Curine, an Alkaloid Isolated from Chondrodendron platyphyllum Inhibits Prostaglandin E₂ in Experimental Models of Inflammation and Pain

Abstract

Curine is a bisbenzylisoquinoline alkaloid that is isolated from Chondrodendron platyphyllum, a plant that is used to treat malaria, inflammation, and pain. Recent reports have demonstrated the antiallergic effects of curine at nontoxic doses. However, its anti-inflammatory and analgesic properties remain to be elucidated. This study investigated the anti-inflammatory and analgesic effects of curine in mice. We analyzed the effects of an oral treatment with curine in the formation of paw edema, vascular permeability, abdominal contortion, licking behavior, and hyperalgesia using different inflammatory stimuli. Curine significantly inhibited the formation of paw edema by decreasing vascular permeability, inhibited the acetic acid-induced writhing response, inhibited the licking behavior during inflammation but not during the neurogenic phase of the formalin test, and inhibited carrageenan-induced hyperalgesia. Finally, curine inhibited prostaglandin E₂ production in vitro without affecting cyclooxygenase-2 expression. The effects of curine treatment were similar to the effects of indomethacin, but were different from the effects of morphine treatment, suggesting that the analgesic effects of curine do not result from the direct inhibition of neuronal activation but instead depend on anti-inflammatory mechanisms that, at least in part, result from the inhibition of prostaglandin E₂ production. In conclusion, curine presents anti-inflammatory and analgesic effects at nontoxic doses and has the potential for use in anti-inflammatory drug development.

Key words

pain - inflammation - PGE₂ - curine - Chondrodendron platyphyllum - Menispermaceae

