Extracts of Prunella vulgaris Enhanced Pentobarbital-Induced Sleeping Behavior in Mice Potentially via Adenosine A_2A Receptor Activity

Abstract

The increasing prevalence of sleep dysregulation cases has prompted the search for effective and safe sleep-enhancing agents. Numerous medications used in the treatment of sleep disorders function by enhancing γ-aminobutyric acid neurotransmitter activity. Unfortunately, these substances may induce significant adverse effects in chronic users, such as dependence and motor behavior impairments. Consequently, there is a growing interest in exploring therapeutic sleep-enhancing agents derived from natural sources, with the anticipation of causing less severe side effects. Prunella vulgaris (PV), a perennial plant indigenous to South Korea, exhibits various pharmacological effects, likely attributed to its chemical composition. Rosmarinic acid, one of its components, has previously demonstrated sleep-potentiating properties, suggesting the potential for PV to exhibit similar pharmacological effects. This study aims to investigate the potential effects of repeated administration of PV extract on the sleep behavior, brainwave activity, sleep–wake cycle, and physiological behavior of mice. Findings indicate that PV extracts exhibit sleep-enhancing effects in mice, characterized by prolonged sleep duration and a reduced onset time of pentobarbital-induced sleep. However, PV extracts only reduced alpha wave powers, with minor alterations in wakefulness and rapid-eye-movement sleep duration. In contrast to diazepam, PV extracts lack adverse effects on locomotor activity, motor coordination, or anxiety in mice. Receptor-binding assay and caffeine treatment support the potential involvement of adenosine A_2A receptors in the effects of PV, suggesting distinct mechanisms of action compared to diazepam, despite both exhibiting sleep-altering effects. Overall, our results suggest that PV holds promise as a potential source of sleep-aiding agents.

Keywords

Prunella vulgaris - Lamiaceae - sleep - adenosine A_2A receptor - EEG - sleep–wake cycle - caffeine

^a Indicates the first author of the manuscript.

