Mechanism of antiulcerogenic activity of semi-synthetic crotonin obtained from Croton cajucara Benth.

Almeida, Ana Beatriz A.; Miotto, Alexandre M.; Nunes, Domingos S.; Spadari-Bratifisch, Regina C.; Brito, Alba R. M. Souza

doi:10.1590/S0102-695X2002000300050

Abstract

The bark of Croton cajucara Benth. is used in Brazilian folk medicine to treat gastrointestinal disorders. Transdehydrocrotonin (DHC) isolated from the bark of Croton cajucara has antiulcerogenic activity25. The presence of similar activity in semi-synthetic crotonin obtained from dehydrocrotonin from Croton cajucara was observed in gastric ulcer-induced models (HCl/ethanol, ethanol, indomethacin, stress and pylorus ligature). The aim of the present study was to assess the mechanisms involved in the antiulcerogenic activity of semi-synthetic crotonin. We investigated the effects of semi-synthetic crotonin on the response to histamine of right atria isolated from guinea pigs and on the response to carbachol of stomach fundus strips from rats. Semi-synthetic crotonin (3, 10 or 30 mM) induced a shift to the right in the concentrationresponse curves to carbachol in the isolated rat stomach at the pD2 level (pD2: 5.42±0.05, 5.76±0.061, 5.77±0.076, 6.48±0.012, respectively), without any alteration in the maximum response. Semi-synthetic crotonin also induced a shift to the right in the concentration-response curves to histamine in guinea pig right atria, pD2 (5.54±0.06, 6.01±0.06, 5.89±0.06, 5.92±0.03) and (%) maximum response (80±6.18, 118±6.18, 114±6.18, 122±1.4), respectively. Thus, the protective effect of semi-synthetic crotonin on induced gastric lesions could be due to antagonism of histaminergic and cholinergic effects on gastric secretion.

Mechanism of antiulcerogenic activity of semi-synthetic crotonin obtained from Croton cajucara Benth.

Ana Beatriz A. Almeida^I,^* * anabia5@hotmail.com ; Alexandre M. Miotto^II; Domingos S. Nunes^III; Regina C. Spadari-Bratifisch^II; Alba R. M. Souza Brito^II

^IDepartamento de Farmacologia, F.C.M., UNICAMP, Cidade Universitária Zeferino Vaz, CP 6109, 13083-970, Campinas, SP, Brasil

^IIDepartamento de Fisiologia e Biofísica, I.B., UNICAMP

^IIIDepartamento de Química, Universidade Estadual de Ponta Grossa

ABSTRACT

The bark of Croton cajucara Benth. is used in Brazilian folk medicine to treat gastrointestinal disorders. Transdehydrocrotonin (DHC) isolated from the bark of Croton cajucara has antiulcerogenic activity25. The presence of similar activity in semi-synthetic crotonin obtained from dehydrocrotonin from Croton cajucara was observed in gastric ulcer-induced models (HCl/ethanol, ethanol, indomethacin, stress and pylorus ligature). The aim of the present study was to assess the mechanisms involved in the antiulcerogenic activity of semi-synthetic crotonin. We investigated the effects of semi-synthetic crotonin on the response to histamine of right atria isolated from guinea pigs and on the response to carbachol of stomach fundus strips from rats. Semi-synthetic crotonin (3, 10 or 30 mM) induced a shift to the right in the concentrationresponse curves to carbachol in the isolated rat stomach at the pD2 level (pD2: 5.42±0.05, 5.76±0.061, 5.77±0.076, 6.48±0.012, respectively), without any alteration in the maximum response. Semi-synthetic crotonin also induced a shift to the right in the concentration-response curves to histamine in guinea pig right atria, pD2 (5.54±0.06, 6.01±0.06, 5.89±0.06, 5.92±0.03) and (%) maximum response (80±6.18, 118±6.18, 114±6.18, 122±1.4), respectively. Thus, the protective effect of semi-synthetic crotonin on induced gastric lesions could be due to antagonism of histaminergic and cholinergic effects on gastric secretion.

