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International Journal of Pharmacology

Year: 2013 | Volume: 9 | Issue: 2 | Page No.: 108-124
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ABSTRACT

Many medicinal plants have been identified in Traditional Iranian Medicine (TIM) for the treatment of Peptic Ulcer (PU) but they are still unknown to scientific community. In the present study anti PU activity of these remedies were systematically reviewed and identified. For this purpose, medicinal plants proposed for the management of PU in TIM were collected from TIM sources and they were searched in modern medical databases like PubMed, Scirus, Sciencedirect and Google Scholar to find studies confirmed their efficacy. Findings from modern investigations support the claims of TIM about the efficacy of many of these plants in PU. For example, the oleogum resin of Boswellia carterii and B. serrata as a beneficial remedy for PU in TIM were demonstrated to have wound healing, cytoprotective, antisecretory, antacid, prostaglandin production and inflammatory modulating properties. Fruit and leaves of Myrtus communis was found to be antioxidant, anti H. pylori, wound healing, antisecretory, antacid and cytoprotective. The aerial part from Melissa officinalis exerts its beneficial effects in PU by antioxidant, anti H. pylori, prostaglandin elevating, cytoprotective, antisecretory, antacid and leukotriene reducing properties. Furthermore, Polygonum species demonstrated its function on PU with prostaglandin enhancement, inflammatory modulation, wound healing, cytoprotection, antacid, antioxidant and anti-H. pylori activity. In contrast, for some of herbal remedies used in TIM such as Dolichos lablab flower, Symphytum species, Zizyphus spina-christi fruit, Alisma plantago-aquatica, Cupressus sempervirens fruit, Acacia Arabica gum, Cyperus species root, Althaea officinalis flower and Nymphaea alba flower there is no enough evidence in modern medicine to prove their effectiveness in the management of PU. Pharmacological and clinical studies for evaluation of efficacy of these herbs in PU and their possible mechanisms of action are recommended.
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Received: January 18, 2013;   Accepted: March 19, 2013;   Published: June 05, 2013

INTRODUCTION

Peptic Ulcer disease (PU) is a complex and multicausal disease which encompass gastric and duodenal ulcer, occurs when biological balance between defense and aggressive factors in gastrointestinal tract is disturbed (Sumbul et al., 2011). Among aggressive factors, gastric acid and pepsin secretion (Borrelli and Izzo, 2000), active free radicals and oxidants (Repetto and Llesuy, 2002), leukotrienes (Wallace et al., 1990), endothelins (Borrelli and Izzo, 2000) and exogenous factors such as ethanol (Soll and Graham, 2009) or NSAIDs (Takeuchi, 2012) can be listed. In contrast, gastric mucus, bicarbonate (Allen and Garner, 1980), normal blood flow (Borrelli and Izzo, 2000), prostaglandins (Cryer, 2001), nitric oxide (NO) (Martin et al., 2001) and antioxidant enzymes such as catalase or Glutathione (GSH) (Repetto and Llesuy, 2002) work defensive. Most of the gastric lesions originate in a chronic infection of gastric mucosa with Helicobacter pylori (H. pylori). H. pylori is a common human pathogen with asymptomatic stomach colonization in nearly 70% of the population and approximately in 10 B 20% are susceptible for PU (Vitor and Vale, 2011). Medicinal plants identified in traditional medicine have a long history of consumption in nutrition and medicine in different nations. Thus, traditional medicines is a virgin resource for investigation on their efficacy and phytochemical constituents (Rahimi et al., 2012; Rahimi and Ardekani, 2013; Ardekani et al., 2011; Rahimi et al., 2013; Khanavi et al., 2012). There are many natural remedies in Traditional Iranian Medicine (TIM) that have been used for management of PU. Various mechanisms have been explained in TIM sources for their effectiveness including astringent, wound healing, antiseptic and anti-inflammatory activities (Aghili, 2009; Avicenna, 1983; Arzani, 2005). Present study conducted to review medicinal plants considered as gastroprotective and healing agents on PU in TIM resources and beside that to gather evidence for their effectiveness and biological mechanisms in modern investigation.

Methods: In order to achieving this aim, electronic databases including Scirus, Sciencedirect, PubMed, Scopus, Web of Science and Google Scholar were explored for each of the medicinal plants proposed in TIM for PU and all retrieved articles were evaluated to achieve any in vitro, in vivo, or clinical evidence for their efficacy and possible mechanisms. The retrieved studies either demonstrate obviously effectiveness of these herbs or indirectly their efficacy on the involved mechanisms in the treatment of PU.