Publication History

Received: 14 March 2024

Accepted after revision: 02 July 2024

Article published online:
24 July 2024

• References

• 1 Medic G, Wille M, Hemels MEH. Short- and long-term health consequences of sleep disruption. Nat Sci Sleep 2017; 9: 151-161
• 2 Sleep Disorders: Types, Causes, Symptoms & Treatment. Cleveland Clinic. 2023. Accessed January 16, 2024 at: https://my.clevelandclinic.org/health/diseases/11429-sleep-disorders
• 3 Konjarski M, Murray G, Lee VV, Jackson ML. Reciprocal relationships between daily sleep and mood: A systematic review of naturalistic prospective studies. Sleep Med Rev 2018; 42: 47-58
• 4 Sewell KR, Erickson KI, Rainey-Smith SR, Peiffer JJ, Sohrabi HR, Brown BM. Relationships between physical activity, sleep and cognitive function: A narrative review. Neurosci Biobehav Rev 2021; 130: 369-378
• 5 Lee S, Kin JH, Chung JH. The association between sleep quality and quality of life: a population-based study. Sleep Med 2021; 84: 121-126
• 6 Skaer TL. Sleep deprivation and economic burden. Sleep deprivation and disease: Effects on the body. Brain and Behavior. New York, NY: Springer New York; 2013: 269-279
• 7 Ockert W. A new dawn in the sleep disorders pipeline?. Nat Rev Drug Discov 2012; 11: 595-596
• 8 Szabadi E. Drugs for sleep disorders: Mechanisms and therapeutic prospects. Br J Clin Pharmacol 2006; 61: 761-766
• 9 Kishi T, Nomura I, Matsuda Y, Sakuma K, Okuya M, Ikuta T, Iwata N. Lemborexant vs. suvorexant for insomnia: A systematic review and network meta-analysis. J Psychiatr Res 2020; 128: 68-74
• 10 Huo S, Cheng L, Li S, Xu F. Effects of eszopiclone on sleep quality and cognitive function in elderly patients with Alzheimerʼs disease and sleep disorder: A randomized controlled trial. Brain Behav 2022; 12: e2488
• 11 Yu Z, Han L, Yan P, Liu W, Ren L, Xu Y, Yang L, Ma L, Liu Y, Wang S. Doxepin is more effective than zolpidem in improving executive function in patients with insomnia disorder. Sleep Breath 2023; 28: 929-934
• 12 Suraev AS, Marshall NS, Vandrey R, McCartney D, Benson MJ, McGregor IS, Grunstein RR, Hoyos CM. Cannabinoid therapies in the management of sleep disorders: A systematic review of preclinical and clinical studies. Sleep Med Rev 2020; 53: 101339
• 13 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: 285-294
• 14 Baek YH, Kim HJ, Bae JH, Lee H, Oh IS, Kim WJ, Shin JY. Benzodiazepine-related cognitive impairment or dementia: A signal detection study using a case/non-case approach. Psychiatry Investig 2020; 17: 587
• 15 Lazarus M, Chen JF, Huang ZL, Urade Y, Fredholm BB. Adenosine and Sleep. Handb Exp Pharmacol 2019; 253: 359-381
• 16 Liao L, Liu L, Guo QS, Wang ZY, Chen YH. Morphological and chemical variation of Prunella vulgaris populations from different locations in China. Chin Herb Med 2010; 2: 305-311
• 17 Wang SJ, Wang XH, Dai YY, Ma MH, Rahman K, Nian H, Zhang H. Prunella vulgaris: A comprehensive review of chemical constituents, pharmacological effects and clinical applications. Curr Pharm Des 2019; 25: 359-369
• 18 Zholdasbayev ME, Atazhanova GA, Musozoda S, Poleszak E. Prunella vulgaris L.: An updated overview of botany, chemical composition, extraction methods, and biological activities. Pharmaceuticals 2023; 16: 1106
• 19 Pan J, Wang H, Chen Y. Prunella vulgaris L. – A review of its ethnopharmacology, phytochemistry, quality control and pharmacological effects. Front Pharmacol 2022; 13: 903171
• 20 Kwon YO, Hong JT, Oh KW. Rosmarinic acid potentiates pentobarbital-induced sleep behaviors and non-rapid eye movement (NREM) sleep through the activation of GABAa-ergic systems. Biomol Ther (Seoul) 2017; 25: 105-111
