Pharmaceutical Biology
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Proulcerogenic effect of water extract of Boswellia sacra oleo gum resin in rats Mohammed Asad & Meshal Alhomoud To cite this article: Mohammed Asad & Meshal Alhomoud (2015): Proulcerogenic effect of water extract of Boswellia sacra oleo gum resin in rats, Pharmaceutical Biology To link to this article: http://dx.doi.org/10.3109/13880209.2015.1028553
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http://informahealthcare.com/phb ISSN 1388-0209 print/ISSN 1744-5116 online Editor-in-Chief: John M. Pezzuto Pharm Biol, Early Online: 1–6 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/13880209.2015.1028553
ORIGINAL ARTICLE
Proulcerogenic effect of water extract of Boswellia sacra oleo gum resin in rats Mohammed Asad and Meshal Alhomoud
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College of Applied Medical Colleges, Shaqra University, Shaqra, Saudi Arabia
Abstract
Keywords
Context: The water extract of Boswellia sacra Flueck. (Burseraceae) is used in the treatment of gastric and hepatic disorders in the Arab countries. Objective: The effect of Boswellia sacra water extract on gastric secretion and experimentally induced gastric ulcers in rats was studied. Materials and methods: Acetic acid-induced chronic gastric ulcers, pylorus ligation, aspirininduced, ethanol-induced, and restraint plus cold stress-induced gastric ulcer models were employed. The effect on normal rats was also studied. The water extract of B. sacra was administered orally at doses of 2 and 5 ml/kg once daily ranging from single dose to 30 d treatment depending on the model. The extract was subjected to GC-MS analysis to determine the presence of various phytoconstituents. Results: Boswellia sacra water extract (5 ml/kg, p.o (per os)) aggravated acetic acid-induced chronic ulcers, wherein an increase in ulcer index (p50.01) and ulcer score (p50.05) was observed. In pylorus-ligated rats, the extract increased gastric content volume (p50.01), free acidity (p50.01), total acidity (p50.01), ulcer index (p50.01), and pepsin activity (p50.05). There was no significant effect on the development of ethanol-induced and aspirin-induced ulcers while an increase in the development of stress-induced ulcers was observed (p50.01). The extract did not produce any ulcers when administered to normal rats. The dose of 2 ml/kg was less proulcerogenic compared with 5 ml/kg. The GC-MS analysis revealed the presence of several phytoconstituents that included menthol, 3-cyclohexen-1-ol, and octanoic acid. Conclusion: Boswellia sacra water extract has proulcerogenic activity due to its gastric hypersecretory effect.
Gastric cytoprotection, gastric secretion, ulcer index, volatile oils
Introduction Herbal remedies are employed for the management of acidity and treatment of peptic ulcers since ancient times (SchmedaHirschmann & Yesilada, 2005). Many of these traditionally used herbs have been proved scientifically to possess antiulcer properties. We have earlier reported the antiulcer effect of traditionally used herbs such as Momordica charantia L. (Cucurbitaceae), Allium sativum L. (Liliaceae), Moringa oleifera Lam. (Moringaceae), and Plantago lanceolata L. (Plantaginaceae) (Alam et al., 2009; Azamthulla et al., 2009; Devaraj et al., 2007; Melese et al., 2011). Boswellia sacra Flueck. (Burseraceae) oleo gum resin is one of the most widely used house hold medicine. It is commonly known as frankincense and is marketed throughout the world (Ben-Yehoshua et al., 2012). Frankincense is used in perfumery, aromatherapy, and religious rites. The dried oleo gum resin is cream to light brown in color with characteristic odor. Boswellia oleo gum resin, known in
Correspondence: Dr. Mohammed Asad, College of Applied Medical Colleges, Shaqra University, P O Box 1383, Shaqra 11961, Saudi Arabia. Tel: +966 50 4984171. E-mail: [email protected]
History Received 19 July 2014 Revised 15 January 2015 Accepted 24 January 2015 Published online 8 April 2015
Arabic as ‘‘Luban’’, is chewed for its essence in Middle East and Arab-African countries. In parts of Oman, smoke generated from the burning of frankincense is used as perfume to house, cloths, and hair (Ghazanfar, 1998). Frankincense resin is used traditionally in many Asian countries to cure bronchial and urinary infections. In China, it is used to relieve menstrual pain, gum, mouth, and throat complaints, and also as a rejuvenating medicine in India. Furthermore, B. sacra resin is known to help in healing wounds, sores, ulcers, carbuncles, hemorrhoids, and inflammation. The essential oil of the frankincense is believed to possess antiseptic, astringent, carminative, digestive, diuretic, sedative, uterine, and vulnerary therapeutic properties (Khan, 2012). The water extract of this gum resin (frankincense) is used traditionally in the treatment of cough, stomach problems, and liver problems in Middle Eastern and Arab-African countries (Bosworth et al., 1983). Although this house-hold medicine is widely used, there is no scientific report on the claimed medical benefits. The present study was undertaken to determine the effect of administration of water extract of B. sacra on stomach and on the development of experimentally induced gastric ulcers in rats.
