Planta Med 2013; 79(15): 1385-1391
DOI: 10.1055/s-0033-1350709
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Characterization of the Anxiolytic Activity of Nunavik Rhodiola rosea

Christian Cayer
1   Centre for Advanced Research in Environmental Genomics, Department of Biology, University of Ottawa, Ottawa, Canada
2   School of Psychology, University of Ottawa, Ottawa, Canada
3   University of Ottawa Institute of Mental Health Research, University of Ottawa, Ottawa, Canada
,
Fida Ahmed
1   Centre for Advanced Research in Environmental Genomics, Department of Biology, University of Ottawa, Ottawa, Canada
,
Vicky Filion
1   Centre for Advanced Research in Environmental Genomics, Department of Biology, University of Ottawa, Ottawa, Canada
,
Ammar Saleem
1   Centre for Advanced Research in Environmental Genomics, Department of Biology, University of Ottawa, Ottawa, Canada
,
Alain Cuerrier
4   Jardin botanique de Montréal, Institut de recherche en biologie végétale, Université de Montréal, Montréal, Canada
,
Marc Allard
5   Nunavik Biosciences Inc., Montréal, Canada
,
Guy Rochefort
5   Nunavik Biosciences Inc., Montréal, Canada
,
Zul Merali
2   School of Psychology, University of Ottawa, Ottawa, Canada
3   University of Ottawa Institute of Mental Health Research, University of Ottawa, Ottawa, Canada
6   Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada
,
John T. Arnason
1   Centre for Advanced Research in Environmental Genomics, Department of Biology, University of Ottawa, Ottawa, Canada
› Author Affiliations
Further Information

Publication History

received 03 April 2013
revised 10 July 2013

accepted 15 July 2013

Publication Date:
23 August 2013 (online)

Abstract

Rhodiola rosea is a medicinal plant used by the indigenous Inuit people of Nunavik and Nunatsiavut, Eastern Canada, as a mental and physical rejuvenating agent. This traditional use led to the present investigation of R. rosea in the context of anxiety disorders. An alcohol extract of R. rosea roots was characterized phytochemically and orally administered for three consecutive days to Sprague-Dawley rats at 8 mg/kg, 25 mg/kg, and 75 mg/kg body weight. The rats were subjected to three behavioral paradigms of anxiety, including the elevated plus maze, social interaction, and contextual conditioned emotional response tests. Rhodiola rosea showed dose-dependent anxiolytic activity in the elevated plus maze and conditioned emotional response tests, with moderate effects in the higher-anxiety SI test. The active dose varied according to the anxiety test. In order to elucidate a mechanism, the extract was further tested in an in vitro GABAA-benzodiazepine receptor-binding assay, where it demonstrated low activity. This study provides the first comparative assessment of the anxiolytic activity of Nunavik R. rosea in several behaviour models and suggests that anxiolytic effects may be primarily mediated via pathways other than the GABAA-benzodiazepine site of the GABAA receptor.

