Euphorbia hirta reverses chronic stress-induced anxiety and mediates its action through the GABA A receptor benzodiazepine receptor-Cl − channel complex Article First Online: 18 December 2007 Received: 13 July 2007 Accepted: 07 September 2007 DOI:
Cite this article as: Anuradha, H., Srikumar, B., Shankaranarayana Rao, B. et al. J Neural Transm (2008) 115: 35. doi:10.1007/s00702-007-0821-6 Summary.
Chronic stress is known to result in impairment of learning and memory and precipitate several affective disorders including depression and anxiety. Drugs of natural origin are known to possess several effects on the central nervous system and are emerging as promising alternative therapies. In this context, the hydroalcoholic extract of
Euphorbia hirta (Eh) was evaluated for anxiolytic property in chronically stressed rats subjected to elevated plus maze (EPM) and open field test (OFT). Eh treatment (200 mg/kg, p.o.; seven days) showed marked anti-anxiety activity in chronic immobilization stress. In contrast, the forced swim stress-induced anxiety was only partially decreased by Eh. Co-treatment of rats with flumazenil (0.5 mg/kg, i.p.), bicuculline (1 mg/kg, i.p.) or picrotoxin (1 mg/kg, i.p.) resulted in a significant reduction of anxiolytic effect of Eh indicating that its actions are mediated through GABA A receptor-benzodiazepine receptor-Cl − channel complex. Thus, our studies indicate that Eh is a potential anxiolytic drug, which might be beneficial in the treatment of stress-induced anxiety disorders. Keywords: Anxiety; stress; herbal drugs; Euphorbia hirta; elevated plus maze; open field test
Correspondence: B. S. Shankaranarayana Rao, Department of Neurophysiology, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, PB 2900, Bangalore 560 029, India
References Adamec, RE, Burton, P, Shallow, T, Budgell, J 1999 NMDA receptors mediate lasting increases in anxiety-like behavior produced by the stress of predator exposure – implications for anxiety associated with posttraumatic stress disorder Physiol Behav 65 723 737 PubMed CrossRef Google Scholar Beaubrun, G, Gray, GE 2000 A review of herbal medicines for psychiatric disorders Psychiatry Serv 51 1130 1134 CrossRef Google Scholar Carlini, EA 2003 Plants and the central nervous system Pharmacol Biochem Behav 75 501 512 PubMed CrossRef Google Scholar Chaki, S, Nakazato, A, Kennis, L, Nakamura, M, Mackie, C, Sugiura, M, Vinken, P, Ashton, D, Langlois, X, Steckler, T 2004 Anxiolytic- and antidepressant-like profile of a new CRF1 receptor antagonist, R278995/CRA0450 Eur J Pharmacol 485 145 158 PubMed CrossRef Google Scholar Chaki, S, Oshida, Y, Ogawa, S, Funakoshi, T, Shimazaki, T, Okubo, T, Nakazato, A, Okuyama, S 2005 MCL0042: a nonpeptidic MC4 receptor antagonist and serotonin reuptake inhibitor with anxiolytic- and antidepressant-like activity Pharmacol Biochem Behav 82 621 626 PubMed CrossRef Google Scholar Ernst, E 2002 The risk-benefit profile of commonly used herbal therapies: Ginkgo, St. John’s Wort, Ginseng, Echinacea, Saw Palmetto, and Kava Ann Intern Med 136 42 53 PubMed Google Scholar Feltenstein, MW, Lambdin, LC, Ganzera, M, Ranjith, H, Dharmaratne, W, Nanayakkara, NP, Khan, IA, Sufka, KJ 2003 Anxiolytic properties of Piper methysticum extract samples and fractions in the chick social-separation-stress procedure Phytother Res 17 210 216 PubMed CrossRef Google Scholar Ferris, P, Seward, E, Dawson, GR 2001 Interactions between LY354740, a group II metabotropic agonist and the GABA(A)-benzodiazepine receptor complex in the rat elevated plus-maze J Psychopharmacol 15 76 82 PubMed CrossRef Google Scholar Galvez, J, Zarzuelo, A, Crespo, ME, Lorente, MD, Ocete, MA, Jimenez, J 1993 Antidiarrhoeic activity of Euphorbia hirta extract and isolation of an active flavonoid constituent Planta Medica 59 333 336 PubMed CrossRef Google Scholar Govindarajan, A, Shankaranarayana Rao, BS, Nair, D, Trinh, M, Mawjee, N, Tonegawa, S, Chattarji, S 2006 Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects Proc Natl Acad Sci USA 103 13208 13213 PubMed CrossRef Google Scholar Hamner, MB, Robert, S, Frueh, BC 2004 Treatment-resistant posttraumatic stress disorder: strategies for intervention CNS Spectr 9 740 752 PubMed Google Scholar Heinrichs, SC, De Souza, EB, Schulteis, G, Lapsansky, JL, Grigoriadis, DE 2002 Brain penetrance, receptor occupancy and antistress in vivo efficacy of a small molecule corticotropin releasing factor type I receptor selective antagonist Neuropsychopharmacology 27 194 202 PubMed CrossRef Google Scholar Johnson, PB, Abdurahman, EM, Tiam, EA, Abdu-Aguye, I, Hussaini, IM 1999 Euphorbia hirta leaf extracts increase urine output and electrolytes in rats J Ethnopharmacol 65 63 69 PubMed CrossRef Google Scholar Kienzle-Horn, S 2002 Herbal medicines for neurological diseases Curr Opin Investig Drugs 3 763 767 PubMed