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Materials and methods Materials
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The water extract of B. sacra oleo gum resin was purchased from the market in the month of March 2014. The extract was verified by characteristic odor of B. sacra. The most widely used brand in Saudi Arabia (Luban-e-hakim) was used in the present study. The extract was a clear solution with a very strong essence similar to that of dried B. sacra oleo gum resin. Preparation of water extract by the traditional method in our laboratory, which involves boiling the oleo gum resin (covered in muslin cloth) with water in a closed jar for 30 min at 100 C or soaking B. sacra oleo gum resin in water overnight, did not produce an extract with such strong odor. Hence, the marketed extract was used in the present study. All other chemicals used were of analytical grade from different companies.
Pharm Biol, Early Online: 1–6
glacial acetic acid (0.05 ml) was applied onto the serosal surface using cylindrical mould (6 mm) for 60 s. The acid solution was then removed by rinsing the mold with normal saline to prevent damage to the surrounding tissues. The stomach was placed back carefully and the abdominal wall was closed (Asad et al., 2001). The animals were treated with B. sacra extract at either 2 or 5 ml/kg orally once a day for 10 d after induction of ulcer while the control group received only vehicle. Rats were killed 6 h after the last dose; stomach was removed and was cut open along the greater curvature. The total mucosal area and the total ulcerated area were measured. The ulcer index was determined using the formula: Ulcer index ¼
10 X
where X is the total mucosal area/total ulcerated area.
Animals
Pylorus ligation-induced gastric ulcers
Wistar albino rats of either sex weighing between 180 and 210 g were used. The animals were maintained under standard conditions of 12:12 h light dark cycle at a temperature of 25 ± 2 C. The experimental protocol was approved by the research committee of the institute for its ethical and scientific content (SU/CAMS/15/12-2014).
The animals were fasted for 36 h in cages with meshed bottoms to avoid cannibalism and coprophagy. They received water ad libitum during the fasting period. Normal saline (1 ml/rat, p.o (per os)) was administered twice daily to all the animals (Asad et al., 2003). Under light ether anesthesia, the pyloric portion of the stomach was ligated (Shay et al., 1945). The low and the high dose of B. sacra extract were administered intraduodenally after pylorus ligation. Six hours after pylorus ligation, animals were sacrificed (Kulkarni, 1999). The stomach was isolated and the content of the stomach was used for the estimation of free and total acidity (Hawk et al., 1947), pepsin content (Debnath et al., 1974), total proteins (Lowry et al., 1951), and mucin content (Prabha et al., 2003). The ulcer index was determined using the same formula as mentioned above.
Gas chromatography-mass spectroscopy (GC-MS) analysis of extract For performing the GC-MS analysis, the water extract of B. sacra was further extracted using dichloromethane. The dichloromethane extract was injected into the GC-MS system (Shimadzu-QP2010S, Shimadzu Corporation, Kyoto, Japan). For GC-MS detection, an electron impact ionization system was used. Helium gas (99.95%) was used as a carrier gas at a constant flow rate of 1 ml/min, and an injection volume of 1 ll was employed (a split ratio of 10:1). The injector temperature was maintained at 250 C, the ion-source temperature was 200 C, the oven temperature was programmed from 60 C (isothermal for 2 min), with gradual increase to 325 C at 15 min. Mass spectra were taken at 1.4 kV. The relative percentage amount of each component was calculated by comparing its average peak area to the total areas. Interpretation of mass-spectrum GC-MS was conducted using NIST, WILEY, and SZTRIP libraries. The spectrum of the unknown components was compared with the spectrum of known components. Effect of administration of B. sacra extract to normal rats Boswellia sacra extract was administered at two different doses of 2 and 5 ml/kg orally to rats for a period of 30 d. The doses were selected based on the human dose (15 ml three times a day). At the end of the experimental period, the animals were sacrificed and the stomachs were opened along the greater curvature to detect the gastric damage.
Ethanol-induced gastric ulcers Animals were fasted for 36 h before administration of ethanol (1 ml/200 g, p.o). Boswellia sacra extract at two different doses was administered 1 h before ethanol administration and animals were sacrificed 1 h after ethanol administration (Brzozowski et al., 1998). The ulcer index was determined as mentioned earlier. Aspirin-induced gastric ulcers The ulcers were induced by administering aspirin (200 mg/kg, p.o) to the animals fasted for 36 h. Boswellia sacra extract was administered 30 min before aspirin administration and, after 4 h, all animals were sacrificed, stomachs were isolated, and the ulcer index was determined (Kumar et al., 2013). Cold-restraint stress-induced ulcers
Effect on gastric ulcers
The animals were placed in a restraint cage, and the cage was placed at a temperature of 2 C for 3 h. Boswellia sacra extract was administered 30 min prior to subjection of stress. The animals were sacrificed, stomach was isolated, and the ulcer index was determined (Parmar & Desai, 1993).
Acetic acid-induced chronic gastric ulcer
Statistical analysis
The animals were fasted for 24 h prior to the experiment. Under light ether anesthesia, the stomach was exposed;
Values are expressed as mean ± standard error of mean (SEM). Statistical significance was determined by one-way
Proulcerogenic effect of B. sacra water extract
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DOI: 10.3109/13880209.2015.1028553
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Figure 1. GC-MS chromatogram of water extract of Boswellia sacra.