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Acknowledgements

This study was financed by the Brazilian agency FAPESP (nº 9803442-2)

1 Almeida ABA, Melo PS, Gracioso JS, Nunes DS, Haun M, Souza Brito ARM. Antiulcerogenic and cytotoxic activity of semi-synthetic crotonin of Croton cajucara Benth. (submitted Toxicon, 2001)
2 Bado A, Laigneau JP, Moizo L, Cherifi Y, Lewin MJM. H3- Receptor activation inhibits cholinergic stimulation of acid secretion in isolated rabbit fundic glands. The Journal of Pharmacology and Experimental Therapeutics. 1995; 275: 1099-1103
3 Berridge MJ. Inositol triphosphate and calcium signalling. Nature. 1993, 361: 315-325
4 Dial EW, Thompson WJ, Rosenfeld GC. Isolated parietal cells: histamine response and pharmacology. The Journal of Pharmacology and Experimental Therapeutics. 1981; 219: 585-90
5 Hirschowitz BI, Keeling D, Lewin M, Okabe S, Sewing K, Wallmark B, Sachs G. Pharmacological aspects of acid secretion. Digestive Diseases and Sciences. 1995; 40: 3S-23S
6 Hiruma-Lima CA, Spadari-Bratfisch RC, Nunes DS, Grassi-Kassisse DM, Souza Brito ARM. Antiulcerogenic mechanisms of dehydrocrotonin, a diterpene lactone obtained from Croton cajucara Planta Medica. 1999; 65: 325-330
7 Itokawa H, Ichihara Y, Kojima H, Watanabe K, Takeya K. Nor-Clerodane diterpenes from Croton cajucara Phytochemistry 1989; 28(6):1667-1669
8 Kajimura M, Reuben MA, Sachs G. The muscarinic receptor gene expressed in rabbit parietal cells is the M3 subtype. Gastroenterology. 1992; 103: 870-875
9 Kilbinger H, Nafziger M. Two types of neuronal muscarine receptors modulating acetylcholine release from guinea-pig myenteric plexus. Naunyn-Schmiedeberg's Arch. Pharmacol. 1986; 328: 304-9
10 Korolkiewicz R, Sliwinski W, Rekowski P, Halama-Borowiec A, Mucha P, Szczurowicz A, Korolkiewicz KZ. Galanin, galantinde ND galanin (1-14)-[a-aminobutyric acid]-scyliorhinin-1: structure dependent effects on the rat isolated gastic fundus. Pharmacology Research. 1997; 35: 7-16
11 Krielaart MJ, Veenstra DMJ, Van Buuren KJH. Mechanism of action of H2-receptors of spontaneously beating guinea-pig atrium. Agents Actions. 1990; 31: 23-34
12 Lin S, Kajimura M, Takeuchi K, Kodaira M, Hanai H, Kaneko E. Expression of muscarinic receptor subtypes in rat gastric muscle - Effect of M3 selective antagonist on gastric motility and emptying. Digestive Diseases and Sciences. 1997; 42: 907-14
13 Mertz-Nielsen A, Hillingso J, Eskerod O, Buknave K, Raskmadsen J. Muscarinic M1 receptor inhibition reduces gastoduodenal bicarbonate secretion and promotes gastric prostaglandin E2 synthesis in healthy volunteers. Gut. 1995; 36: 528-33
14 Mertz-Nielsen A, Munck LK, Bukhave K, Rask-Madsen J. Muscarinic M1- receptors regulate gastric mucosal prostaglandin E2 formation. Eur. J. Gastroenterol. Hepatol. 1989; 1: 57-62
15 Mitra SK, Gopumadhavan S, Hemavathi TS, Muralidhar TS, Venkataranganna MV. Protective effect of UL-409, a herbal formulation against physical and chemical factor induced gastric and duodenal ulcers in experimental animals. Journal of Ethnopharmacology. 1996; 52: 165-169
16 Oishi K, Ishibashi T, Nakamura S, Mita M, Uchida MK. Protein kinase C promotes spontaneous relaxation of streptolysin-opermeabilized smooth muscle cells from the guinea-pig stomach. Life Sciences. 1999; 64: 1975-87
17 Pfeiffer A, Rochlitz H, Noelke B, Tacke R, Moser U, Mutschler E. Muscarinic receptor mediating acid secretion are of M3 type. Gastroenterology. 1990; 98: 218-22
18 Prinz C, Kajimura M, Scott DR, Mercier F, Helander HF, Sachs G. Histamine secretion from rat enterocromaffinlike cells. Gastroenterology. 1993; 105: 449-461
19 Prinz C, Neumayer N, Mahr S, Classen M, Schepp W. Gastroenterology. 1997; 12: 364-375
20 Rangachari PK. Histamine: Mercurial messenger in the gut. Am. J. Physiol. 1992; 262: G1-G13
21 Sandvik AK, Waldum HL. Scand. J. Gastroenterol. 1988; 23: 696-700
22 Schubert ML, Harrington L, Makhlouf GM. Reciprocal paracrine pathways link histamine and somatostatin secretion in the fundus of rat stomach. Gastroenterology. 1993; 104: A188
23 Shamburek RD, Scubert ML. Pharmacology of gastric acid inhibition. Baillieres Cli. Gastroenterol. 1993; 7: 23-54
24 Soll AH, Berglindh T. In: Physiology of the Gastrointestinal Tract. Ed. Johnson, L.R. 1994; 2: 1139-1169
25 Souza Brito ARM, Rodriguez Já, Hiruma-Lima CA, Haun M, Nunes DS. Antiulcerogenic activity of trans-dehydrocrotonin from Croton cajucara Planta Medica. 1998; 64: 126-129
26 Souza-Formigoni MLO, Oliveira MGM, Monteiro MG, Silveira-Filho NG, Braz S, Carlini EA. Journal of Ethnopharmacology. 1991; 34: 21-27
27 Stephenson RP. A modification of receptor theory. Br. J. Pharmacol. 1956; 11: 379-393
28 Takeuchi K, Yagi K, Kato S, Uakawa H. Gastroenterology. 1997; 113: 1553-1559
29 Van der Berg. Plantas medicinais da Amazônia - Contribuição ao seu conhecimento sistemático, Museu Paraense Emílio Goeldi. Belém. 1993; p. 223
30 Vane JR. A sensitive method for the assay of 5-hydroxytryptamine. Br. J. Pharmacol. Chemother. 1957; 12: 344-349
31 Vuyyuru L, Schubert ML. Histamine, acting via H3 receptors, inhibits somatostatin and stimulates acid secretion in isolated mouse stomach. Gastroenterology. 1997; 113: 1545-1552
32 Weigert N, Schaffer K, Wegner U, Schusdziarra V, Classen M, Schepp W. Functional characterization of muscarinic receptor stimulating gastrin release from rabbit antral G-cells in primary culture. European Journal of Pharmacology. 1994; 264: 337-344