FINDINGS AND DISCUSSION

Medicinal plants used for the treatment of PU in TIM
Acacia arabica: A. senegal gum protected against cold restraint stress-induced gastric ulcer in rat (Omayma et al., 2011). Aqueous extract of A. arabica gum showed protection against meloxicam-induced intestinal damage and attenuated intestinal enzymes (lipase, amylase, alkaline phosphatase and lactate dehydrogenase) activity (Abd El-Mawla and Eldien, 2011).

Acorus calamus L.: The rhizome showed antioxidant activity in vitro and in vivo in ethanol-induced oxidative stress in rat (Ilaiyaraja and Khanum, 2011). The rhizome protected against gastric ulcer induced by pyloric ligation, indomethacin, reserpine and duodenal ulcer induced by cysteamine. It also protected against cytodestructive agents and reduced acidity of gastric juice (Rafatullah et al., 1994). The rhizome did not show inhibitory activity against H. pylori in vitro (Babarikina et al., 2011). A. calamus leaves demonstrated wound healing activity in rat (Jain et al., 2010).

Alisma plantago-aquatica: It showed antioxidant activity in vitro (Kim et al., 2007). Its rhizome inhibited iNOS expression in vitro (Kim et al., 1999). The rhizome as a constituent in a polyherbal formulation demonstrated protective activity against ethanol-induced ulcer in rat via its antioxidant activity (Jeon et al., 2012).

Althaea officinalis L.: It exhibited protective effect on ethanol-induced gastric ulcer in rats (Hage-Sleiman et al., 2011) and inhibited urease enzyme (a vital enzyme for H. pylori growth in stomach) in vitro (Nabati et al., 2012). Its hydroalcoholic extract demonstrated antioxidant activity (Jahed Khaniki et al., 2012).

Bambusa arundinacea: B. vulgaris secretions inhibited urease enzyme in vitro (Nabati et al., 2012). B. arundinacea leaves demonstrated antioxidant activity and protected against aspirin and pylorus ligation-induced gastric ulcer in rats with no significant effect on gastric juice secretion and acidity (Muniappan and Sundararaj, 2003; Naz et al., 2012).

Boswellia carterii and B. serrata: Boswellic acids isolated from the oleo gum resin of B. serrata protected gastric mucosa against acute and chronic ethanol/HCl-, cold restraint stress-, asprin-, indomethacin-and pyloric ligation-induced ulcer in rat. The mechanism of gastroprotective function is attributed to production of prostaglandins, increasing pH and reducing volume of gastric juice, inhibition of leukotriene synthesis and improvement of gastric cytoprotection (Singh et al., 2008). Oleo gum resin from B. carterii and B. serrata healed acetic acid-induced chronic gastric ulcer in rat via., enhancing regeneration of mucosal ulcers (Mei and Zeng, 2012). A topical formulation from B. serrata oleo gum resin showed in vivo wound healing activity (Mallik et al., 2010).

Cupressus sempervirens: Essential oil isolated from fruits in al topical formulation did not exhibit remarkable wound healing activity in rats (Tumen et al., 2012). The essential oil inhibited the growth of H. pylori in vitro (Ohno et al., 2003).

Cyperus species: C. rotundus rhizome showed significant wound healing activity in rat (Puratchikody et al., 2006). It protected against ischemia and reperfusion gastric damage induced by celiac artery clamping in rat via., its antioxidant activity (Guldur et al., 2010).

Dolichos lablab: D. lablab in a polyherbal formulation showed antacid activity in vitro (Wu et al., 2010). Seed extract of D. lablab had antioxidant properties in vitro (Marathe et al., 2011). It did not show significant antibacterial properties against H. pylori (Lee et al., 2003). The leaves of D. lablab demonstrated gastroprotective activity against aspirin and ethanol-induced ulcer (Tarin and Chichioco-Hernandez, 2011).

Hyssopus officinalis: The aerial parts also exhibited wound healing properties via enhancement of collagen and antioxidant activity on cell culture (Alexandru et al., 2011).

Laurus nobilis: Gastroprotective activity of aqueous and oily fraction of seeds on ethanol-induced gastric ulcer in rats has been proven (Afifi et al., 1997). The fruits demonstrated strong gastroprotective function against ethanol-induced ulcer in rat (Gurbuz et al., 2002). L. nobilis leaves demonstrated wound healing (Nayak et al., 2006), anti H. pylori (Mahady et al., 2005) and antioxidant activities (Speroni et al., 2011).

