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The gastric ulcer protective effect of boswellic acids, a leukotriene inhibitor from Boswellia serrata, in rats.

Abstract

Aim of the study is to evaluate the anti-ulcer efficacy of the boswellic acids (BA), a triterpenoid known as anti-inflammatory/anti-arthritic agent, which is in clinical use. The reason for the study is that, the known non-steroidal anti-inflammatory drugs (NSAIDs) are full of side effects especially ulceration which is at the top. BA, although, used as an anti-arthritic agent yet it is not only devoid of ulcer production but protective also. The activity evaluation was done by the following universally accepted animal models viz., pyloric ligation, ethanol-HCl, acetylsalicylic acid, indomethacin and cold restrained stress-induced ulceration in rats. Results of the present study revealed that BA possess a dose dependent antiulcer effect against different experimental models. It showed different degree of inhibition of the ulcer score towards different ulcerogenic agents. The ulcer score against various ulcer inducing agents viz., pyloric ligation, ethanol/HCl, (acute and chronic) acetylsalicylic acid, indomethacin and cold restraint stress, was inhibited by 39%, 38%, 51%, 31%, 37% and 42% respectively at 250mg/kg. From the data it is concluded that BA inhibited ulcer production non-specifically in all the experimental models, whereby, it is not possible to propose a single specific mechanism. Nevertheless it is possible that BA might be acting by increasing the gastric mucosal resistance and local synthesis of cytoprotective prostaglandins and inhibiting the leukotriene synthesis. [c] 2008 Elsevier GmbH. All rights reserved.

Keywords: Boswellia serrata; Boswellic acids; Anti-ulcer; Anti-inflammatory; Leukotriene; Ligation

Introduction

Gastric ulcer demonstrates a morphological defect that extends through the muscularis mucosa into the submucosa or deeper. 98% of all upper gastrointestinal ulcers are found with in the duodenum and stomach in the ratio of approximately 4:1. Although in most cases the etiology of ulcer is unknown yet breach of the "mucosal barrier" leads to ulceration. It is generally accepted that it results from an imbalance between aggressive and defensive factors i.e. mucosal defense mechanism and the offending chemicals (endogenous and exogenous) and/or infectious agents (Wallace and Granger, 1996). The sudden or rapid development of mucosal ulceration with stress can be encountered in shock, burn or severe trauma. Non-judicious use of alcohol, NSAIDs and even bile reflex can also lead to mucosal ulceration. A number of products have been used for the treatment of gastric ulcers such as antacids, proton pump inhibitors or antihistaminics, but most of these drugs produce several adverse reactions (Brunton, 1996). Thus, there is a need for more effective and safe anti-ulcer agents. Several therapeutic agents including plant products are used for the inhibition of excessive gastric secretions, or to boost mucosal defense mechanism, shift in proton pump, stabilizing surface epithelial cells or interfering with prostaglandin synthesis (Lewis and Hanson, 1991). However, plants are the most important source for the new drug development due to the resurgence of the interest in the use of herbal preparations. Our aim of the present study is to access the possible anti-ulcerogenic activity of a plant product, boswellic acids isolated from the gum resin of Boswellia serrata.

In general, the traditional anti-inflammatory drugs both steroidal as well as non-steroidal are mostly associated with a common list of unwanted side effects including ulceration, which are the most common and a serious problem (Kim et al., 2004). BA has been studied extensively for a number of activities including anti-inflammatory, immunomodulatory, anti-tumor, and inflammatory bowel disease (Singh et al., 1996; Sharma et al., 1996; Ammon et al., 1991; Hostanska et al., 2002; Gupta et al., 2001). It also belongs to a non-steroidal anti-inflammatory class of drugs with a different mechanism of action than those of the common NSAIDs (Safayhi et al., 1992). In view of their multi facet therapeutic potential as well as non-toxic nature, we envisaged to evaluate it for anti-ulcer activity in different experimental animals models. The study conducted with BA as well as the four major pure isolates. The observations revealed that the pure isolates showed less antiulcer effect in comparison to the total mixture. Keeping this fact into consideration BA has been taken for the further study in detail.

Materials and methods

Chemicals

All reagents used were of high-grade purity. Acetonitrile and acetic acid were of Rancham Fine Chemicals Limited New Delhi, India, acetylsalicylic acid and indomethacin were procured from Sigma-Aldrich Corporation USA, whereas cimetidine was of M/s Cadila pharmaceutical Company India. All the chemicals used in the other solutions were of analytical grade.