Table 1. List of major chemical constituents present in the water extract of Boswellia sacra. Number 1 2 3 4 5 6 7
Retention time 8.634 9.964 12.346 12.433 12.496 13.843 13.949
Name of the compound 1,8-Cineole 1-Octanol ()-Menthol 3-Cyclohexen-1-ol Octanoic acid Thymol Carvacrol
analysis of variance (ANOVA) followed by Dunnett’s test for comparison of all parameters. Statistical significance for ulcer score was determined using the Kruskal–Wallis test with posttest. The statistical analysis was done using computer software (Graphpad lnstat DATASET 1, ISD, software version 3.0 for Windows, GraphPad Software Inc., San Diego, CA). Values of p50.05 were considered to indicate statistical significance.
Results GC-MS analysis of B. sacra extract GC-MS chromatogram analysis of the water extract of B. sacra shows many peaks indicating the presence of several volatile constituents (Figure 1). By comparing the mass spectra of the constituents with the NIST, WILEY 7, and SZTERP libraries, several phytoconstituents were characterized and identified. Some of the major constituents are shown in Table 1. Of all the compounds identified, the most abundant compounds were 1,8-cineole (4.16%), 1-octanol (6.91%), () menthol (10.81%), 3-cyclohexen-1-ol (21.33%), octanoic acid (18.91%), thymol (6.14%), and carvacrol (5.67%). Effect in normal rats The extract at both the tested doses did not produce any noticeable damage to gastric mucosa when administered to
Molecular formula
Molecular weight
Peak area %
C10H18O C8H18O C10H20O C10H20O C8H16O2 C10H14O C10H14O
154 130 156 156 144 150 150
4.16 6.91 10.81 21.33 18.91 6.14 5.67
normal animals for 30 d compared with vehicle-treated control. Effect on gastric ulcers Effect on acetic acid-induced chronic gastric ulcers Application of glacial acetic acid on the serosal surface at the antral region of the stomach produced penetrating ulcers in all the groups. Administration of B. sacra extract at two different doses aggravated the acetic acid-induced gastric ulcers as evidenced by 22% and 33% increase in ulcer index after treatment with B. sacra extract of 2 ml/kg and B. sacra extract of 5 ml/kg, respectively. The higher dose of B. sacra extract (5 ml/kg) also produced a significant increase in ulcer score (p50.05). The mortality rate was more in B. sacra extracttreated groups as compared with control (Table 2). Effect in pylorus-ligated rats Boswellia sacra extract (5 ml/kg) showed a significant increase in volume of gastric secretion, free acidity, total acidity, ulcer index (p50.01), and pepsin activity (p50.05) when compared with control. The lower dose of B. sacra extract (2 ml/kg) produced less severe effect compared with the higher dose (5 ml/kg) in increasing free acidity, total acidity, and ulcer index while it did not produce any significant change in the volume of gastric secretion and
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Table 2. Effect of Boswellia sacra water extract on different gastric ulcer models in rats. Acetic acid-induced chronic gastric ulcers Groups Control Boswellia sacra water extract (2 ml/kg, p.o) Boswellia sacra water extract (5 ml/kg, p.o)
Ulcer index in different models
Ulcer index
Ulcer score
Mortality
Ethanol-induced gastric ulcers
Aspirin-induced gastric ulcers
Stress-induced gastric ulcers
0.36 ± 0.023 0.44 ± 0.016*
1.33 ± 0.210 2.00 ± 0.258
0/6 2/8
0.66 ± 0.08 0.71 ± 0.13
0.15 ± 0.02 0.14 ± 0.03
0.185 ± 0.024 0.254 ± 0.0172*
0.48 ± 0.028**
2.50 ± 0.224*
4/10
0.72 ± 0.09
0.16 ± 0.02
0.287 ± 0.0169**
All values are mean ± SEM, n ¼ 6, *p50.05, **p50.01 compared with control. p.o, per os.
Table 3. Effect of Boswellia sacra water extract in pylorus-ligated rats.
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Groups Control Boswellia sacra water extract (2 ml/kg, p.o) Boswellia sacra water extract (5 ml/kg, p.o)
Volume of gastric Free acidity secretion (ml) (mEq/l)
Total acidity (mEq/l)
Ulcer index
Mucin content Total proteins (mg/g) Pepsin activity (mg/ml)
9.15 ± 0.377 7.68 ± 0.483
52.6 ± 3.64 117.8 ± 3.15 71.7 ± 2.71** 129.5 ± 2.65*
0.54 ± 0.02 0.78 ± 0.03**
7.25 ± 0.426 6.85 ± 0.365
0.085 ± 0.023 0.178 ± 0.027
52.68 ± 8.56 68.15 ± 10.25
5.51 ± 0.463**
74.9 ± 3.02** 135.8 ± 2.51** 0.84 ± 0.02**
6.55 ± 0.514
0.186 ± 0.034* 72.58 ± 7.98
All values are mean ± SEM, n ¼ 6, *p50.05, **p50.01 compared with control, p.o, per os.
pepsin activity. None of the treatments produced any significant effect on gastric mucin secretion and protein content in gastric juice (Table 3). Effect on ethanol-induced gastric ulcers, aspirin-induced gastric ulcers, and stress-induced gastric ulcers Boswellia sacra extract did not show any significant alteration in the development of ethanol-induced and aspirin-induced gastric ulcers at both the tested doses while a significant increase in the development of cold plus-restraint stressinduced ulcers was seen after administration of both doses of extract (Table 2).