Supporting Information

 
  • References

  • 1 Kessler R, Berglund P, Demler O, Jin R, Walters E. Lifetime prevalence and age-of-onset distributionsʼ of DSM-IV disorders in the national comorbidity survey replication. Arch Gen Psychiatry 2005; 62: 593-602
  • 2 Atack JR. The benzodiazepine binding site of GABAA receptors as a target for the development of novel anxiolytics. Expert Opin Investig Drugs 2005; 14: 601-618
  • 3 Trincavelli ML, da Pozzo E, Daniele S, Martini C. The GABAA-BZR complex as target for the development of anxiolytic drugs. Curr Top Med Chem 2012; 12: 254-269
  • 4 Ravindran LN, Stein MB. The pharmacologic treatment of anxiety disorders: a review of progress. J Clin Psychiatry 2010; 71: 839-854
  • 5 Kessler R, Soukup J, Davis R, Foster D, Wilkey S, Van Rompay M, Eisenberg D. The use of complementary and alternative therapies to treat anxiety and depression in the United States. Am J Psychiatry 2001; 158: 289-294
  • 6 Van Der Watt G, Laugharne J, Janca A. Complementary and alternative medicine in the treatment of anxiety and depression. Curr Opin Psychiatry 2008; 21: 37-42
  • 7 Awad R, Ahmed F, Bourbonnais-Spear N, Mullally M, Ta CA, Tang A, Merali Z, Maquin P, Caal F, Cal V, Poveda L, Sanchez Vindas P, Trudeau VL, Arnason JT. Ethnopharmacology of Qʼeqchiʼ Maya antiepileptic and anxiolytic plants: effects on the GABAergic system. J Ethnopharmacol 2009; 125: 257-264
  • 8 Bourbonnais-Spear N, Awad R, Merali Z, Maquin P, Cal V, Arnason JT. Ethnopharmacological investigation of plants used to treat susto, a folk illness. J Ethnopharmacol 2007; 109: 380-387
  • 9 Mullally M, Kramp K, Cayer C, Saleem A, Ahmed F, McRae C, Baker J, Goulah A, Otorola M, Sanchez P, Garcia M, Poveda L, Merali Z, Durst T, Trudeau VL, Arnason JT. Anxiolytic activity of a supercritical carbon dioxide extract of Souroubea sympetala (Marcgraviaceae). Phytother Res 2011; 25: 264-270
  • 10 Panossian A, Wikman G, Sarris J. Rosenroot (Rhodiola rosea): traditional use, chemical composition, pharmacology and clinical efficacy. Phytomedicine 2010; 17: 481-493
  • 11 Cuerrier A, Hermanutz L. Our plants… our land: plants of Nain and Torngat mountains basecamp & research station (Nunatsiavut). Montréal & St-Johnʼs: IRBV, MUN; 2012: 126
  • 12 Qu Z, Zhou Y, Zeng Y, Li Y, Chung P. Pretreatment with Rhodiola rosea extract reduces cognitive impairment induced by intracerebroventricular streptozotocin in rats: implication of anti-oxidative and neuroprotective effects. Biomed Environ Sci 2009; 22: 318-326
  • 13 Palumbo DR, Occhiuto F, Spadaro F, Circosta C. Rhodiola rosea extract protects human cortical neurons against glutamate and hydrogen peroxide-induced cell death through reduction in the accumulation of intracellular calcium. Phytother Res 2012; 26: 878-883
  • 14 Chen QG, Zeng YS, Qu ZQ, Tang JY, Qin YJ, Chung P, Wong R, Haegg U. The effects of Rhodiola rosea extract on 5-HT level, cell proliferation and quantity of neurons at cerebral hippocampus of depressive rats. Phytomedicine 2009; 16: 830-838
  • 15 Olsson EMG, Von Schéele B, Panossian AG. A randomised, double-blind, placebo-controlled, parallel-group study of the standardised extract SHR-5 of the roots of Rhodiola rosea in the treatment of subjects with stress-related fatigue. Planta Med 2009; 75: 105-112
  • 16 Filion VJ. A novel phytochemical and ecological study of the in Nunavik medicinal plant Rhodiola rosea [dissertation]. Ottawa: University of Ottawa; 2008
  • 17 Cuerrier A. Elders of Kangiqsualujjuaq. The botanical knowledge of the Inuit of Kangiqsualujjuaq, Nunavik. Montréal: Avataq Cultural Institute; 2012: 78
  • 18 Filion VJ, Saleem A, Rochefort G, Allard M, Cuerrier A, Arnason JT. Phytochemical analysis of Nunavik Rhodiola rosea L. Nat Prod Commun 2008; 3: 721-726
  • 19 Avula B, Wang Y, Ali Z, Smillie TJ, Filion V, Cuerrier A, Arnason JT, Khan IA. RP-HPLC determination of phenylalkanoids and monoterpenoids in Rhodiola rosea and identification by LC-ESI-TOF. Biomed Chromatogr 2009; 23: 865-872
  • 20 Perfumi M, Mattioli L. Adaptogenic and central nervous system effects of single doses of 3 % rosavin and 1 % salidroside Rhodiola rosea L. extract in mice. Phytother Res 2007; 21: 37-43
