Solanum paniculatum L. (Jurubeba): potent inhibitor of gastric acid secretion in mice.
Solanum paniculatum L. is used commonly in Brazilian folk medicine for the treatment of liver and gastrointestinal disorders. The freeze-dried aqueous extracts (WEs) obtained from distinct parts of the plant (flowers, fruits, leaves, stems and roots) were tested to determine their antiulcer and anti-secretory gastric acid activities using mice. The aqueous extracts of roots, stems and flowers inhibited gastric acid secretion in pylorus-ligated mice with [ED.sub.50] values of 418, 777 and 820 mg/kg body wt. (i.d.), respectively. Extracts of leaves (0.5-2 g/kg body wt., i.d.) did not affect gastric secretion, whereas fruit extracts (0.5-2 g/kg body wt., i.d.) stimulated gastric acid secretion. The stimulatory effect of the fruit extract was inhibited by pretreatment with atropine (5 mg/kg body wt., i.m.) but not with ranitidine (80 mg/kg body wt., i.p.) suggesting that the fruit extract activates the muscarinic pathway of gastric acid secretion. In contrast, administration of the root extract into the duodenal lumen inhibited histamine- and bethanechol-induced gastric secretion in pylorus-ligated mice. In addition, the aqueous extract of roots ([ED.sub.50] value, 1.2 g/kg body wt., p.o.) protected the animals against production of gastric lesions subsequent to the hypersecretion induced in mice by stress following cold restraint. This effect was not reproduced when the lesions were induced by blockade of prostaglandins synthesis via subcutaneous injection of indomethacin. Thus, antiulcer activity of the plant extracts appears to be related directly to a potent anti-secretory activity. No toxic signs were observed following administration of different extracts up to 2 g/kg body wt., p.o. Collectively, the results validate folk use of Solanum paniculatum L. plant to treat gastric disorders.
Key words: Solanurn paniculatum, Solanaceae, antiacid, antiulcer, medicinal plant, gastric acid secretion, pylorus ligature.
Solanum paniculatum L (Solanaceae), known popularly as either jurubeba, jurupeba, juripeba, jubeba, juvena, juina or juna (Correa, 1984; Coimbra 1958) is a widespread plant species used in Brazilian folk medicine as a tonic, antifever agent (Santos et al., 1988), colagogue, bitter, and eupeptic to treat liver and gastric dysfunctions (Costa, 1975; Penna 1964). The plant is a component of various pharmaceutical formulations including: syrups, infusions or decoctions (2%), ethanolic extracts, tinctures, and elixirs (Costa, 1940; Farmacopeia Brasileira, 1959). The flower's infusion (0.3%) is also indicated for bronchitis and cough; the root's macerate (6%) for arthritis and that from the fruits (16%) for anemia (Matos, 1987).
Many steroidal compounds have been isolated from this species. These alkaloids include jurubebina, jubebine, and solanine; and the resins jupebina and jupebenina (Siqueira-Jaccound et al., 1982; Costa, 1940). Fructose, glucose and galactose were detected in the fruits (Leekning and Rocca, 1968), and solanine was isolated from its roots and stems (Siqueira and Macan, 1976). Saponins were also identified in the roots of this species as isojuripidine, isojurubidine, isopaniculidine and jurubidine (Ripperger et al., 1967a,b; Schreiber et al., 1965). Jurubidine, a sugar-free steroid obtained via acid hydrolysis of the glucoside jurubine, was also isolated from S. paniculatum roots (Schreiber and Ripperger, 1966). No reports have been found relating the biological activity of the plant extract to its constituents.
The aim of the present study was to validate the popular use of S. paniculatum for gastric disturbances. Different parts of the plant used in folk medicine for different afflictions were tested separately for their effects on gastric secretion.
Material and Methods
Carbamyl-[beta]-methylcholine chloride (Sigma), histamine dihydrochloride (Sigma), ranitidine (Antak-Glaxo), atropine (Merck) and indomethacin (Indocid-MSD) were purchased from the sources indicated. All the other chemicals were of the highest commercial grade available.
