PROTOPANAXADIOL SAPONINS IN THE CAUDEXES AND LEAVES OF PANAX NOTOGINSENG COULD BE THE MAIN CONSTITUENTS THAT CONTRIBUTE TO ITS ANTIDEPRESSANT EFFECTS
Keywords:
Effective fraction, SCLPN, Ginsengnoside Rb3, Ginsengnoside Rd, Ginsengnoside Rb1, Ginsengnoside Rg1, Notoginsenoside R1, Antidepressant, Animal model, Macroporous resinAbstract
Objective: We previously found that total saponins, purified from the caudexes and leaves of Panax notoginseng (SCLPN), had antidepressant effects. In the present study, we investigated saponin monomers of SCLPN that may be the main constituents that contribute to the antidepressant effects of SCLPN.
Methods: Three effective fractions of SCLPN, purified using a macroporous resin method, at doses of 50 and 100 mg/kg were tested in four different animal models of stress, including the learned helplessness test, tail suspension test, forced swim test, open field test, and reserpine-induced syndrome model. Using the same models of stress and the same doses, we then evaluated the antidepressant effects of four main and representative saponin monomers (ginsenosides Rd, Rb1 and Rg1 and notoginsenoside R1) in different effective fractions. We also examined the effects of Rd and Rb3 on monoamine neurotransmitter levels. To investigate the biotransformation of Rb1 and Rb3 orally administered in mice, Rb1 and Rb3 metabolites in blood and brain were determined by high-performance liquid chromatography.
Results: Effective fraction A and C exerted greater antidepressant effects than fraction B in the behavioral tests and reserpine-induced syndrome model. Among the four saponin monomers, Rd had the strongest antidepressant effects, which improved depressive-like behavior in all four animal models of depression. We then found that Rb3 (50 and 100 mg/kg) and Rd (100 mg/kg) increased the levels of 5-hydroxytryptamine, dopamine, and norepinephrine, whereas 50 mg/kg Rd had no effect on the levels of these three neurotransmitters. Ginsenoside Rh2, C-K, and 20 (S)-protopanaxadiol saponins were detected in blood samples from mice that received Rb1 and Rb3, and protopanaxadiol saponins were found in the brain.
Conclusion: The present results indicate that protopanaxadiol saponins in SCLPN have potential antidepressant-like effects.
Downloads
References
Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62(6):617-27.
Gonzalez O, Berry J, McKnight-Eily L, Strine T, Edwards V, Lu H, et al. Current depression among adults: United States, 2006 and 2008. Morb Mortal Wkly Rev 2010;59:1225-39.
Torpy JM, Burke AE, Glass RM. JAMA patient page: depression. JAMA 2010;303(19):1994.
Belmaker RH, Agam G. Major depressive disorder. N Engl J Med 2008;358(1):55-68.
Maes M, Meltzer H. The serotonin hypothesis of major depression. Psychopharmacol 1995;10:933-34.
Posener JA, Schildkraut JJ, Williams GH, Gleason RE, Salomon MS, Mecheri G, et al. Acute and delayed effects of corticotropin-releasing hormone on dopamine activity in man. Biol Psychiatry 1994;36(9):616-21.
Nutt DJ. The role of dopamine and norepinephrine in depression and antidepressant treatment. J Clin Psychiatry 2006;67 Suppl 6:3-8.
Nemeroff CB. The burden of severe depression: a review of diagnostic challenges and treatment alternatives. J Psychiatr Res 2007;41(3-4):189-206.
Little A. Treatment-resistant depression. Am Fam Physician 2009;80(2):167-72.
Dang H, Chen Y, Liu X, Wang Q, Wang L, Jia W, et al. Antidepressant effects of ginseng total saponins in the forced swimming test and chronic mild stress models of depression. Prog Neuropsychopharmacol Biol Psychiatry 2009;33(8):1417-24.
Kennedy S. A review of antidepressant treatments today. Eur Neuropsychopharmacol 2006;16:S619-23.