Melissa officinalis L.: The aerial parts showed antioxidant properties in vitro (Canadanovic-Brunet et al., 2008). The essential oil and the main component citral inhibited contraction of isolated rat ileum in response to KCl, acetylcholine and serotonin in a concentration-dependent manner (Sadraei et al., 2003). The leaves and essential oil revealed antimicrobial activity against H. pylori in vitro (Mahady et al., 2005; Weseler et al., 2005). The leaf extract protected gastric mucosa from indomethacin and pylorus ligation-induced gastric ulcer through suppressing gastric acidity, acid secretion and leukotriene in gastric juice and increasing defense factors including mucin, pepsin and prostaglandin E2 in gastric juice (Khayyal et al., 2006).

Myrtus communis L.: A topical formulation of M. communis in low doses demonstrated wound healing activity in rat excision wounds (Rezaie et al., 2012). M. communis fruits protected against gastric ulcer caused by ethanol, indomethacin and pyloric ligation in rat via suppressing gastric secretion and acidity and enhancing its mucosal barrier (Sumbul et al., 2010). M. communis essential oil demonstrated strong antimicrobial activity against H. pylori in vitro (Deriu et al., 2007). M. communis leaf, stem and flower essential oil and methanolic extract showed antioxidant properties in vitro (Wannes et al., 2010).

Nymphaea alba: Its extract strongly inhibited urease enzyme in vitro (Nabati et al., 2012). N. alba rhizome showed antidiarrheal action via fluid infiltration and reduction in gastrointestinal tract transit in the rat (Bose et al., 2012a). It also revealed antioxidant activity in vitro (Bose et al., 2012b). N. lotus in a polyherbal formulation exhibited wound healing activity in rats (Dwivedi et al., 2010).

Oxalis species: O. corniculata whole plant demonstrated wound healing activity in rats (Taranalli et al., 2004). It also protected against gastric ulcer induced by pylorus ligation and indomethacin via reducing gastric secretion and free and total acidity (Sakat et al., 2012). Furthermore, O. corniculata leaves exhibited gastroprotective function on pyloric ligation-and ethanol-induced ulcer in rat through antioxidant activity and reducing gastric secretion and acidity (Patil et al., 2011).

Pistacia lentiscus: The oleo-gum resin showed antioxidant activity in vitro (Mahmoudi et al., 2010). Topical administration of P. lentiscus virgin fatty oil revealed wound healing properties (Djerrou et al., 2010). The oleo-gum resin demonstrated gastroprotective activity on different models of gastric ulcer in rats. It also reduced gastric free acidity in pylorus-ligated rats. It did not demonstrate significant protection in cysteamine-induced duodenal ulcers (Al-Said et al., 1986). Al-Habbal et al. (1984) showed significant healing activity of the oleo-gum resin in patients with duodenal ulcer and the same was confirmed in vitro (Marone et al., 2001). The oleo-gum resin and its major constituent, triterepenic acids, reduced growth of H. pylori in stomach of the infected mice without significant suppression of chronic gastritis and inflammatory infiltration associated with H. pylori (Paraschos et al., 2007). In a randomized pilot clinical study, the oleo-gum resin demonstrated antibacterial activity against H. pylori and exhibited significant eradication of the bacteria (Dabos et al., 2010). In contrast, Loughlin et al., (2003) reported that mastic gum could not eradicate H. pylori infection in mice and did not show significant reduction in their gastric bacterial load.

Plantago species: P. ovata water soluble seed husk polysaccharides promoted proliferation of human epithelial cells through growth factor receptors (Deters et al., 2005). P. ovata husk stimulated NO synthase in rabbit jejunum in vitro. Furthermore, it demonstrated secretion stimulating and muscarinic activity at doses of 100 and 300 mg kg-1 and antisecretory and antidiarrheal activity at higher doses (Mehmood et al., 2011). Mucopolysaccharides derived from the husk showed wound cleansing and wound healing properties in guinea pigs (Westerhof et al., 2001). P. lanceolata leaves revealed dose dependent peptic ulcer ameliorating activity in acetic acid-induced chronic gastric ulcer in rat and protective effect in indomethacin-and pylorus ligation-induced gastric ulcer and cysteamine-induced duodenal ulcer by its antisecretory and cytoprotective activity in mice, rats and mice, respectively (Melese et al., 2011). P. major leaf demonstrated gastroprotective activity and decreased total acidity in aspirin-and ethanol-induced ulcer in rat (Atta et al., 2005; Phipps and Mahmood, 2006; Than et al., 1996). It also showed wound healing properties in rats (Mahmood and Phipps, 2006). Aerial parts of P. major showed anti H. pylori activity in vitro. In contrast, its inhibition on urease enzyme was poor (Castillo-Juarez et al., 2009; Nabati et al., 2012).