Solanum paniculatum was supplied by Dr. Josvaldo de Ataide from the Universidade Federal da Paraiba (Joao Pessoa, PB, Brazil) and a voucher of this specimen was deposited at the Herbario Atico Seabra under number 14. Isolated parts of the plant (fruits, flowers, leaves, stems and roots) were dried in the shade for 4 days, ground and extracted (5%) in hot water (73 [degrees]C) for 30 min. The aqueous extracts (WEs) were concentrated in vacue to one-quarter of the original volume and freeze-dried. The yields of extraction were 7.6%, 22.3%, 8.28%, 16.8% and 18.4% , respectively for root (RE), fruit (FrE), stem (SE), flower (FlE) and leaf (LE) extracts. The freeze-dried powders were redissolved in water prior to administration.
F1 mice (25-30 g), a hybrid from a cross between inbred C57B1/6 females and Balb/C males, of either sex, were used in this study. All animals were kept under a controlled light/dark cycle and temperature (22 [+ or -] 2 [degrees]C). For the antisecretory study the animals were deprived of solid food, with free access to water, for 15-18 h before the experiments.
A pylorus ligature was performed carefully in mice under ether anesthesia and the WEs of the various parts of the plant (RE, FlE, SE, FrE and LE, 0.5 to 2.0 g/kg body wt.) were injected into the duodenal lumen (i.d.). After 4 h, the animals were killed by deep ether anesthesia, the stomachs opened by the great curvature and the gastric secretion collected. The final volume and pH were directly determined after washing the mucosal side of the stomach with 2 ml of distilled water. Total acidity of the gastric juice was titrated with 0.01 N NaOH using 2% phenolphtalein as indicator. The RE (1 g/kg body wt., i.d.) was also tested on gastric acid secretion induced by bethanechol (3 mg/kg body wt.) or histamine (10 mg/kg body wt.) injected subcutaneously 1 h after surgery. The FrE (1 g/kg body wt., i.d.) was tested on gastric acid secretion of pylorus ligated mice treated with atropine (5 mg/kg body wt., i.m.) or ranitidine (80 mg/kg body wt., i.d.) 1 h after surgery (Vela et al., 1997).
Fasted mice were treated with the root extracts (0.5-2.0 g/kg body wt., p.o.). After 1 h, gastric lesions were induced either by stress (restraint for 2 h at 4 [degrees]C or indomethacin (10 mg/kg body wt., s.c.). The animals were killed under ether anesthesia after either 2 h of restraint at 4 [degrees]C or 3 h after indomethacin injection. The stomach was dissected out, and the mucosal side was gently washed to remove remaining food and inspected under magnification to determine the number of ulcers and score the index of mucosal damage (IMD). This was done independently by two different colleages after the same preparation, considering the color, edema and hemorrhage of the gastric folds, the number of petechiae, and the number and size of ulcers (Vela et al. 1997).
Data were expressed as means [+ or -] S.E.M. Statistical significance of the results was determined using a one-way analysis of variance followed by the Tukey Kramer test. Data were considered significantly different at p < 0.05. The [IC.sub.50] values were calculated by fitting the data to the equation: Vi/Vo = 11(1 + [I]/[IC.sub.50]), using the Kaleida Graph for Windows program (Synergy Software-Pennsylvania). Vi = fractional activity; Vo = remaining activity.
In control pylorus ligated mice, the volume of gastric juice secreted over 4 h was 0.81 [+ or -] 0.08 ml with a pH level of 3.4 [+ or -] 0.24 and total acidity of 3.65 [+ or -] 0.78 mEq[H.sup.+]/l/4h (n = 8). Previous administration of ranitidine (50 mg/kg body wt., i.d., n = 8) decreased the total acidity of the gastric juice by 67% (from 4.30 [+ or -] 0.82 to 1.42 [+ or -] 0.23 mEq[H.sup.+]/l/4h); pH was increased by 2 log units but the secreted volume (0.75 [+ or -] 0.09 ml) was not altered. At the highest dose of the flower extract (FlE 2 g/kg body wt., i.d., n = 5) the volume and total acidity of the gastric secretion were reduced by 70% and 62%, respectively. The pH of the gastric secretion was not altered. Extract of the leaves (LE 0.5-2 g/kg body wt., i. d.) did not modify gastric acid secretion at any dose tested (Table 1).