Extraction and isolation

BA is an enriched mixture of tetra- and penta-cyclic triterpenic acids isolated from the gum resin of Boswellia serrata Roxb collected from Tirumala hills of Andra pardesh and identified by Dr. B.K. Kapahi, scientist, botany department IIIM Jammu. A voucher sample under accession no. 19921 has been deposited in the herbarium of the institute. The BA fraction is prepared by extracting Boswellia serrata gum resin (Singh et al., 2007). For the standardization, its total acid contents were estimated by acid base titration method, which was found to be 93 [+ or -] 3 %. The major four pentacyclic triterpenic acids (Fig. 1) were also separated by column chromatography over silica gel and identified by comparison of their physical and spectral data (Pardhy and Bhattacharaya, 1978). BA was also standardized on the basis of its HPLC finger printing and confirmed by LC-MS.

[FIGURE 1 OMITTED]

HPLC standardization of BA was performed on a Shimadju LC-10 AT model on a 5 [micro]m particle size C-18 column (250 mm x 4 mm) on the basis of four pentacyclic triterpenoic acids (Fig. 1) using the mobile phase -acetonitrile:water:acetic acid (99:1:0.01). The detection of the peaks was made on a PDA detector at a wavelength of 210 nm. In HPLC chromatogram of BA both boswellic acid (BA-1) and its acetyl derivative (BA-2) were detected as twin peaks comprising a mixture of ([alpha]+[beta]) isomers (a mixture physically inseparable by normal column chromatography) in the ratio of 37:63 and 22: 78, respectively, while 11-keto-[beta]-boswellic acid (BA-3) and its 3-acetyl derivative (BA-4) were detected as single peaks. The presence of marker molecules were also established on the basis of [M.sup.+] ion and fragmentation patterns on LC-MS performed on Agilent 1000 series HPLC coupled with Esquire 3000 Brucker Daltonics MS using the same column and mobile phase (Fig. 2).

[FIGURE 2 OMITTED]

Animals

Male Wistar rats weighing 160-180g were housed at 24 [+ or -] 1 [degrees]C on a 12:12h light and dark cycles with free access to pallet food (Ashirwad Industries, Chandigarh, India) and water. All the experiments were conducted between 10-00 and 17.00h and were in accordance with the ethical guidelines of the International association for Study of Pain (Zimmerman, 1983) and approved by the institutional ethics committee.

Pyloric ligation-induced gastric ulceration

The pyloric ligation-induced gastric ulceration assay was carried out according to the method of Shay et al. (1945). In brief, male Wistar rats (180-200g) were fasted for 24 h with free access to water before the start of experimentation. Test drug and vehicle were administered orally to test and control group of rats, 1 h before the experiment. The pylorus of each rat was ligated under light ether anesthesia by the abdominal incision and closed after surgery. The rats were sacrificed 6h later, their stomach removed and opened along the greater curvature, examined for severity of lesions. The gastric fluid was collected for the determination of volume and pH. The degree of ulceration was graded according to an arbitrary scale as 0 = no lesions (normal stomach); 0.5 = hyperemia; 1 = hemorrhagic spots; 2 = 1-5 small ulcers; 3 = many small ulcers; 4 = 1-5 small and 1-3 large ulcers; 5 = many small and large ulcers; 6 = stomach full of ulcers along with perforations. Percent protection was calculated in comparison to the untreated control group.

Ethanol/HCl-induced gastric ulceration in rats (Acute)

The experiment was performed according to the method of Mizui and Dotuchi (1983) with slight modifications. In brief 24 h fasted rats in the weight range of 180-200g with free access to water were treated with different doses of freshly prepared homogenized mixture of different doses of BA. One group was kept as vehicle control and another group treated with cimetidine, a standard drug. One hour after the drug administration the animals received 1.5 ml of a mixture of 70% alcohol + 5% HC1 as ulcerogenic agent. The animals were sacrificed 4h after the ulcerogenic dose of ethanol/HCl mixture by cervical dislocation. The stomach removed, cut opened along the greater curvature washed with normal saline and observed for the severity of the ulcers according to the scale mentioned above. The gastric fluid was collected for the determination of its volume and pH.

Ethanol/HCl-induced gastric ulceration in rats (Chronic)

The experiment was performed according to the method of Mizui and Dotuchi (1983) with certain modifications. Twenty-four hour fasted rats in the weight range of 180-200g were taken. Drug and ulcerogenic agent were given according to the following schedule.