Discussion The results of the present study revealed the proulcerogenic effect of B. sacra water extract in rats. The extract increased the secretion of gastric aggressive factors such as gastric acid secretion and gastric pepsin secretion without significantly altering the secretion of gastric defensive mucus secretion. As mentioned earlier, B. sacra oleo gum resin, commonly known as frankincense or incense, is widely used in different parts of the world. The water extract of B. sacra oleo gum resin is a house-hold medicine used for the treatment of cough, stomach problems, and liver problems (Bosworth et al., 1983). The word ‘‘stomach problems’’ is confusing and discussion with traditional healers revealed that stomach problems include acidity and many other stomach diseases. Traditionally, the water extract of B. sacra oleo gum resin is prepared by different methods. The commonest method used for the preparation involves covering the resin in a muslin cloth or a wire mesh, and immersing it in boiling water for 15–30 min. Another method used employs soaking of frankincense in water overnight followed by filtration (Highet, 2006; Paul et al., 2012). However, most of the people now prefer to buy the readymade water extract
available in the market. We tried the first two methods in our laboratory, but could not get the strong flavor of frankincense present in the marketed water extract. Hence, the water extract of B. sacra purchased from the market was used in the present study. This study was carried out using experimental models of gastric ulcer that produce ulcerogenesis by distinct mechanisms. The overall effect on gastric ulcers was studied in acetic acid-induced chronic gastric ulcers while the gastric secretory effect of B. sacra extract was determined in pylorus-ligated rats. The ulcer formation in pylorus-ligated rats is influenced by changes in secretion of gastric acid, pepsin, and mucus secretion (Kulkarni, 1999; Shay et al., 1945). The ethanolinduced gastric ulcer model was used to determine the effect on acid-independent gastric cytoprotection, and aspirininduced gastric ulcers provide information for the effect on prostaglandin synthesis (Asad et al., 2001; Kumar et al., 2013). The stress-induced gastric ulcers depend on gastric acid secretion and gastric motility. Drugs interfering with gastric secretion and/or motility or those having direct calming effect on the central nervous system reduce stressinduced gastric ulcers (Asad et al., 2001; Parmar & Desai 1993). Boswellia sacra water extract aggravated the acetic acid-induced gastric ulcers compared with vehicle-treated control. The proulcerogenic effect of B. sacra water extract was due to augmented secretion of gastric acid and pepsin, as demonstrated in pylorus-ligated rats. There was no effect on gastric cytoprotection in ethanol-induced gastric ulcers and aspirin-induced gastric ulcers. The aggravation of stressinduced gastric ulcers could also be due to the gastric hypersecretory effect of B. sacra extract. Boswellia species include Boswellia serrata Roxb., Boswellia frereana Birw., and Boswellia sacra (syn. Boswellia carterii) and these are reported to possess several pharmacological activities (Paul et al., 2012). The main constituents responsible for their pharmacological activity are
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DOI: 10.3109/13880209.2015.1028553
boswellic acids. The boswellic acids from B. serrata are also reported to possess gastric ulcer-protective effect in rats (Singh et al., 2008). However, in the present study, the GCMS analysis did not reveal the presence of boswellic acids. This was expected as boswellic acids are insoluble in water (Shah et al., 2009). The GC-MS analysis of the water extract showed the presence of several chemical constituents. Ironically, literature review on these constituents for their effect on gastric ulcers revealed that some of these constituents and/or their derivatives have been reported for antiulcer/gastro-protective effects and none of these constituents are known for their gastric hypersecretory or ulcerogenic effects. Derivative of 2(5H)-furanone is reported to possess antiulcer effect (Tamai et al., 1993) while cineole, linalool, phytol, and formic acid are reported as possible chemical constituents, responsible for antiulcer effect of plant extracts in which they are found (Barocelli et al., 2004; Haider et al., 2012; Takayama et al., 2011). Carvacrol is reported for antiulcer action (Oliveira et al., 2012; Rao et al., 2004; Silva et al., 2012). Prodrugs of ibuprofen with thymol had reduced ulcerogenic effect that is observed with ibuprofen alone indicating the ulcer-preventive effect of thymol (Redasani & Bari, 2012). The volatile oils from several plants have also been reported for antiulcer/ gastro-protective effects (Bonamin et al., 2014; Guo et al., 2014; Moraes et al., 2013; Ovalle-Magallanes et al., 2014). Hence, it is difficult to predict the constituent(s) responsible for the proulcerogenic effect of this extract. Further investigations into mechanisms of ulcer-protective effect of constituents reported for antiulcer effect and evaluation of constituents not reported for their effect on gastric secretion and ulcer formation may help in identifying the constituent(s) responsible for this proulcerogenic effect.