Wheatley D. LI 160, an extract of St. John's wort, versus amitriptyline in mildly to moderately depressed outpatients: a controlled 6-week clinical trial. Pharmacopsychiatry 1997;30 Suppl 2:77-80.
Singer A, Wonnemann M, Muller WE. Hyperforin, a major antidepressant constituent of St. John's Wort, inhibits serotonin uptake by elevating free intracellular Na+1. J Pharmacol Exp Ther 1999;290(3):1363-8.
Yu ZF, Kong LD, Chen Y. Antidepressant activity of aqueous extracts of Curcuma longa in mice. J Ethnopharmacol 2002;83(1-2):161-5.
Singh GK, Garabadu D, Muruganandam AV, Joshi VK, Krishnamurthy S. Antidepressant activity of Asparagus racemosus in rodent models. Pharmacol Biochem Behav 2009;91(3):283-90.
Seol G, Shim H, Kim P, Moon H, Lee K, Shim I, et al. Antidepressant-like effect of Salvia sclarea is explained by modulation of dopamine activities in rats. J Ethnopharmacol 2010;130:187-90.
Sarris J, Panossian A, Schweitzer I, Stough C, Scholey A. Herbal medicine for depression, anxiety and insomnia: a review of psychopharmacology and clinical evidence. Eur Neuropsychopharmacol 2011;21(12):841-60.
Lu G, Zhou Q, Sun S, Leung K, Zhang H, Zhao Z. Differentiation of Asian ginseng, American ginseng and Notoginseng by Fourier transform infrared spectroscopy combined with two-dimensional correlation infrared spectroscopy. J Mol Struct 2008;883(91-98):91-8.
Cicero AF, Bandieri E, Arletti R. Orally administered Panax notoginseng influence on rat spontaneous behaviour. J Ethnopharmacol 2000;73(3):387-91.
Ng TB. Pharmacological activity of sanchi ginseng (Panax notoginseng). J Pharm Pharmacol 2006;58(8):1007-19.
Liu H, Yang J, Du F, Gao X, Ma X, Huang Y, et al. Absorption and disposition of ginsenosides after oral administration of Panax notoginseng extract to rats. Drug Metab Dispos 2009;37(12):2290-8.
Wan JB, Yang FQ, Li SP, Wang YT, Cui XM. Chemical characteristics for different parts of Panax notoginseng using pressurized liquid extraction and HPLC-ELSD. J Pharm Biomed Anal 2006;41(5):1596-601.
Li L, Sheng Y, Zhang J, Guo D. Determination of four active saponins of Panax notoginseng in rat feces by high-performance liquid chromatography. J Chromatogr Sci 2005;43(8):421-5.
Liu C, Han J, Duan Y, Huang X, Wang H. Purification and quantification of ginsenoside Rb3 and Rc from crude extracts of caudexes and leaves of Panax notoginseng. Sep Purif Technol 2007;54:198-203.
Tan X, Tang L. Observation of curative effect about treatment of 600 examples by Seven Leaves Spirit Calmness Tablet toward neurasthenia neurosis. Lishizhen Med Materia Med Res 1999;10:613.
Gong Y, Liu Y. Observation of self-control about Seven Leaves Spirit Calmness Tablet toward anxiety neurosis. Med J Commun 1998;12:173.
Xiang H, Liu Y, Zhang B, Huang J, Li Y, Yang B, et al. The antidepressant effects and mechanism of action of total saponins from the caudexes and leaves of Panax notoginseng in animal models of depression. Phytomed 2011;18(8-9):731-8.
Cui J, Jiang L, Xiang H. Ginsenoside Rb3 exerts antidepressant-like effects in several animal models. J Psychopharmacol 2012;26(5):697-713.
Sherman AD, Sacquitne JL, Petty F. Specificity of the learned helplessness model of depression. Pharmacol Biochem Behav 1982;16(3):449-54.