• 21 Kim TH, Bormate KJ, Custodio RJP, Cheong JH, Lee BK, Kim HJ, Jung YS. Involvement of the adenosine A1 receptor in the hypnotic effect of rosmarinic acid. Biomed Pharmacother 2022; 146: 112483
• 22 Morde A, Acharya M, Tahilani P, Banweer J. Rosmarinic acid – A potential therapeutic agent for sleep disorders. Int J Pharm Sci 2023; 3: 1-6
• 23 Lin TF, Qiu JN, Zhang S, Zhang Y, Zhang Y, Sun M, Zhang JH, Liu B, Cheng FF, Jiang YY. Screening out the anti-insomnia components from Prunella vulgaris L. based on plasma pharmacochemistry combined with pharmacodynamic experiments and UPLC-MS/MS analysis. J Ethnopharmacol 2021; 279: 114373
• 24 Krystal AD, Edinger JD. Measuring sleep quality. Sleep Med 2008; 9: 10-17
• 25 Lopes JP, Pliássova A, Cunha RA. The physiological effects of caffeine on synaptic transmission and plasticity in the mouse hippocampus selectively depend on adenosine A1 and A2A receptors. Biochem Pharmacol 2019; 166: 313-321
• 26 Uygun DS, Basheer R. Circuits and components of delta wave regulation. Brain Res Bull 2022; 188: 223-232
• 27 Adamantidis AR, Gutierrez Herrera C, Gent TC. Oscillating circuitries in the sleeping brain. Nat Rev Neurosci 2019; 20: 746-762
• 28 McKillop LE, Fisher SP, Milinski L, Krone LB, Vyazovskiy VV. Diazepam effects on local cortical neural activity during sleep in mice. Biochem Pharmacol 2021; 191: 114515
• 29 Ko LW, Su CH, Yang MH, Liu SY, Su TP. A pilot study on essential oil aroma stimulation for enhancing slow-wave EEG in sleeping brain. Sci Rep 2021; 11: 1078
• 30 Chandharakool S, Koomhin P, Sinlapasorn J, Suanjan S, Phungsai J, Suttipromma N, Songsamoe S, Matan N, Sattayakhom A. Effects of tangerine essential oil on brain waves, moods, and sleep onset latency. Molecules 2020; 25: 4865
• 31 Ogilvie RD. The process of falling asleep. Sleep Med Rev 2001; 5: 247-270
• 32 Benca RM, Obermeyer WH, Larson CL, Yun B, Dolski I, Kleist KD, Weber SM, Davidson RJ. EEG alpha power and alpha power asymmetry in sleep and wakefulness. Psychophysiology 1999; 36: 430-436
• 33 Dela Peña IJI, Kim HJ, de la Peña JB, Kim M, Botanas CJ, You KY, Woo T, Lee YS, Jung JC, Kim KM, Cheong JH. A tryptic hydrolysate from bovine milk αs1-casein enhances pentobarbital-induced sleep in mice via the GABAA receptor. Behav Brain Res 2016; 313: 184-190
• 34 Ai Z, He H, Wang T, Chen L, Huang C, Chen C, Xu P, Zhu G, Yang M, Song Y, Su D. Validation of the thyrotoxicosis-associated insomnia model induced by thyroxine through sympathetic stimulation: Face, construct and predictive perspectives. Exp Neurobiol 2021; 30: 387-400
• 35 Dauvilliers Y, Schenck CH, Postuma RB, Iranzo A, Luppi PH, Plazzi G, Montplaisir J, Boeve B. REM sleep behaviour disorder. Nat Rev Dis Primers 2018; 4: 19
• 36 Miyazaki S, Uchida S, Mukai J, Nishihara K. Clonidine effects on all-night human sleep: Opposite action of low- and medium-dose clonidine on human NREM–REM sleep proportion. Psychiatry Clin Neurosci 2004; 58: 138-144
• 37 Kunz D, Mahlberg R, Müller C, Tilmann A, Bes F. Melatonin in patients with reduced REM sleep duration: Two randomized controlled trials. J Clin Endocrinol Metab 2004; 89: 128-134
• 38 Kummangal BA, Kumar D, Mallick HN. Intracerebroventricular injection of orexin-2 receptor antagonist promotes REM sleep. Behav Brain Res 2013; 237: 59-62
• 39 Gotter AL, Forman MS, Harrell CM, Stevens J, Svetnik V, Yee KL, Li X, Roecker AJ, Fox SV, Tannenbaum PL, Garson SL, Lepeleire ID, Calder N, Rosen L, Struyk A, Coleman PJ, Herring WJ, Renger JJ, Winrow CJ. Orexin 2 receptor antagonism is sufficient to promote NREM and REM sleep from mouse to man. Sci Rep 2016; 6: 27147
• 40 Pádua-Reis M, Nôga DA, Tort ABL, Blunder M. Diazepam causes sedative rather than anxiolytic effects in C57BL/6 J mice. Sci Rep 2021; 11: 9335
• 41 McCarley RW. Neurobiology of REM and NREM sleep. Sleep Med 2007; 8: 302-330