Conclusion The water extract of B. sacra oleo gum resin attenuated the healing of acetic acid-induced chronic gastric ulcers. This proulcerogenic effect was due to an increase in gastric acid and gastric pepsin secretion, as observed in pylorus-ligated rats. The water extract of B. sacra also increased the development of stress-induced gastric ulcers while it did not affect the development of ethanol-induced and aspirininduced gastric ulcers. The GC-MS analysis of B. sacra water extract revealed the presence of several constituents.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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Proulcerogenic effect of water extract of Boswellia sacra oleo gum resin in rats Mohammed Asad & Meshal Alhomoud To cite this article: Mohammed Asad & Meshal Alhomoud (2015): Proulcerogenic effect of water extract of Boswellia sacra oleo gum resin in rats, Pharmaceutical Biology To link to this article: http://dx.doi.org/10.3109/13880209.2015.1028553
Published online: 08 Apr 2015.
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Date: 18 October 2015, At: 14:45
http://informahealthcare.com/phb ISSN 1388-0209 print/ISSN 1744-5116 online Editor-in-Chief: John M. Pezzuto Pharm Biol, Early Online: 1–6 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/13880209.2015.1028553
ORIGINAL ARTICLE
Proulcerogenic effect of water extract of Boswellia sacra oleo gum resin in rats Mohammed Asad and Meshal Alhomoud
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College of Applied Medical Colleges, Shaqra University, Shaqra, Saudi Arabia
Abstract
Keywords
Context: The water extract of Boswellia sacra Flueck. (Burseraceae) is used in the treatment of gastric and hepatic disorders in the Arab countries. Objective: The effect of Boswellia sacra water extract on gastric secretion and experimentally induced gastric ulcers in rats was studied. Materials and methods: Acetic acid-induced chronic gastric ulcers, pylorus ligation, aspirininduced, ethanol-induced, and restraint plus cold stress-induced gastric ulcer models were employed. The effect on normal rats was also studied. The water extract of B. sacra was administered orally at doses of 2 and 5 ml/kg once daily ranging from single dose to 30 d treatment depending on the model. The extract was subjected to GC-MS analysis to determine the presence of various phytoconstituents. Results: Boswellia sacra water extract (5 ml/kg, p.o (per os)) aggravated acetic acid-induced chronic ulcers, wherein an increase in ulcer index (p50.01) and ulcer score (p50.05) was observed. In pylorus-ligated rats, the extract increased gastric content volume (p50.01), free acidity (p50.01), total acidity (p50.01), ulcer index (p50.01), and pepsin activity (p50.05). There was no significant effect on the development of ethanol-induced and aspirin-induced ulcers while an increase in the development of stress-induced ulcers was observed (p50.01). The extract did not produce any ulcers when administered to normal rats. The dose of 2 ml/kg was less proulcerogenic compared with 5 ml/kg. The GC-MS analysis revealed the presence of several phytoconstituents that included menthol, 3-cyclohexen-1-ol, and octanoic acid. Conclusion: Boswellia sacra water extract has proulcerogenic activity due to its gastric hypersecretory effect.
Gastric cytoprotection, gastric secretion, ulcer index, volatile oils
Introduction Herbal remedies are employed for the management of acidity and treatment of peptic ulcers since ancient times (SchmedaHirschmann & Yesilada, 2005). Many of these traditionally used herbs have been proved scientifically to possess antiulcer properties. We have earlier reported the antiulcer effect of traditionally used herbs such as Momordica charantia L. (Cucurbitaceae), Allium sativum L. (Liliaceae), Moringa oleifera Lam. (Moringaceae), and Plantago lanceolata L. (Plantaginaceae) (Alam et al., 2009; Azamthulla et al., 2009; Devaraj et al., 2007; Melese et al., 2011). Boswellia sacra Flueck. (Burseraceae) oleo gum resin is one of the most widely used house hold medicine. It is commonly known as frankincense and is marketed throughout the world (Ben-Yehoshua et al., 2012). Frankincense is used in perfumery, aromatherapy, and religious rites. The dried oleo gum resin is cream to light brown in color with characteristic odor. Boswellia oleo gum resin, known in
Correspondence: Dr. Mohammed Asad, College of Applied Medical Colleges, Shaqra University, P O Box 1383, Shaqra 11961, Saudi Arabia. Tel: +966 50 4984171. E-mail: [email protected]
History Received 19 July 2014 Revised 15 January 2015 Accepted 24 January 2015 Published online 8 April 2015
Arabic as ‘‘Luban’’, is chewed for its essence in Middle East and Arab-African countries. In parts of Oman, smoke generated from the burning of frankincense is used as perfume to house, cloths, and hair (Ghazanfar, 1998). Frankincense resin is used traditionally in many Asian countries to cure bronchial and urinary infections. In China, it is used to relieve menstrual pain, gum, mouth, and throat complaints, and also as a rejuvenating medicine in India. Furthermore, B. sacra resin is known to help in healing wounds, sores, ulcers, carbuncles, hemorrhoids, and inflammation. The essential oil of the frankincense is believed to possess antiseptic, astringent, carminative, digestive, diuretic, sedative, uterine, and vulnerary therapeutic properties (Khan, 2012). The water extract of this gum resin (frankincense) is used traditionally in the treatment of cough, stomach problems, and liver problems in Middle Eastern and Arab-African countries (Bosworth et al., 1983). Although this house-hold medicine is widely used, there is no scientific report on the claimed medical benefits. The present study was undertaken to determine the effect of administration of water extract of B. sacra on stomach and on the development of experimentally induced gastric ulcers in rats.