Boissier JR, Simon P. [Action of caffeine on the spontaneous motility of the mouse]. Arch Int Pharmacodyn Ther 1965;158(1):212-21.
Steru L, Chermat R, Thierry B, Simon P. The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl) 1985;85(3):367-70.
Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature 1977;266(5604):730-2.
Rojas-Corrales MO, Berrocoso E, Gibert-Rahola J, Mico JA. Antidepressant-like effects of tramadol and other central analgesics with activity on monoamines reuptake, in helpless rats. Life Sci 2002;72(2):143-52.
Seligman ME, Beagley G. Learned helplessness in the rat. J Comp Physiol Psychol 1975;88(2):534-41.
Bourin M, Poncelet M, Chermat R, Simon P. The value of the reserpine test in psychopharmacology. Arzneimittelforsch 1983;33(8):1173-6.
Sanchez-Mateo C, Bonkanka C, Prado B, Rabanal R. Antidepressant activity of some Hypericum reflexum L. fil. extracts in the forced swimming test in mice. J Ethnopharmacol 2007;112:115-21.
Kato M, Katayama T, Iwata H, Yamamura M, Matsuoka Y, Narita H. In vivo characterization of T-794, a novel reversible inhibitor of monoamine oxidase-A, as an antidepressant with a wide safety margin. J Pharmacol Exp Ther 1998;284(3):983-90.
Corne SJ, Pickering RW, Warner BT. A method for assessing the effects of drugs on the central actions of 5-hydroxytryptamine. Br J Pharmacol Chemother 1963;20:106-20.
Morpurgo C. Aggressive behavior induced by large doses of 2-(2,6-dichlorphenylamino)-2-imidazoline hydrochloride (ST 155) in mice. Eur J Pharmacol 1968;3(4):374-7.
Serra G, Collu M, D'Aquila PS, De Montis GM, Gessa GL. Possible role of dopamine D1 receptor in the behavioural supersensitivity to dopamine agonists induced by chronic treatment with antidepressants. Brain Res 1990;527(2):234-43.
Goodwin FK, Bunney WE Jr. Depressions following reserpine: a reevaluation. Semin Psychiatry 1971;3(4):435-48.
Li P, Liu C, Guo J, He D, Yu H, Jin F. Comparison of the saponin compositionin the stem and leaf of different type of ginseng. J Anhui Agri Sci 2010;38:13077-9.
Qi LW, Wang CZ, Yuan CS. Isolation and analysis of ginseng: advances and challenges. Nat Prod Rep 2011;28(3):467-95.
Ceglia I, Acconcia S, Fracasso C, Colovic M, Caccia S, Invernizzi RW. Effects of chronic treatment with escitalopram or citalopram on extracellular 5-HT in the prefrontal cortex of rats: role of 5-HT1A receptors. Br J Pharmacol 2004;142(3):469-78.
Sanchez C, Hyttel J. Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. Cell Mol Neurobiol 1999;19(4):467-89.
Laverty R, Taylor KM. Behavioural and biochemical effects of 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (St 155) on the central nervous system. Br J Pharmacol 1969;35(2):253-64.
Grigoriadis N, Simeonidou C, Parashos SA, Albani M, Guiba-Tziampiri O. Ontogenetic development of the locomotor response to levodopa in the rat. Pediatr Neurol 1996;14(1):41-5.
Park CS, Yoo MH, Noh KH, Oh DK. Biotransformation of ginsenosides by hydrolyzing the sugar moieties of ginsenosides using microbial glycosidases. Appl Microbiol Biotechnol 2010;87(1):9-19.
Qian T, Cai Z. Biotransformation of ginsenosides Rb1, Rg3 and Rh2 in rat gastrointestinal tracts. Chin Med 2010;5:19.
Wan JB, Zhang QW, Ye WC, Wang YT. Quantification and separation of protopanaxatriol and protopanaxadiol type saponins from Panax notoginseng with macroporous resins. Sep Purif Technol 2008;60(2):198-205.