*

anabia5@hotmail.com

Publication Dates

Publication in this collection
05 Oct 2009
Date of issue
2002

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

[1] 1 Almeida ABA, Melo PS, Gracioso JS, Nunes DS, Haun M, Souza Brito ARM. Antiulcerogenic and cytotoxic activity of semi-synthetic crotonin of Croton cajucara Benth. (submitted Toxicon, 2001)

[2] 2 Bado A, Laigneau JP, Moizo L, Cherifi Y, Lewin MJM. H3- Receptor activation inhibits cholinergic stimulation of acid secretion in isolated rabbit fundic glands. The Journal of Pharmacology and Experimental Therapeutics. 1995; 275: 1099-1103

[3] 3 Berridge MJ. Inositol triphosphate and calcium signalling. Nature. 1993, 361: 315-325

[4] 4 Dial EW, Thompson WJ, Rosenfeld GC. Isolated parietal cells: histamine response and pharmacology. The Journal of Pharmacology and Experimental Therapeutics. 1981; 219: 585-90

[5] 5 Hirschowitz BI, Keeling D, Lewin M, Okabe S, Sewing K, Wallmark B, Sachs G. Pharmacological aspects of acid secretion. Digestive Diseases and Sciences. 1995; 40: 3S-23S

[6] 6 Hiruma-Lima CA, Spadari-Bratfisch RC, Nunes DS, Grassi-Kassisse DM, Souza Brito ARM. Antiulcerogenic mechanisms of dehydrocrotonin, a diterpene lactone obtained from Croton cajucara Planta Medica. 1999; 65: 325-330

[7] 7 Itokawa H, Ichihara Y, Kojima H, Watanabe K, Takeya K. Nor-Clerodane diterpenes from Croton cajucara Phytochemistry 1989; 28(6):1667-1669

[8] 8 Kajimura M, Reuben MA, Sachs G. The muscarinic receptor gene expressed in rabbit parietal cells is the M3 subtype. Gastroenterology. 1992; 103: 870-875

[9] 9 Kilbinger H, Nafziger M. Two types of neuronal muscarine receptors modulating acetylcholine release from guinea-pig myenteric plexus. Naunyn-Schmiedeberg's Arch. Pharmacol. 1986; 328: 304-9

[10] 10 Korolkiewicz R, Sliwinski W, Rekowski P, Halama-Borowiec A, Mucha P, Szczurowicz A, Korolkiewicz KZ. Galanin, galantinde ND galanin (1-14)-[a-aminobutyric acid]-scyliorhinin-1: structure dependent effects on the rat isolated gastic fundus. Pharmacology Research. 1997; 35: 7-16