1.5 ml of ethanol/HCl mixture (70% ethanol and 5% HC1) were given on the first day, half its dose in the same volume on the second day and further half of the second dose in the same volume on the third day. Different doses of freshly prepared homogenized mixture of BA (50 mg to 500mg/kg per oral) were administered. Drug administration started from day 1 to 10. One group was kept as vehicle control in which only vehicle, 1% gum acacia, was given whereas two groups were treated with cimetidine at 50 and 100mg/kg per oral as positive control. Feed was withdrawn 24 h before the last dose of drug. One hour after the last dose, 1.5 ml of ethanol/HCl mixture (70% ethanol and 5% HC1) was given by intubation and the animals were sacrificed after 4h The stomach was observed for percent protection of ulcer score according to the scale already mentioned.

Acetylsalicylic acid (ASA)-induced gastric ulcer

Gastric ulcerations were induced experimentally in male Wistar rats according to the method of Asano et al. (1990). Following a 24h fasting with water ad libitum, rats were dosed orally with different doses of BA, cimitedine and vehicle. One hour later 300mg/kg per oral of ASA was administered. The animals were sacrificed 4h after ASA dosing, stomach was removed and observed for percent protection of ulcerative lesions.

Indomethacin-induced gastric ulcer

Male Wistar rats (180-200 g) were deprived of food for 24h with free access to water prior to the experiment. The animals received oral doses of BA, cimitedine and vehicle, following 1h before administration of 20mg/kg per oral of indomethacin. Six hour after indomethacin administration the animals were sacrificed, their stomach removed and examined for ulcer protection (Asano et al., 1990).

Thermal stress-induced gastric ulceration

Male Wistar rats weighing 180-200g were deprived of food for 24h but had free access to water prior to the experiment. The test drug, cimetidine and vehicle were administered orally 10 min before the rats were restraint in a wire mesh for the ulcerative lesions by the method described by Goldenberg (1976). Each restrained rat was exposed to the cold (7 [degrees]C) in a refrigerator for 2h. The rats were then sacrificed by an overdose of ether and the stomach removed. Ulceration or hemorrhagic lesions on the glandular region of stomach were calculated according to the scale described. Percent change due to drug administration was calculated in comparison to the untreated control group.

Statistical analysis

All the data from in vivo experiments are expressed as mean [+ or -] standard error (SE). The statistical significance of difference between groups was evaluated by using Student's t-test through Graphpad Instat tm v 2.04a 941245s. p < 0.05 was considered as significant.

Results

Ethanol/HCl-induced gastric ulceration

The characteristic striated lesions, which result from the oral intake of ethanol/HCl solution, were found in the glandular portion of the rat stomach. BA pretreatment provides a significant dose related protection against ulceration caused by ethanol/HCl. The mean ulcer score was reduced from 5.60 (control) to 2.90 for the group, which received a dose of 500mg/kg with a highly significant value (<0.001). The other doses i.e., 250 and 100mg also showed significant reduction in ulcer score except for the 50mg/kg. Cimetidine, which has been taken as + ve control, significantly inhibited the ulcer formation at both the doses applied (Table 1). The effect of BA enhanced when the drug was given for prolong treatment in chronic model of ethanol/HCl-induced ulceration. The effect enhanced at all dose levels between 10% and 20% including cimetidine as compared to the acute ulcer effects. The non-significant dose (50mg/kg) of BA in acute ulceration showed significant effect with chronic ulceration method (Table 1). The comparative effect of BA with pure isolates is shown in Fig. 3. Out of the pure isolates 11-keto-[beta]-boswellic acid showed the maximum effect, (23.34%). In comparison to pure isolates BA produced 43.40% protection, whereas, cimetidine inhibited the ulcer score by 50% (Fig. 3). pH value and gastric fluid volume were also significantly influenced in a dose dependent manner by BA and cimetidine (Fig. 4).

Pyloric ligation-induced gastric ulceration

Pyloric ligation for 4h resulted in the presence of considerable ulceration in the form of hemorrhagic mucosal lesions in the stomach, accumulation of gastric secretion and increase in the titrable acidity. BA produced dose-dependent decrease in the ulcer score as compared to the control group. The reduction in the ulcer score was from 15.57% to 51.43% at doses from 50 to 500 mg/kg. Cimetidine at 50 and 100 mg/kg produced a protection of 34.42% and 56.96%, respectively (Table 1).
Table 1. Anti-ulcerogenic effect of BA against different ulcerogenic
agents in rats

Treatment and dose Different ulcer-inducing agents

 ligation Ethanol/HCl Ethanol/HCl
 (Acute) (Chronic)