Liu X, Xiao G, Chen W, Xu Y, Wu J. Quantification and purification of mulberry anthocyanins with macroporous resins. J Biomed Biotechnol 2004;2004(5):326-31.
Liu W, Zhang S, Zu YG, Fu YJ, Ma W, Zhang DY, et al. Preliminary enrichment and separation of genistein and apigenin from extracts of pigeon pea roots by macroporous resins. Bioresour Technol 2010;101(12):4667-75.
Zhao Y, Chen B, Yao SZ. Separation of 20(S)-protopanaxdiol type ginsenosides and 20(S)-protopanaxtriol type ginsenosides with the help of macroporous resin adsorption and microwave assisted desorption. Separation and Purification Technology 2007;52(3):533-38.
Kim DH. Chemical diversity of Panax ginseng, Panax quinquifolium, and Panax notoginseng. J Ginseng Res 2012;36(1):1-15.
Junxian W, Liangyu C, Jufen W, Friedrichs E, Jores M, Puff H, et al. [Two new Dammaran sapogenins from leaves of Panax notoginseng.]. Planta Med 1982;45(3):167-71.
Radad K, Moldzio R, Rausch W. Ginsenosides and their CNS targets. CNS Neurosci Ther 2011;17:761-68.
Liebelt E. An update on antidepressant toxicity: an evolution of unique toxicities to master. Clin Pediatr Emerg Med 2008;9:24-34.
Tsang D, Yeung HW, Tso WW, Peck H. Ginseng saponins: influence on neurotransmitter uptake in rat brain synaptosomes. Planta Med 1985;3:221-4.
Itoh T, Zang YF, Murai S, Saito H. Effects of Panax ginseng root on the vertical and horizontal motor activities and on brain monoamine-related substances in mice. Planta Med 1989;55(5):429-33.
Xue JF, Liu ZJ, Hu JF, Chen H, Zhang JT, Chen NH. Ginsenoside Rb1 promotes neurotransmitter release by modulating phosphorylation of synapsins through a cAMP-dependent protein kinase pathway. Brain Res 2006;1106(1):91-8.
Sengupta S, Toh SA, Sellers LA, Skepper JN, Koolwijk P, Leung HW, et al. Modulating angiogenesis: the yin and the yang in ginseng. Circulation 2004;110(10):1219-25.
Hasegawa H. Proof of the mysterious efficacy of ginseng: basic and clinical trials: metabolic activation of ginsenoside: deglycosylation by intestinal bacteria and esterification with fatty acid. J Pharmacol Sci 2004;95(2):153-7.
Tawab MA, Bahr U, Karas M, Wurglics M, Schubert-Zsilavecz M. Degradation of ginsenosides in humans after oral administration. Drug Metab Dispos 2003;31(8):1065-71.
Kong H, Wang M, Venema K, Maathuis A, van der Heijden R, van der Greef J, et al. Bioconversion of red ginseng saponins in the gastro-intestinal tract in vitro model studied by high-performance liquid chromatography-high resolution Fourier transform ion cyclotron resonance mass spectrometry. J Chromatogr A 2009;1216(11):2195-203.
Li X, Wang G, Sun J, Hao H, Xiong Y, Yan B, et al. Pharmacokinetic and absolute bioavailability study of total Panax notoginsenoside, a typical multiple constituent traditional Chinese medicine (TCM) in rats. Biol Pharm Bull 2007;30(5):847-51.
Zhou Z, Zhen J, Karpowich N, Goetz R, Law C, Reith M, et al. LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake. Science 2007;317:1390-93.
Qi LW, Wang CZ, Yuan CS. American ginseng: potential structure-function relationship in cancer chemoprevention. Biochem Pharmacol 2010;80(7):947-54.
Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58(11):1685-93.
Chen R, Chung T, Li F, Lin N, Tzen J. Effect of sugar positions in ginsenosides and their inhibitory potency on Na+/K+-ATPase activity. Acta Pharmacol Sin 2009;30:61-9.