Google Scholar Kulkarni, SK 1977 Open field test: its status in psychopharmacology Indian J Pharmacol 9 241 246 Google Scholar Langen, B, Egerland, U, Bernoster, K, Dost, R, Unverferth, K, Rundfeldt, C 2005 Characterization in rats of the anxiolytic potential of ELB139 [1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on], a new agonist at the benzodiazepine binding site of the GABAA receptor J Pharmacol Exp Ther 314 717 724 PubMed CrossRef Google Scholar Lanhers, MC, Fleurentin, J, Cabalion, P, Rolland, A, Dorfman, P, Misslin, R, Pelt, JM 1990 Behavioral effects of Euphorbia hirta L.: sedative and anxiolytic properties J Ethnopharmacol 29 189 198 PubMed CrossRef Google Scholar Lanhers, MC, Fleurentin, J, Dorfman, P, Mortier, F, Pelt, JM 1991 Analgesic, antipyretic and anti-inflammatory properties of Euphorbia hirta Planta Medica 57 225 231 PubMed CrossRef Google Scholar McEwen, BS 2000 The neurobiology of stress: from serendipity to clinical relevance Brain Res 886 172 189 PubMed CrossRef Google Scholar McEwen, BS 2002The end of stress as we know it National Academies Press Washington, DC Google Scholar Millan, MJ 2003 The neurobiology and control of anxious states Prog Neurobiol 70 83 244 PubMed CrossRef Google Scholar Padovan, CM, Del Bel, EA, Guimaraes, FS 2000 Behavioral effects in the elevated plus maze of an NMDA antagonist injected into the dorsal hippocampus: influence of restraint stress Pharmacol Biochem Behav 67 325 330 PubMed CrossRef Google Scholar Pericic, D, Svob, D, Jazvinscak, JM, Mirkovic, KK 2001 The involvement of alpha2-adrenoceptors in the anticonvulsive effect of swim stress in mice Psychopharmacology (Berl) 158 87 93 CrossRef Google Scholar Rao, TL, Kokare, DM, Sarkar, S, Khisti, RT, Chopde, CT, Subhedar, N 2003 GABAergic agents prevent alpha-melanocyte stimulating hormone induced anxiety and anorexia in rats Pharmacol Biochem Behav 76 417 423 PubMed CrossRef Google Scholar Roche, M, Commons, KG, Peoples, A, Valentino, RJ 2003 Circuitry underlying regulation of the serotonergic system by swim stress J Neurosci 23 970 977 PubMed Google Scholar Smith, KK, Dharmaratne, HR, Feltenstein, MW, Broom, SL, Roach, JT, Nanayakkara, NP, Khan, IA, Sufka, KJ 2001 Anxiolytic effects of kava extract and kavalactones in the chick social separation-stress paradigm Psychopharmacology (Berl) 155 86 90 CrossRef Google Scholar Srikumar, BN, Raju, TR, Shankaranarayana Rao, BS 2006 The involvement of cholinergic and noradrenergic systems in behavioral recovery following oxotremorine treatment to chronically stressed rats Neuroscience 143 679 688 PubMed CrossRef Google Scholar Srikumar, BN, Raju, TR, Shankaranarayana Rao, BS 2007 Contrasting effects of bromocriptine on learning of a partially baited radial arm maze task in the presence and absence of restraint stress Psychopharmacology (Berl) 193 363 374 CrossRef Google Scholar Sunanda, , Shankaranarayana Rao, BS, Raju, TR 2000 Chronic restraint stress impairs acquisition and retention of spatial memory task in rats Curr Sci 79 1581 1584 Google Scholar Tona, L, Cimanga, RK, Mesia, K, Musuamba, CT, De Bruyne, T, Apers, S, Hernans, N, Van Miert, S, Pieters, L, Totte, J, Vlietinck, AJ 2004 In vitro antiplasmodial activity of extracts and fractions from seven medicinal plants used in the Democratic Republic of Congo J Ethnopharmacol 93 27 32 PubMed CrossRef Google Scholar Tona, L, Kambu, K, Mesia, K, Cimanga, K, Apers, S, De Bruyne, T, Pieters, L, Totte, J, Vlietinck, AJ 1999a Biological screening of traditional preparations from some medicinal plants used as antidiarrhoeal in Kinshasa, Congo Phytomedicine 6 59 66 Google Scholar Tona, L, Kambu, K, Ngimbi, N, Mesia, K, Penge, O, Lusakibanza, M, Cimanga, K, De Bruyne, T, Apers, S, Totte, J, Pieters, L, Vlietinck, AJ 2000 Antiamoebic and spasmolytic activities of extracts from some antidiarrhoeal traditional preparations used in Kinshasa, Congo Phytomedicine 7 31 38 PubMed Google Scholar Tona, L, Ngimbi, NP, Tsakala, M, Mesia, K, Cimanga, K, Apers, S, De Bruyne, T, Pieters, L, Totte, J, Vlietinck, AJ 1999b Antimalarial activity of 20 crude extracts from nine African medicinal plants used in Kinshasa, Congo J Ethnopharmacol 68 193 203 CrossRef Google Scholar Vijaya, K, Ananthan, S, Nalini, R 1995 Antibacterial effect of theaflavin, polyphenon 60 (Camellia sinensis) and Euphorbia hirta on Shigella spp. – a cell culture study J Ethnopharmacol 49 115 118 PubMed Google Scholar Vyas, A, Mitra, R, Shankaranarayana Rao, BS, Chattarji, S 2002 Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons J Neurosci 22 6810 6818 PubMed Google Scholar Wright, IK, Upton, N, Marsden, CA 1992 Effect of established and putative anxiolytics on extracellular 5-HT and 5-HIAA in the ventral hippocampus of rats during behaviour on the elevated X-maze Psychopharmacology (Berl) 109 338 346 CrossRef Google Scholar