Control 4.88 [+ or -] 5.60 [+ or -] 5.86 [+ or -]
 0.42 0.22 0.38

BA-50 4.12 [+ or -] 4.85 [+ or -] 4.52 [+ or -]
 0.33 (15.57) 0.18 (13.38) 0.27 (a) (22.86)

BA-100 3.85 [+ or -] 4.22 [+ or -] 3.34 [+ or -]
 0.36 (21.10) 0.24 (b) (21.07) 0.31 (c) (43.00)

BA-250 2.94 [+ or -] 3.44 [+ or -] 2.82 [+ or -]
 0.29 (b) (39.75) 0.32 (c) (38.56) 0.24 (c) (51.87)

BA-500 2.37 [+ or -] 2.90 [+ or -] 1.80 [+ or -]
 0.31 (b) (51.43) 0.29 (c) (48.21) 0.28 (c) (69.28

Cimetidine-50 3.20 [+ or -] 3.80 [+ or -] 3.00 [+ or -]
 0.24 (b) (34.42) 0.36 (b) (32.14) 0.26 (c) (48.80)

Cimetidine-100 2.10 [+ or -] 2.76 [+ or -] 2.12 [+ or -]
 0.26 (c) (56.96) 0.24 (c) (50.71) 0.24 (c) (63.82)

Treatment and dose

 ASA Indomethacin Thermal
 stress

Control 3.84 [+ or -] 3.62 [+ or -] 3.14 [+ or -]
 0.25 0.26 0.18

BA-50 3.60 [+ or -] 3.15 [+ or -] 2.22 [+ or -]
 0.28 (6.26) 0.26 (13.25) 0.21 (a) (19.74)

BA-100 2.90 [+ or -] 2.82 [+ or -] 2.10 [+ or -]
 0.25 (a) (24.47) 0.18 (a) (22.09) 0.14 (b) (33.12)

BA-250 2.62 [+ or -] 2.25 [+ or -] 1.82 [+ or -]
 0.35 (a) (31.77) 0.22 (b) (37.84) 0.16 (c) (42.07)

BA-500 2.22 [+ or -] 1.95 [+ or -] 1.32 [+ or -]
 0.24 (b) (42.18) 0.15 (c) (46.13) 0.14 (c) (57.96)

Cimetidine-50 2.50 [+ or -] 2.12 [+ or -] 2.15 [+ or -]
 0.25 (b) (34.89) 0.18 (b) (41.43) 0.12 (b) (31.52)

Cimetidine-100 1.96 [+ or -] 1.42 [+ or -] 1.35 [+ or -]
 0.24 (c) (48.95) 0.12 (c) (60.77) 0.14 (c) (57.00)

* Values are the mean [+ or -] S.E of five observations.
* Percent inhibition calculated as compared to the normal control group
and given in parenthesis.
* P-value a < 0.05, b < 0.01, c < 0.001.


Aspirin-induced gastric ulceration

Aspirin treatment resulted in the production of gastric lesions in glandular segment of the stomach. Oral treatment of BA at different dose levels inhibited the appearance of gastric lesions in a dose dependent manner. Significant anti-ulcer effect started at a dose of 100 mg/kg with an inhibition of 24.47% as compared to the untreated control group. Further increase in ulcer protection was observed in 250 and 500 mg/kg dose of BA. Similarly, cimetidine also protected ulcer production significantly at both the doses (Table 1).

Indomethacin-induced gastric ulceration

Indomethacin in a usual manner like other NSAIDs produces hemorrhagic lesions in the glandular region of the rat stomach. Pretreatment of BA at different concentrations showed reduction in the ulcer score as compared to the untreated control group where only vehicle was given. BA at 500 mg/kg showed a protective response up to 46.13% with a highly significant value ( < 0.001). The doses of BA at 250 and l00mg/kg reduced the ulcer score up to 38% and 22%, respectively. This inhibitory effect of BA was better than 50 mg/kg of cimetidine (Table 1).

Thermal stress-induced gastric ulceration

The animals subjected to cold-restraint stress showed the presence of considerable ulceration in the form of hemorrhagic mucosal lesions in stomach. A highly significant gastro-protective action of BA was observed when treated with different doses in a dose dependent manner. The maximum protective response observed at 500mg/kg was 57%. Cimetidine was equipotent at 100 mg/kg (Table 1).