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Materials and methods Materials
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The water extract of B. sacra oleo gum resin was purchased from the market in the month of March 2014. The extract was verified by characteristic odor of B. sacra. The most widely used brand in Saudi Arabia (Luban-e-hakim) was used in the present study. The extract was a clear solution with a very strong essence similar to that of dried B. sacra oleo gum resin. Preparation of water extract by the traditional method in our laboratory, which involves boiling the oleo gum resin (covered in muslin cloth) with water in a closed jar for 30 min at 100 C or soaking B. sacra oleo gum resin in water overnight, did not produce an extract with such strong odor. Hence, the marketed extract was used in the present study. All other chemicals used were of analytical grade from different companies.
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glacial acetic acid (0.05 ml) was applied onto the serosal surface using cylindrical mould (6 mm) for 60 s. The acid solution was then removed by rinsing the mold with normal saline to prevent damage to the surrounding tissues. The stomach was placed back carefully and the abdominal wall was closed (Asad et al., 2001). The animals were treated with B. sacra extract at either 2 or 5 ml/kg orally once a day for 10 d after induction of ulcer while the control group received only vehicle. Rats were killed 6 h after the last dose; stomach was removed and was cut open along the greater curvature. The total mucosal area and the total ulcerated area were measured. The ulcer index was determined using the formula: Ulcer index ¼
10 X
where X is the total mucosal area/total ulcerated area.
Animals
Pylorus ligation-induced gastric ulcers
Wistar albino rats of either sex weighing between 180 and 210 g were used. The animals were maintained under standard conditions of 12:12 h light dark cycle at a temperature of 25 ± 2 C. The experimental protocol was approved by the research committee of the institute for its ethical and scientific content (SU/CAMS/15/12-2014).
The animals were fasted for 36 h in cages with meshed bottoms to avoid cannibalism and coprophagy. They received water ad libitum during the fasting period. Normal saline (1 ml/rat, p.o (per os)) was administered twice daily to all the animals (Asad et al., 2003). Under light ether anesthesia, the pyloric portion of the stomach was ligated (Shay et al., 1945). The low and the high dose of B. sacra extract were administered intraduodenally after pylorus ligation. Six hours after pylorus ligation, animals were sacrificed (Kulkarni, 1999). The stomach was isolated and the content of the stomach was used for the estimation of free and total acidity (Hawk et al., 1947), pepsin content (Debnath et al., 1974), total proteins (Lowry et al., 1951), and mucin content (Prabha et al., 2003). The ulcer index was determined using the same formula as mentioned above.
Gas chromatography-mass spectroscopy (GC-MS) analysis of extract For performing the GC-MS analysis, the water extract of B. sacra was further extracted using dichloromethane. The dichloromethane extract was injected into the GC-MS system (Shimadzu-QP2010S, Shimadzu Corporation, Kyoto, Japan). For GC-MS detection, an electron impact ionization system was used. Helium gas (99.95%) was used as a carrier gas at a constant flow rate of 1 ml/min, and an injection volume of 1 ll was employed (a split ratio of 10:1). The injector temperature was maintained at 250 C, the ion-source temperature was 200 C, the oven temperature was programmed from 60 C (isothermal for 2 min), with gradual increase to 325 C at 15 min. Mass spectra were taken at 1.4 kV. The relative percentage amount of each component was calculated by comparing its average peak area to the total areas. Interpretation of mass-spectrum GC-MS was conducted using NIST, WILEY, and SZTRIP libraries. The spectrum of the unknown components was compared with the spectrum of known components. Effect of administration of B. sacra extract to normal rats Boswellia sacra extract was administered at two different doses of 2 and 5 ml/kg orally to rats for a period of 30 d. The doses were selected based on the human dose (15 ml three times a day). At the end of the experimental period, the animals were sacrificed and the stomachs were opened along the greater curvature to detect the gastric damage.
Ethanol-induced gastric ulcers Animals were fasted for 36 h before administration of ethanol (1 ml/200 g, p.o). Boswellia sacra extract at two different doses was administered 1 h before ethanol administration and animals were sacrificed 1 h after ethanol administration (Brzozowski et al., 1998). The ulcer index was determined as mentioned earlier. Aspirin-induced gastric ulcers The ulcers were induced by administering aspirin (200 mg/kg, p.o) to the animals fasted for 36 h. Boswellia sacra extract was administered 30 min before aspirin administration and, after 4 h, all animals were sacrificed, stomachs were isolated, and the ulcer index was determined (Kumar et al., 2013). Cold-restraint stress-induced ulcers
Effect on gastric ulcers
The animals were placed in a restraint cage, and the cage was placed at a temperature of 2 C for 3 h. Boswellia sacra extract was administered 30 min prior to subjection of stress. The animals were sacrificed, stomach was isolated, and the ulcer index was determined (Parmar & Desai, 1993).
Acetic acid-induced chronic gastric ulcer
Statistical analysis
The animals were fasted for 24 h prior to the experiment. Under light ether anesthesia, the stomach was exposed;
Values are expressed as mean ± standard error of mean (SEM). Statistical significance was determined by one-way
Proulcerogenic effect of B. sacra water extract
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DOI: 10.3109/13880209.2015.1028553
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Figure 1. GC-MS chromatogram of water extract of Boswellia sacra.