Pretreatment with the fruit extract (FrE 0.5, 1 and 2 g/kg body wt., i.d., n = 5) did not alter the volume of gastric secretion, but increased the total acidity by 2-3 times depending on the dose (Table 1). With the higher dose, the pH of the gastric secretion was decreased by 1.4 log units (Figure 1a). Pretreatment with ranitidine (80 mg/kg body wt., i.p.) did not inhibit the stimulatory effect of the FrE, while pretreatment with atropine (5 mg/kg body wt., i.m.) reduced this effect by 78% (Figure 1b).
When mice were treated with the stem extract (SE 0.5, 1.0and 2 g/kg body wt., i.d.) the total acidity of the gastric juice was reduced in a dose-dependent manner ([ED.sub.50] value, 777 mg/kg body wt.) (Table 1). Administration of the root extract (RE 0.5 to 2 g/kg body wt., i.d.) decreased the total acid secretion ([ED.sub.50] value,, 418 mg/kg body wt.). The highest dose reduced the secreted volume by 44% and increased its pH by 1 log unit. Injection of the secretagogues histamine (10 mg/kg body wt., s.c.) or bethanechol (3 mg/kg body wt., s.c.) increased total acidity of gastric secretion in pylorusligated mice by 486% and 344%, respectively. Pretreatment with RE (1g/kg body wt., i.d., n = 5) inhibited the effects of both histamine and bethanecol on gastric acid secretion (Figure 2).
Mice immobilized in the cold for 2 h developed ulcers (2.2 [+ or -] 0.5 ulcers/ [cm.sup.2]) and other signs of gastric damage. The index of mucosal damage (IMD) scored 11.2 [+ or -] 2.0. Pretreatment with the root extract (0.5-2.0 g/kg body wt., p.o.) decreased the number of lesions and ulcers induced by stress. The IMD was decreased to an [ED.sub.50] value of 830 mg/kg body wt. after pretreatment with the root extract. In the same way, control mice injected with indomethacin (10 mg/kg body wt., s.c.) presented 23.8 [+ or -] 0.6 ulcers/[cm.sup.2] and an TMD of 51.2 [+ or -] 10.9. Previous treatment with RE (0.5-2.0 g/kg body wt., p.o.) did not protect mice against indomethacin-induced lesions (Figure 3).
Solanum paniculatum is a widespread species used in Brazilian folk medicine to treat liver and gastrointestinal disorders. The present paper was primarily concerned with the validation of the folk use of S. paniculatum water extracts for gastric disturbances.
Extractions of all plant parts are mentioned in Brazilian phytomedicine formularies (Coimbra, 1958, Silva, 1977). The root is considered the most active part of the plant and its strong bitterness is taken as a sign of its potency. The results have shown that the gastric activities of S. paniculatum vary when different parts of the plant are extracted in water. The root extract showed higher antisecretory gastric acid activity than extracts of stems and flowers, and no effect was observed with the leaf extract. In contrast, treatment with fruit extracts stimulated gastric acid secretion. The results could be explained by different synthetic/metabolic rates leading to the non-uniform distribution of the plant's constituents. The chemical composition of Solanum paniculatum has long been studied and many substances have been isolated from the entire plant. For example, alkaloids are in higher quantity in roots (0.98%) than in stems (0.28%) and few are found (0.20%) in the leaves (Meyer and Bernoulli, 1961; Sique ira-Jaccound et al., 1982). These differences may correlate with the higher activity of the root extract in our experiments. Thus, the anti-secretory activity of the roots can be related to the high concentration of alkaloids in this part of the plant. To our knowledge, the results presented above are the first report of bioactivity of S. paniculatum affecting gastric acid secretion.