• References

• 1 Correa PM. Dicionário das plantas úteis do Brasil e das exóticas cultivadas. Brasília: Instituto Brasileiro de Desenvolvimento Florestal; 1984
• 2 Gotfredsen E. Liber Herbarum II: Chondrodendron platyphyllum (A.St.Hil.) Miers. Available at http://www.liberherbarum.com Accessed September 29, 2013.
• 3 Silva CV. Alcaloides benzofenantridínicos e outros metabólitos do caule e do fruto de Zanthoxylum tingoassuiba St. Hill. [dissertation]. Salvador: Universidade Federal da Bahia; 2006: 123
• 4 Souto AL, Tavares JF, da Silva MS, Diniz Mde F, de Athayde-Filho PF, Barbosa Filho JM. Anti-inflammatory activity of alkaloids: an update from 2000 to 2010. Molecules 2011; 16: 8515-8534
• 5 Dias CS, Barbosa-Filho JM, Lemos VS, Cortes SF. Mechanisms involved in the vasodilator effect of curine in rat resistance arteries. Planta Med 2002; 68: 1049-1051
• 6 Guedes DN, Barbosa JM, Lemos VS, Cortes SF. Mechanism of the vasodilator effect of 12-O-methylcurine in rat aortic rings. J Pharm Pharmacol 2002; 54: 853-858
• 7 Medeiros MA, Pinho JF, De-Lira DP, Barbosa-Filho JM, Araujo DA, Cortes SF, Lemos VS, Cruz JS. Curine, a bisbenzylisoquinoline alkaloid, blocks L-type Ca(2)(+) channels and decreases intracellular Ca(2)(+) transients in A7r5 cells. Eur J Pharmacol 2011; 669: 100-107
• 8 Ribeiro-Filho J, Calheiros AS, Vieira-de-Abreu A, de Carvalho KI, da Silva Mendes D, Melo CB, Martins MA, da Silva Dias C, Piuvezam MR, Bozza PT. Curine inhibits eosinophil activation and airway hyper-responsiveness in a mouse model of allergic asthma. Toxicol Appl Pharmacol 2013; 273: 19-26
• 9 Whittle BA. The use of changes in capillary permeability in mice to distinguish between narcotic and nonnarcotic alalgesics. Br J Pharmacol Chemother 1964; 22: 246-253
• 10 Hunskaar S, Hole K. The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain 1987; 30: 103-114
• 11 Sammons MJ, Raval P, Davey PT, Rogers D, Parsons AA, Bingham S. Carrageenan-induced thermal hyperalgesia in the mouse: role of nerve growth factor and the mitogen-activated protein kinase pathway. Brain Res 2000; 876: 48-54
• 12 Kidd BL, Urban LA. Mechanisms of inflammatory pain. Br J Anaesth 2001; 87: 3-11
• 13 Campos MM, Calixto JB. Neurokinin mediation of edema and inflammation. Neuropeptides 2000; 34: 314-322
• 14 Ivanovska N, Georgieva P, Barot-Ciorbaru R. Correlation between inhibited alternative complement activity and the protective effect induced by Nocardia lysozyme digest (NLD) during Klebsiella pneumoniae infection in mice. Int J Immunopharmacol 1996; 18: 515-519
• 15 Kondo Y, Imai Y, Hojo H, Hashimoto Y, Nozoe S. Selective inhibition of T-cell-dependent immune responses by bisbenzylisoquinoline alkaloids in vivo . Int J Immunopharmacol 1992; 14: 1181-1186
• 16 Luo CN, Lin X, Li WK, Pu F, Wang LW, Xie SS, Xiao PG. Effect of berbamine on T-cell mediated immunity and the prevention of rejection on skin transplants in mice. J Ethnopharmacol 1998; 59: 211-215
• 17 Kupeli E, Kosar M, Yesilada E, Husnu K, Baser C. A comparative study on the anti-inflammatory, antinociceptive and antipyretic effects of isoquinoline alkaloids from the roots of Turkish Berberis species. Life Sci 2002; 72: 645-657
• 18 Wong CW, Seow WK, Zeng TS, Halliday WJ, Thong YH. Comparative immunopharmacology and toxicology of the bisbenzylisoquinoline alkaloids tetrandrine and berbamine. Int J Immunopharmacol 1991; 13: 579-585
• 19 Bezerra-Santos CR, Vieira-de-Abreu A, Vieira GC, Filho JR, Barbosa-Filho JM, Pires AL, Martins MA, Souza HS, Bandeira-Melo C, Bozza PT, Piuvezam MR. Effectiveness of Cissampelos sympodialis and its isolated alkaloid warifteine in airway hyperreactivity and lung remodeling in a mouse model of asthma. Int Immunopharmacol 2012; 13: 148-155
• 20 Costa HF, Bezerra-Santos CR, Barbosa Filho JM, Martins MA, Piuvezam MR. Warifteine, a bisbenzylisoquinoline alkaloid, decreases immediate allergic and thermal hyperalgesic reactions in sensitized animals. Int Immunopharmacol 2008; 8: 519-525
• 21 Tjolsen A, Berge OG, Hunskaar S, Rosland JH, Hole K. The formalin test: an evaluation of the method. Pain 1992; 51: 5-17
• 22 Vane JR, Botting RM. Mechanism of action of anti-inflammatory drugs. Scand J Rheumatol Suppl 1996; 102: 9-21
• 23 Tabas I, Glass CK. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 2013; 339: 166-172
• 24 Fiorucci S, Meli R, Bucci M, Cirino G. Dual inhibitors of cyclooxygenase and 5-lipoxygenase. A new avenue in anti-inflammatory therapy?. Biochem Pharmacol 2001; 62: 1433-1438
• 25 van Rossum DB, Patterson RL. PKC and PLA2: probing the complexities of the calcium network. Cell Calcium 2009; 45: 535-545
• 26 Mambu L, Martin MT, Razafimahefa D, Ramanitrahasimbola D, Rasoanaivo P, Frappier F. Spectral characterisation and antiplasmodial activity of bisbenzylisoquinolines from Isolona ghesquiereina . Planta Med 2000; 66: 537-540
• 27 Posadas I, Bucci M, Roviezzo F, Rossi A, Parente L, Sautebin L, Cirino G. Carrageenan-induced mouse paw oedema is biphasic, age-weight dependent and displays differential nitric oxide cyclooxygenase-2 expression. Br J Pharmacol 2004; 142: 331-338
• 28 Leite DF, Echevarria-Lima J, Ferreira SC, Calixto JB, Rumjanek VM. ABCC transporter inhibition reduces zymosan-induced peritonitis. J Leukoc Biol 2007; 82: 630-637
• 29 Nardi GM, Dalbo S, Monache FD, Pizzolatti MG, Ribeiro-do-Valle RM. Antinociceptive effect of Croton celtidifolius Baill (Euphorbiaceae). J Ethnopharmacol 2006; 107: 73-78
• 30 Koster R, Anderson M, Debeer EJ. Acetic acid for analgesic screening. Federation Proceedings 1959; 18: 412