Table 1. List of major chemical constituents present in the water extract of Boswellia sacra. Number 1 2 3 4 5 6 7
Retention time 8.634 9.964 12.346 12.433 12.496 13.843 13.949
Name of the compound 1,8-Cineole 1-Octanol ()-Menthol 3-Cyclohexen-1-ol Octanoic acid Thymol Carvacrol
analysis of variance (ANOVA) followed by Dunnett’s test for comparison of all parameters. Statistical significance for ulcer score was determined using the Kruskal–Wallis test with posttest. The statistical analysis was done using computer software (Graphpad lnstat DATASET 1, ISD, software version 3.0 for Windows, GraphPad Software Inc., San Diego, CA). Values of p50.05 were considered to indicate statistical significance.
Results GC-MS analysis of B. sacra extract GC-MS chromatogram analysis of the water extract of B. sacra shows many peaks indicating the presence of several volatile constituents (Figure 1). By comparing the mass spectra of the constituents with the NIST, WILEY 7, and SZTERP libraries, several phytoconstituents were characterized and identified. Some of the major constituents are shown in Table 1. Of all the compounds identified, the most abundant compounds were 1,8-cineole (4.16%), 1-octanol (6.91%), () menthol (10.81%), 3-cyclohexen-1-ol (21.33%), octanoic acid (18.91%), thymol (6.14%), and carvacrol (5.67%). Effect in normal rats The extract at both the tested doses did not produce any noticeable damage to gastric mucosa when administered to
Molecular formula
Molecular weight
Peak area %
C10H18O C8H18O C10H20O C10H20O C8H16O2 C10H14O C10H14O
154 130 156 156 144 150 150
4.16 6.91 10.81 21.33 18.91 6.14 5.67
normal animals for 30 d compared with vehicle-treated control. Effect on gastric ulcers Effect on acetic acid-induced chronic gastric ulcers Application of glacial acetic acid on the serosal surface at the antral region of the stomach produced penetrating ulcers in all the groups. Administration of B. sacra extract at two different doses aggravated the acetic acid-induced gastric ulcers as evidenced by 22% and 33% increase in ulcer index after treatment with B. sacra extract of 2 ml/kg and B. sacra extract of 5 ml/kg, respectively. The higher dose of B. sacra extract (5 ml/kg) also produced a significant increase in ulcer score (p50.05). The mortality rate was more in B. sacra extracttreated groups as compared with control (Table 2). Effect in pylorus-ligated rats Boswellia sacra extract (5 ml/kg) showed a significant increase in volume of gastric secretion, free acidity, total acidity, ulcer index (p50.01), and pepsin activity (p50.05) when compared with control. The lower dose of B. sacra extract (2 ml/kg) produced less severe effect compared with the higher dose (5 ml/kg) in increasing free acidity, total acidity, and ulcer index while it did not produce any significant change in the volume of gastric secretion and
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Table 2. Effect of Boswellia sacra water extract on different gastric ulcer models in rats. Acetic acid-induced chronic gastric ulcers Groups Control Boswellia sacra water extract (2 ml/kg, p.o) Boswellia sacra water extract (5 ml/kg, p.o)
Ulcer index in different models
Ulcer index
Ulcer score
Mortality
Ethanol-induced gastric ulcers
Aspirin-induced gastric ulcers
Stress-induced gastric ulcers
0.36 ± 0.023 0.44 ± 0.016*
1.33 ± 0.210 2.00 ± 0.258
0/6 2/8
0.66 ± 0.08 0.71 ± 0.13
0.15 ± 0.02 0.14 ± 0.03
0.185 ± 0.024 0.254 ± 0.0172*
0.48 ± 0.028**
2.50 ± 0.224*
4/10
0.72 ± 0.09
0.16 ± 0.02
0.287 ± 0.0169**
All values are mean ± SEM, n ¼ 6, *p50.05, **p50.01 compared with control. p.o, per os.
Table 3. Effect of Boswellia sacra water extract in pylorus-ligated rats.
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Groups Control Boswellia sacra water extract (2 ml/kg, p.o) Boswellia sacra water extract (5 ml/kg, p.o)
Volume of gastric Free acidity secretion (ml) (mEq/l)
Total acidity (mEq/l)
Ulcer index
Mucin content Total proteins (mg/g) Pepsin activity (mg/ml)
9.15 ± 0.377 7.68 ± 0.483
52.6 ± 3.64 117.8 ± 3.15 71.7 ± 2.71** 129.5 ± 2.65*
0.54 ± 0.02 0.78 ± 0.03**
7.25 ± 0.426 6.85 ± 0.365
0.085 ± 0.023 0.178 ± 0.027
52.68 ± 8.56 68.15 ± 10.25
5.51 ± 0.463**
74.9 ± 3.02** 135.8 ± 2.51** 0.84 ± 0.02**
6.55 ± 0.514
0.186 ± 0.034* 72.58 ± 7.98
All values are mean ± SEM, n ¼ 6, *p50.05, **p50.01 compared with control, p.o, per os.
pepsin activity. None of the treatments produced any significant effect on gastric mucin secretion and protein content in gastric juice (Table 3). Effect on ethanol-induced gastric ulcers, aspirin-induced gastric ulcers, and stress-induced gastric ulcers Boswellia sacra extract did not show any significant alteration in the development of ethanol-induced and aspirin-induced gastric ulcers at both the tested doses while a significant increase in the development of cold plus-restraint stressinduced ulcers was seen after administration of both doses of extract (Table 2).