In our experiments, the root, stem and flower extracts decreased gastric acid secretion but this effect was not seen in the leafe or fruit extracts. In fact, the fruit extracts increased acid gastric secretion. The stimulatory effect of the fruit extract of S. paniculatum was inhibited by the muscarinic antagonist, atropine, but not by the [H.sub.2] -receptor antagonist, ranitidine, indicating that the stimulatory effect of the fruit extracts is due to activation of the muscarinic pathway of gastric secretion. Histamine stimulates gastric acid secretion by direct interaction at the parietal cell [H.sub.2]-receptors that are coupled to the adenylyl cyclase system through G proteins. Activation of adenylyl cyclase increases the production of cAMP, which further activates cAMP-dependent protein kinases. This action results in phosporylation of certain phosphatases that subsequentely activate the proton pump (Obrink, 1991; Chew, 1985). Bethanecol, on the other hand, interacting with the muscarinic receptors on th e parietal cell, activates phospholipase C and phosphoinositide hydrolysis, with consequent production of inositol triphosphate ([IP.sub.3]) and diacylglycerol (DAG). These second messengers increase cytosol calcium levels through its mobilization from the sarcoplasmic reticulum or through stimulation of calcium influx from the extracellular space (Chiba et al., 1988; Pfeiffer et al., 1990). The root extract of S. paniculatum reduced spontaneous gastric acid-secretion, and the secretion induced by histamine or by bethanechol with the same effectiveness. These inhibitory or stimulatory effects cannot be attributed to a topical effect on the gastric mucosa, because the extract was always injected into the duodenal lumen.
Our results do not permit precise determination of the mechanism of action; however, it is reasonable to propose that either blockade of the muscarinic receptor or events involving second messengers downstream from the receptor can lead to the activities described above. Increases in intracellular calcium and activation of protein kinase C have been considered in in vitro ongoing studies. In addition, specific blockade of different receptors for physiological secretagogues is not expected. Taking into account that stimulation of the gastric secretion by muscarinic and histaminergic agonists involves activation of the proton-pump, this enzyme is a putative site of action for the S. paniculatum root extract. Previously reported results reinforce the muscarinic pathway blockade hypothesis. The steroidal alkaloid ebeinone isolated from Fritillaria imperialis has been shown to inhibit the M2 and M3 type muscarinic receptors (Rahman at el., 1994; Gilani et al., 1997). Anticholinesterasie activity of other alkaloids from Solanum was reported by Faucher and Monnet (1967) and by Fluck and Jaffe (1975). Thus far, the pharmacological activity of S. paniculatum may be attributed to alkaloid steroidal subtances. Isolation of these components, and further chemical identification and determination of their mechanism of action in vitro are still in progress.
Acute gastric lesions were induced by administration of indomethacin or by cold restraint. The root extract was effective only against the stress-induced gastric lesions. The mechanisms involved are different from those induced by indomethacin. Ulcers in the former model occur by complex mechanisms that lead mainly to the stimulation of acid secretion. Activation of the limbic system by stress stimulates gastric secretion through autonomic projections (Kitagawa et al., 1987), gastrointestinal motility (Goldman and Rossof, 1968), glucocorticoids, catecholamines and histamine release (Lorenz et al., 1973) that enhance gastric acid secretion. On the other hand, the mechanism of gastric lesion formation by subcutaneous injection of indomethacin involves the blockade of important cytoprotective factors, the activation of which are stimulated by prostaglandins, inhibited in this model (Djahanguiri, 1969; Menguey and Desbaillets, 1967). Several factors have been implicated in gastric mucosa damage by anti-inflammato ry drugs such as indomethacin. Although the mechanisms are not completely understood, two main pathogenic mechanisms have been suggested for the lesions induced by these kinds of compounds. The first one involves uncoupling of mitochondrial oxidative phosphorylation, thus increasing gastric permeability, which leads to a "topical" inflammation. The second effect is directly related to inhibition of cyclooxygenase-l (Somasundaram et al., 1995; Somasundaran et al., 1997; Mahmud et al., 1996). Administration of indomethacin by the subcutaneous route avoids the topical action of the compound (Martin, 1963; Szabo, 1987). The observation that the root extract of S. paniculatum inhibited only the lesions induced by stress reinforces the idea that the anti-secretory activity, rather than a purely gastroprotective effect, is involved in the antiulcer action.