  • 21 Montiel-Ruiz RM, Roa-Coria JE, Patiño-Camacho SI, Flores-Murrieta FJ, Déciga-Campos M. Neuropharmacological and toxicity evaluations of ethanol extract from Rhodiola rosea . Drug Dev Res 2012; 73: 106-113
  • 22 Bystritsky A, Kerwin L, Feusner JD. A pilot study of Rhodiola rosea (Rhodax®) for generalized anxiety disorder (GAD). J Altern Complement Med 2008; 14: 175-180
  • 23 Menard J, Treit D. Effects of centrally administered anxiolytic compounds in animal models of anxiety. Neurosci Biobehav Rev 1999; 23: 591-613
  • 24 Rezayat M, Roohbakhsh A, Zarrindast M, Massoudi R, Djahanguiri B. Cholecystokinin and GABA interaction in the dorsal hippocampus of rats in the elevated plus-maze test of anxiety. Physiol Behav 2005; 84: 775-782
  • 25 File S, Seth P. A review of 25 years of the social interaction test. Eur J Pharmacol 2003; 463: 35-53
  • 26 Gonzalez L, Andrews N, File S. 5-HT1A and benzodiazepine receptors in the basolateral amygdala modulate anxiety in the social interaction test, but not in the elevated plus-maze. Brain Res 1996; 732: 145-153
  • 27 Gonzalez L, Ouagazzal A, File S. Stimulation of benzodiazepine receptors in the dorsal hippocampus and median raphe reveals differential GABAergic control in two animal tests of anxiety. Eur J Neurosci 1998; 10: 3673-3680
  • 28 Davis M, Myers KM, Chhatwal J, Ressler KJ. Pharmacological treatments that facilitate extinction of fear: relevance to psychotherapy. NeuroRx 2006; 3: 82-96
  • 29 Tsang SY, Xue H. Development of effective therapeutics targeting the GABAA receptor: naturally occurring alternatives. Curr Pharm Des 2004; 10: 1035-1044
  • 30 Wang F, Huen MSY, Tsang SY, Xue H. Neuroactive flavonoids interacting with GABAA receptor complex. Curr Drug Targets CNS Neurol Disord 2005; 4: 575-585
  • 31 Vignes M, Maurice T, Lanté F, Nedjar M, Thethi K, Guiramand J, Récasens M. Anxiolytic properties of green tea polyphenol (−)-epigallocatechin gallate (EGCG). Brain Res 2006; 1110: 102-115
  • 32 Khom S, Strommer B, Ramharter J, Schwarz T, Schwarzer C, Erker T, Ecker G, Mulzer J, Hering S. Valerenic acid derivatives as novel subunit-selective GABAA receptor ligands – in vitro and in vivo characterization. Br J Pharmacol 2010; 161: 65-78
  • 33 Dubichev AG, Kurkin VA, Zapesochnaya GG, Vorontsov ED. Chemical composition of the rhizomes of the Rhodiola rosea by the HPLC method. Chem Nat Compd 1991; 27: 161-164
  • 34 Grundmann O, Nakajima J, Kamata K, Seo S, Butterweck V. Kaempferol from the leaves of Apocynum venetum possesses anxiolytic activities in the elevated plus maze test in mice. Phytomedicine 2009; 16: 295-302
  • 35 Evstatieva L, Todorova M, Antonova D, Staneva J. Chemical composition of the essential oils of Rhodiola rosea L. of three different origins. Pharmacogn Mag 2010; 6: 256-258
  • 36 Aoshima H, Takeda K, Okita Y, Hossain SJ, Koda H, Kiso Y. Effects of beer and hop on ionotropic γ-aminobutyric acid receptors. J Agric Food Chem 2006; 54: 2514-2519
  • 37 Rodgers R, Cole J, Davies A. Antianxiety and behavioral suppressant actions of the novel 5-HT1A receptor agonist, flesinoxan. Pharmacol Biochem Behav 1994; 48: 959-963
  • 38 Rodgers R, Cutler M, Jackson J. Behavioural effects in mice of subchronic buspirone, ondansetron and tianeptine. II. The elevated plus-maze. Pharmacol Biochem Behav 1997; 56: 295-303
  • 39 Mannucci C, Navarra M, Calzavara E, Caputi AP, Calapai G. Serotonin involvement in Rhodiola rosea attenuation of nicotine withdrawal signs in rats. Phytomedicine 2012; 19: 1117-1124
  • 40 van Diermen D, Marston A, Bravo J, Reist M, Carrupt P, Hostettmann K. Monoamine oxidase inhibition by Rhodiola rosea L. roots. J Ethnopharmacol 2009; 122: 397-401
  • 41 Pellow S, Chopin P, File SE, Briley M. Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 1985; 14: 149-167
  • 42 File SE. Usefulness of animal models with newer anxiolytics. Clin Neuropharmacol 1992; 15 (Suppl. 01) 525A-526A
  • 43 Cruz A, Frei F, Graeff F. Ethopharmacological analysis of rat behavior on the elevated plus-maze. Pharmacol Biochem Behav 1994; 49: 171-176