Discussion The results of the present study revealed the proulcerogenic effect of B. sacra water extract in rats. The extract increased the secretion of gastric aggressive factors such as gastric acid secretion and gastric pepsin secretion without significantly altering the secretion of gastric defensive mucus secretion. As mentioned earlier, B. sacra oleo gum resin, commonly known as frankincense or incense, is widely used in different parts of the world. The water extract of B. sacra oleo gum resin is a house-hold medicine used for the treatment of cough, stomach problems, and liver problems (Bosworth et al., 1983). The word ‘‘stomach problems’’ is confusing and discussion with traditional healers revealed that stomach problems include acidity and many other stomach diseases. Traditionally, the water extract of B. sacra oleo gum resin is prepared by different methods. The commonest method used for the preparation involves covering the resin in a muslin cloth or a wire mesh, and immersing it in boiling water for 15–30 min. Another method used employs soaking of frankincense in water overnight followed by filtration (Highet, 2006; Paul et al., 2012). However, most of the people now prefer to buy the readymade water extract
available in the market. We tried the first two methods in our laboratory, but could not get the strong flavor of frankincense present in the marketed water extract. Hence, the water extract of B. sacra purchased from the market was used in the present study. This study was carried out using experimental models of gastric ulcer that produce ulcerogenesis by distinct mechanisms. The overall effect on gastric ulcers was studied in acetic acid-induced chronic gastric ulcers while the gastric secretory effect of B. sacra extract was determined in pylorus-ligated rats. The ulcer formation in pylorus-ligated rats is influenced by changes in secretion of gastric acid, pepsin, and mucus secretion (Kulkarni, 1999; Shay et al., 1945). The ethanolinduced gastric ulcer model was used to determine the effect on acid-independent gastric cytoprotection, and aspirininduced gastric ulcers provide information for the effect on prostaglandin synthesis (Asad et al., 2001; Kumar et al., 2013). The stress-induced gastric ulcers depend on gastric acid secretion and gastric motility. Drugs interfering with gastric secretion and/or motility or those having direct calming effect on the central nervous system reduce stressinduced gastric ulcers (Asad et al., 2001; Parmar & Desai 1993). Boswellia sacra water extract aggravated the acetic acid-induced gastric ulcers compared with vehicle-treated control. The proulcerogenic effect of B. sacra water extract was due to augmented secretion of gastric acid and pepsin, as demonstrated in pylorus-ligated rats. There was no effect on gastric cytoprotection in ethanol-induced gastric ulcers and aspirin-induced gastric ulcers. The aggravation of stressinduced gastric ulcers could also be due to the gastric hypersecretory effect of B. sacra extract. Boswellia species include Boswellia serrata Roxb., Boswellia frereana Birw., and Boswellia sacra (syn. Boswellia carterii) and these are reported to possess several pharmacological activities (Paul et al., 2012). The main constituents responsible for their pharmacological activity are
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boswellic acids. The boswellic acids from B. serrata are also reported to possess gastric ulcer-protective effect in rats (Singh et al., 2008). However, in the present study, the GCMS analysis did not reveal the presence of boswellic acids. This was expected as boswellic acids are insoluble in water (Shah et al., 2009). The GC-MS analysis of the water extract showed the presence of several chemical constituents. Ironically, literature review on these constituents for their effect on gastric ulcers revealed that some of these constituents and/or their derivatives have been reported for antiulcer/gastro-protective effects and none of these constituents are known for their gastric hypersecretory or ulcerogenic effects. Derivative of 2(5H)-furanone is reported to possess antiulcer effect (Tamai et al., 1993) while cineole, linalool, phytol, and formic acid are reported as possible chemical constituents, responsible for antiulcer effect of plant extracts in which they are found (Barocelli et al., 2004; Haider et al., 2012; Takayama et al., 2011). Carvacrol is reported for antiulcer action (Oliveira et al., 2012; Rao et al., 2004; Silva et al., 2012). Prodrugs of ibuprofen with thymol had reduced ulcerogenic effect that is observed with ibuprofen alone indicating the ulcer-preventive effect of thymol (Redasani & Bari, 2012). The volatile oils from several plants have also been reported for antiulcer/ gastro-protective effects (Bonamin et al., 2014; Guo et al., 2014; Moraes et al., 2013; Ovalle-Magallanes et al., 2014). Hence, it is difficult to predict the constituent(s) responsible for the proulcerogenic effect of this extract. Further investigations into mechanisms of ulcer-protective effect of constituents reported for antiulcer effect and evaluation of constituents not reported for their effect on gastric secretion and ulcer formation may help in identifying the constituent(s) responsible for this proulcerogenic effect.
Conclusion The water extract of B. sacra oleo gum resin attenuated the healing of acetic acid-induced chronic gastric ulcers. This proulcerogenic effect was due to an increase in gastric acid and gastric pepsin secretion, as observed in pylorus-ligated rats. The water extract of B. sacra also increased the development of stress-induced gastric ulcers while it did not affect the development of ethanol-induced and aspirininduced gastric ulcers. The GC-MS analysis of B. sacra water extract revealed the presence of several constituents.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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