• 42 Costenla AR, Cunha RA, De Mendonça A. Caffeine, adenosine receptors, and synaptic plasticity. J Alzheimers Dis 2010; 20: 25-34
• 43 Huang ZL, Qu WM, Eguchi N, Chen JF, Schwarzschild MA, Fredholm BB, Urade Y, Hayaishi O. Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nat Neurosci 2005; 8: 858-859
• 44 Chen JF, Cunha RA. The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinsonʼs disease. Purinergic Signal 2020; 16: 167
• 45 Kaster MP, Machado NJ, Silva HB, Nunes A, Ardais AP, Santana M, Baqi Y, Müller CE, Rodrigues ALS, Porciúncula LO, Chen JF, Tomé ÂR, Agostinho P, Canas PM, Cunha RA. Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress. Proc Natl Acad Sci U S A 2015; 112: 7833-7838
• 46 Canas PM, Porciúncula LO, Cunha GMA, Silva CG, Machado NJ, Oliveira JMA, Oliveira CR, Cunha RA. Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p 38 mitogen-activated protein kinase pathway. J Neurosci 2009; 29: 14741-14751
• 47 Tescarollo FC, Rombo DM, DeLiberto LK, Fedele DE, Alharfoush E, Tomé ÂR, Cunha RA, Sebastião AM, Boison D. Role of adenosine in epilepsy and seizures. J Caffeine Adenosine Res 2020; 10: 45-60
• 48 Shah VK, Choi JJ, Han JY, Lee MK, Hong JT, Oh KW. Pachymic acid enhances pentobarbital-induced sleeping behaviors via GABAA-ergic systems in mice. Biomol Ther (Seoul) 2014; 22: 314
• 49 Kim TH, Custodio RJ, Cheong JH, Kim HJ, Jung YS. Sleep promoting effect of luteolin in mice via adenosine A1 and A2A receptors. Biomol Ther (Seoul) 2019; 27: 584
• 50 Song Z, Liu L, Xu Y, Cao R, Lan X, Pan C, Zhang S, Zhao H. Caffeine-induced sleep restriction alters the gut microbiome and fecal metabolic profiles in mice. Int J Mol Sci 2022; 23: 14837
• 51 Xu JZ, Shen J, Cheng YY, Qu HB. Simultaneous detection of seven phenolic acids in Danshen injection using HPLC with ultraviolet detector. J Zhejiang Univ Sci B 2008; 9: 728
• 52 Custodio RJP, Sayson LV, Botanas CJ, Abiero A, You KY, Kim M, Lee HJ, Yoo SY, Lee KW, Lee YS, Seo JW, Ryu IS, Kim HJ, Cheong JH. 25B-NBOMe, a novel N-2-methoxybenzyl-phenethylamine (NBOMe) derivative, may induce rewarding and reinforcing effects via a dopaminergic mechanism: Evidence of abuse potential. Addict Biol 2020; 25: e12850
• 53 Kim D, Yoon M, Kim S, Um MY, Cho S. Effects of green kiwifruit peel extract on sleep-wake profiles in mice: A polysomnographic study based on electroencephalogram and electromyogram recordings. Nutrients 2022; 14: 4732
• 54 Custodio RJP, Botanas CJ, de la Peña JB, Dela Peña IJ, Kim M, Sayson LV, Abiero A, Ryoo ZY, Kim BN, Kim HJ, Cheong JH. Overexpression of the thyroid hormone-responsive (THRSP) Gene in the striatum leads to the development of inattentive-like phenotype in mice. Neuroscience 2018; 390: 141-150
• 55 Dela Peña IJI, Botanas CJ, de la Peña JB, Custodio RJ, Dela Peña I, Ryoo ZY, Kim BN, Ryu JH, Kim HJ, Cheong JH. The Atxn7-overexpressing mice showed hyperactivity and impulsivity which were ameliorated by atomoxetine treatment: A possible animal model of the hyperactive-impulsive phenotype of ADHD. Prog Neuropsychopharmacol Biol Psychiatry 2019; 88: 311-319
• 56 Atack JR, Ohashi Y, McKernan RM. Characterization of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding to GABAA receptors in postmortem human brain. Br J Pharmacol 2007; 150: 1066-1074
• 57 Olah ME, Ren H, Ostrowski J, Jacobson KA, Stiles GL. Cloning, expression, and characterization of the unique bovine A1 adenosine receptor. Studies on the ligand binding site by site-directed mutagenesis. J Biol Chem 1992; 267: 10764-10770
• 58 Varani K, Gessi S, Dalpiaz A, Borea PA. Pharmacological and biochemical characterization of purified A2a adenosine receptors in human platelet membranes by [3H]-CGS 21680 binding. Br J Pharmacol 1996; 117: 1693-1701