Collectively, the results can explain the traditional use of S. paniculatum in gastric upset but the plant cannot be recommended for general human use as long as the toxicological potential of the water extract is not investigated. Steroid alkaloids from S. paniculatum belong to a class of potential toxic plant constituents with known strong teratogenic effects as well as anti-cholinesterase (Roddick, 1989) activity which may lead to CNS excitation and convulsions (Barbosa-Filho et al., 1991). Solanine, a reported constituent of S. paniculatum, shows strong teratogenic activity (Gaffield and Keeler, 1996, Crawford and Myhr, 1995). Although, up to now only a few steroid alkaloids have been found in S. paniculatum such as jurubebine and juribin, the biological activities of these compounds are unknown. Solasonine and solamargine, two major steroidal alkaloids found in at least 100 Solanum species (reviewed by Blankemeyer et al., 1998) are known to be potent teratogens, but their presence in S. paniculatum has n ot been established. Therefore the use of S. paniculatum extracts as a rational phytopharmaceutical for the treatment of gastric upset can be considered only after its active ingredients have been fully identified, the water extract has been standardized and the potential toxicity determined.
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Table 1 Effects of the flowers (FlE), leaves (LE), fruits (FrE), stem (SE) and root (RE) extracts of Solanum paniculatum L on total gastric acidity (mEq[[H.sup.+]]/L/4h) in mice. Treatment FlE LE (g/kg body wt., i.d.) mEq[[H.sup.+]]/l/4h mEq[[H.sup.+]]/l/4h Control 3.63 [+ or -] 0.78 1.74 [+ or -] 0.70 (n = 8) (n = 5) 0.5 1.94 [+ or -] 1.12 1.60 [+ or -] 0.56 (n = 5) (n = 5) 1.0 1.68 [+ or -] 0.68 0.73 [+ or -] 0.20 (n = 5) (n = 4) 2.0 1.37 [+ or -] 0.88 * 1.67 [+ or -] 0.49 (n = 5) (n = 4) Treatment FrE SE (g/kg body wt., i.d.) mEq[[H.sup.+]]/l/4h mEq[[H.sup.+]]/l/4h Control 2.55 [+ or -] 0.48 4.30 [+ or -] 0.82 (n = 7) (n = 6) 0.5 6.88 [+ or -] 2.23 2.20 [+ or -] 0.60 * (n = 5) (n = 7) 1.0 7.36 [+ or -] 1.74 * 2.07 [+ or -] 0.52 * (n = 5) (n = 5) 2.0 5.60 [+ or -] 1.21 * 1.46 [+ or -] 0.23 * (n = 4) (n = 7) Treatment RE (g/kg body wt., i.d.) mEq[[H.sup.+]]/l/4h Control 4.16 [+ or -] 0.76 (n = 15) 0.5 1.52 [+ or -] 0.27 * (n = 10) 1.0 1.46 [+ or -] 0.47 * (n = 20) 2.0 1.03 [+ or -] 0.22 * (n = 14) * significantly different from the control group (Anova-Tukey Kramer test, p < 0.05)
This work was supported by Central de Medicamentos (CEME) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq). S. Mesia-Vela and M.T. Santos received fellowships from CAPES and CNPq, respectively. We would like to thank Dr. F.C. Kauffman and Rosa I. Sanchez from Rutgers University-USA for their invaluable help in the writing of this paper.
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S. Mesia-Vela (1), M. T. Santos (1), C. Souccar (1), M. T. R. Lima-Landman (1), and A. J. Lapa (1)
(1.) Natural Products Section, Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo, SP, Brazil
Sonia Mesia Vela, Ph.D., Laboratory for Cellular and Biochemical Toxicology, 41 Gordon Rd., Piscataway, NJ 08854 USA
Tel: ++1-732-445-6900; Fax: ++1-732-445-6905; e-mail: email@example.com
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|Author:||Mesia-Vela, S.; Santos, M.T.; Souccar, C.; Lima-Landman, M.T.R.; Lapa, A.J.|
|Publication:||Phytomedicine: International Journal of Phytotherapy & Phytopharmacology|
|Date:||Sep 1, 2002|
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