.017","article-title":"Effects of diazepam and zolpidem on EEG beta frequencies are behavior-specific in rats","volume":"47","author":"Drinkenburg","year":"2004","journal-title":"Neuropharmacology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1093\/sleep\/31.2.259","article-title":"Sleep-stabilizing effects of E-6199, compared to zopiclone, zolpidem and THIP in mice","volume":"31","author":"Alexandre","year":"2008","journal-title":"Sleep"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.pbb.2013.11.029","article-title":"A mouse model mimicking human first night effect for the evaluation of hypnotics","volume":"116","author":"Xu","year":"2014","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1111\/bcpt.13798","article-title":"GABAA receptors as targets for anaesthetics and analgesics and promising candidates to help treat coronavirus infections: A mini-review","volume":"131","author":"Luo","year":"2022","journal-title":"Basic. Clin. Pharmacol. Toxicol."},{"key":"ref_45","first-page":"181","article-title":"Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes","volume":"47","author":"Sieghart","year":"1995","journal-title":"Pharmacol. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"869","DOI":"10.2174\/1568026023393426","article-title":"GABA-A receptors as molecular sites of ethanol action. Direct or indirect actions?","volume":"2","author":"Aguayo","year":"2002","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_47","first-page":"114","article-title":"Potentiation of gamma aminobutyric acid receptors (GABAAR) by ethanol: How are inhibitory receptors affected?","volume":"10","author":"Castro","year":"2016","journal-title":"Front. Cell. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/s41398-023-02514-2","article-title":"Understanding the mechanism of action and clinical effects of neuroactive steroids and GABAergic compounds in major depressive disorder","volume":"13","author":"Cutler","year":"2023","journal-title":"Transl. Psychiatry"},{"key":"ref_49","first-page":"18","article-title":"Therapeutic options in the treatment of insomnia","volume":"66","author":"Erman","year":"2005","journal-title":"J. Clin. Psychiatry"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj3100001","article-title":"The GABAA receptors","volume":"310","author":"Stephenson","year":"1995","journal-title":"Biochem. J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"103","DOI":"10.5665\/sleep.1596","article-title":"Effects of GF-015535-00, a novel alpha1 GABA A receptor ligand, on the sleep-wake cycle in mice, with reference to zolpidem","volume":"35","author":"Anaclet","year":"2012","journal-title":"Sleep"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.2174\/1381612054021024","article-title":"GABA(A) receptor channel pharmacology","volume":"11","author":"Johnston","year":"2005","journal-title":"Curr. Pharm. Des."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1002\/med.2610120604","article-title":"GABA agonists and antagonists","volume":"12","author":"Kerr","year":"1992","journal-title":"Med. Res. Rev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1007\/s004240050915","article-title":"Bicuculline block of small-conductance calcium-activated potassium channels","volume":"438","author":"Khawaled","year":"1999","journal-title":"Pfl\u00fcgers Arch."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"173117","DOI":"10.1016\/j.ejphar.2020.173117","article-title":"Positive allosteric modulation of GABA(A) receptors by a novel antiepileptic drug cenobamate","volume":"879","author":"Sharma","year":"2020","journal-title":"Eur. J. Pharmacol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/24\/5020\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:33:56Z","timestamp":1760132036000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/24\/5020"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,6]]},"references-count":55,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["nu15245020"],"URL":"https:\/\/doi.org\/10.3390\/nu15245020","relation":{},"ISSN":["2072-6643"],"issn-type":[{"type":"electronic","value":"2072-6643"}],"subject":[],"published":{"date-parts":[[2023,12,6]]}}}