Discussion

Present study demonstrates the anti-ulcer activity of BA in a battery of experimental models of gastric ulceration. The anti-ulcer effect was evident by the significant inhibitory effect depicted in Table 1 in comparison to vehicle control and standard drug cimetidine. The results of pH values and fluid volume also support the anti-ulcer effect of BA. Various mechanisms have been thought to be involved in the ulcer production in different experimental models (Parmar and Desai, 1993), hence, it is not possible to propose a single mechanism for anti-ulcer effect to a particular drug. BA produced significant decrease in ulcer score in pyloric ligation model. Digestive effect of the accumulated gastric juice is believed to be responsible for producing ulcers in the pylorus ligated rats. In addition to gastric secretion, reflex or neurogenic effect has also been suggested to play an important role in the formation of gastric ulcers in this model (Goswani et al., 1967).

The mechanisms involved in the cold stress-induced ulceration are: disturbance in gastric secretion, alteration in microcirculation of gastric mucosa and abnormal gastric motility (Kitagawa et al., 1979). Central mechanism including vagal over activation has also been considered for pathogenesis of stress ulcers. Significant inhibitory effect shown by BA points to a possible mechanism related to the increase in the gastric mucosal blood flow and inhibition of gastric acid secretion (Desai et al., 1997).

[FIGURE 3 OMITTED]

[FIGURE 4 OMITTED]

The significant inhibitory effect of BA in aspirin and indomethacin-induced ulceration further support the antiulcer effect of BA. The ulceration induced by aspirin and indomethacin is attributed mainly due to the biosynthesis of cytoprotective prostaglandin resulting in overproduction of leukotrienes and other products of 5-lipoxygenase pathway (Rainsford, 1978). These agents break the mucosal barrier, provoke an increase in gastric mucosal permeability to [H.sup.+] and [Na.sup.+] ions, and drop in the transmucosal potential difference and induce the formation of potential difference and induce the formation of erosions and ulcers (Whittle, 1981; Droy-Lefaix, 1988). These results indicate a possible local increase in synthesis of cytoprotective prostaglandin, inhibition of leukotrienes and gastric mucosal permeability to [H.sup.+] and [Na.sup.+] ions by BA. Moreover, the leukotriene inhibitory mechanism of BA is already known (Safayhi et al., 1992).

Ethanol-induced gastric lesion formation may be due to stress in gastric blood flow that contributes to the development of the hemorrhage and necrotic aspects of tissue injury (Guth et al., 1984). This chemical agent also increases [Na.sup.+] and [K.sup.+] flux into the lumen and increases pepsin secretion along with histamine release. HCl further deepens the necrosis and increase tissue injury. Furthermore, it is well known that ethanol-induced ulcers are not inhibited by the anti-secretary agents, but are inhibited by agents that enhance mucosal defensive factor such as prostaglandin (Morimoto et al., 1991). It has also been reported that leukotriene antagonist and 5-lipoxygenase inhibitors are capable of inhibiting alcohol as well as NSAID-induced gastric ulceration in rats (Parnaham and Brune, 1987). BA is a known inhibitor of leukotrience (LT[B.sub.4]) (Safayhi et al., 1992) the anti-ulcer activity of BA may be because of its leukotriene inhibitory property.

Conclusion

In conclusion, it is demonstrated that BA is undoubtedly an anti-ulcer molecule and not having a single but multiple mechanisms. The anti-ulcer data of BA signifies that it might be either acting by increasing the gastric mucosal resistance, local synthesis of cytoprotective prostaglandins and/or inhibiting the leukotriene synthesis. Hence, it is right to state here that BA, which is used as a therapeutic agent for anti-inflammatory and antiarthritic disorders, has an anti-ulcer potential also and edge over the other NSAIDs because of which patients have to discontinue the therapy in-between. Further work for its specific anti-ulcer mechanism is in progress.

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S. Singh (a), * A. Khajuriaa, S.C. Taneja (b), R.K. Khajuria (b), J. Singh (a), R.K. Johri (a), G.N. Qazi (a), (b)

(a) Department of Pharmacology, Indian Institute of Integrative Medicine (CSIR), Canal Road Jammu Tawi, J&K 180001, India Natural Product Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road Jammu Tawi, J&K 180001, India

(b) Natural Product Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road Jammu Tawi, J&K 180001, India Natural Product Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road Jammu Tawi, J&K 180001, India

* Corresponding author. Tel.: +191 2569000/2569001/259002 x 291.

E-mail address: surjeet 58@yahoo.com (S. Singh).

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Author:Singh, S.; Khajuria, A.; Taneja, S.C.; Khajuria, R.K.; Singh, J.; Johri, R.K.; Qazi, G.N.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Geographic Code:9INDI
Date:Jun 1, 2008
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