[11] 11 Krielaart MJ, Veenstra DMJ, Van Buuren KJH. Mechanism of action of H2-receptors of spontaneously beating guinea-pig atrium. Agents Actions. 1990; 31: 23-34

[12] 12 Lin S, Kajimura M, Takeuchi K, Kodaira M, Hanai H, Kaneko E. Expression of muscarinic receptor subtypes in rat gastric muscle - Effect of M3 selective antagonist on gastric motility and emptying. Digestive Diseases and Sciences. 1997; 42: 907-14

[13] 13 Mertz-Nielsen A, Hillingso J, Eskerod O, Buknave K, Raskmadsen J. Muscarinic M1 receptor inhibition reduces gastoduodenal bicarbonate secretion and promotes gastric prostaglandin E2 synthesis in healthy volunteers. Gut. 1995; 36: 528-33

[14] 14 Mertz-Nielsen A, Munck LK, Bukhave K, Rask-Madsen J. Muscarinic M1- receptors regulate gastric mucosal prostaglandin E2 formation. Eur. J. Gastroenterol. Hepatol. 1989; 1: 57-62

[15] 15 Mitra SK, Gopumadhavan S, Hemavathi TS, Muralidhar TS, Venkataranganna MV. Protective effect of UL-409, a herbal formulation against physical and chemical factor induced gastric and duodenal ulcers in experimental animals. Journal of Ethnopharmacology. 1996; 52: 165-169

[16] 16 Oishi K, Ishibashi T, Nakamura S, Mita M, Uchida MK. Protein kinase C promotes spontaneous relaxation of streptolysin-opermeabilized smooth muscle cells from the guinea-pig stomach. Life Sciences. 1999; 64: 1975-87

[17] 17 Pfeiffer A, Rochlitz H, Noelke B, Tacke R, Moser U, Mutschler E. Muscarinic receptor mediating acid secretion are of M3 type. Gastroenterology. 1990; 98: 218-22

[18] 18 Prinz C, Kajimura M, Scott DR, Mercier F, Helander HF, Sachs G. Histamine secretion from rat enterocromaffinlike cells. Gastroenterology. 1993; 105: 449-461

[19] 19 Prinz C, Neumayer N, Mahr S, Classen M, Schepp W. Gastroenterology. 1997; 12: 364-375

[20] 20 Rangachari PK. Histamine: Mercurial messenger in the gut. Am. J. Physiol. 1992; 262: G1-G13

[21] 21 Sandvik AK, Waldum HL. Scand. J. Gastroenterol. 1988; 23: 696-700

[22] 22 Schubert ML, Harrington L, Makhlouf GM. Reciprocal paracrine pathways link histamine and somatostatin secretion in the fundus of rat stomach. Gastroenterology. 1993; 104: A188

[23] 23 Shamburek RD, Scubert ML. Pharmacology of gastric acid inhibition. Baillieres Cli. Gastroenterol. 1993; 7: 23-54

[24] 24 Soll AH, Berglindh T. In: Physiology of the Gastrointestinal Tract. Ed. Johnson, L.R. 1994; 2: 1139-1169

[25] 25 Souza Brito ARM, Rodriguez Já, Hiruma-Lima CA, Haun M, Nunes DS. Antiulcerogenic activity of trans-dehydrocrotonin from Croton cajucara Planta Medica. 1998; 64: 126-129

[26] 26 Souza-Formigoni MLO, Oliveira MGM, Monteiro MG, Silveira-Filho NG, Braz S, Carlini EA. Journal of Ethnopharmacology. 1991; 34: 21-27

[27] 27 Stephenson RP. A modification of receptor theory. Br. J. Pharmacol. 1956; 11: 379-393

[28] 28 Takeuchi K, Yagi K, Kato S, Uakawa H. Gastroenterology. 1997; 113: 1553-1559

[29] 29 Van der Berg. Plantas medicinais da Amazônia - Contribuição ao seu conhecimento sistemático, Museu Paraense Emílio Goeldi. Belém. 1993; p. 223

[30] 30 Vane JR. A sensitive method for the assay of 5-hydroxytryptamine. Br. J. Pharmacol. Chemother. 1957; 12: 344-349

[31] 31 Vuyyuru L, Schubert ML. Histamine, acting via H3 receptors, inhibits somatostatin and stimulates acid secretion in isolated mouse stomach. Gastroenterology. 1997; 113: 1545-1552

[32] 32 Weigert N, Schaffer K, Wegner U, Schusdziarra V, Classen M, Schepp W. Functional characterization of muscarinic receptor stimulating gastrin release from rabbit antral G-cells in primary culture. European Journal of Pharmacology. 1994; 264: 337-344