Polygonum species: Two compounds isolated from P. tinctorium, tryptanthrin and kaempferol, inhibited H. pylori growth (Kataoka et al., 2001). P. minus extract revealed antioxidant activity in vitro (Huda-Faujan et al., 2007). It also prevented from ethanol-induced gastric ulcer in rat by inhibiting leucocyte infiltration in submucosa and increasing pH of gastric juice (Wasman et al., 2010). Qader et al. (2012) showed gastroprotective activity of different fractions from P. minus leaves in rat ethanol-induced ulcer via promoting antioxidant enzymes activity, increasing pH of gastric juice and mucus content and elevating hexosamine (the main glycoprotein of mucous tissue) and prostaglandin E2 level in gastric mucosa (Qader et al., 2012). The wound healing activity of P. cuspidatum extract has been proved in rat (Wu et al., 2012).

Portulaca oleracea L.: P. oleracea showed antioxidant properties and anti H-pylori activity (Dkhil et al., 2011; Cho et al., 2008). Moreover, it accelerated wound healing in mice (Rashed et al., 2003). The leaves protected mice against HCl-and ethanol-induced gastric ulcer via reducing gastric acidity and increasing pH of gastric juice (Karimi et al., 2004).

Quercus species: Q. ilex L. root bark and its tannic acid showed gastroprotective activity against ethanol-induced gastric ulcer in rats (Gharzouli et al., 1999). Q. suber and Q. coccifera leaves have protective effect on ethanol-induced gastric lesions in mice by inhibition of lipid peroxidation (Khennouf et al., 2003). Modern investigation also demonstrated antioxidant activity of Q. ilex leaves via in vitro assay (Chevolleau et al., 1993). Q. infectoria leaf has revealed wound healing properties through its antioxidant activity (Umachigi et al., 2008). Q. infectoria gall inhibited H. pylori growth in vitro (Voravuthikunchai et al., 2006).

Rosa species: R. damascena Mill. flowers and green leaves showed antioxidant activity in vitro (Baydar and Baydar, 2013). The flower oil revealed gastroprotective activity (Maleev et al., 1972). The flower boiled extract demonstrated laxative activity via osmotic infiltration and transition time reduction in rat intestine (Arezoomandan et al., 2011). R. canina fruits protected against ethanol-induced gastric ulcer and inhibited 100% of the ulcers in rat (Gurbuz et al., 2003). Tellimagrandin I and rugosin isolated from R. rugosa were effective against H. pylori in vitro (Funatogawa et al., 2004).

Symphytum species: Topical preparation from aerial parts of Symphytumxuplandicum Nyman. showed wound healing activity in different clinical trials (Barna et al., 2007, 2012). Wound healing activity of topical formulations from the leaves of S. officinale L. was demonstrated in rat model via reducing infiltration of cellular inflammatory agents and induction of collagen deposition (Araújo et al., 2012). Allantoin and pyrrolizidine alkaloids-free composition of S. asperum roots which containing crude polysaccharides and biopolymer from poly [3-(3,4 dihydroxyphenyl)glyceric acid] exhibited antioxidant and wound healing activities (Barbakadze et al., 2009).

Tragopogon graminifolius DC.: Antioxidant activity of T. porrifolius aerial parts has been demonstrated in vitro (Mroueh et al, 2011). T. collinus DC. aerial part demonstrated protective effect on ethanol-induced gastric ulcers in rat (Farzaei et al., 2012). T. graminifolius aerial parts showed gastroprotective activity against ethanol-induced ulcer in rat (Farzaei et al., 2013). Flavonoids including apigenin, luteolin, quercetin and vitexin are the main constituent of Tragopogon genus (Kroschewsky et al., 1969; Sareedenchai et al., 2009). Quercetin showed protective activity against HCl/ethanol-induced gastric ulcer and healing activity against acetic acid-induced chronic gastric ulcer with inhibition of gastric tissue lipid peroxidation (Suzuki et al., 1998). Helicobacter pylori (H. pylori) urease inhibitory function of quercein has been proven (Xiao et al., 2012). Quercetin-3-O-α-D-glucuronopyranoside protected gastric mucus against indomethacin-induced ulcer by increasing gastric mucus secretion, reduction of myeloperoxidase (MPO) activity and free radical production, preventing the expression of intercellular adhesion molecule protein and down regulation of the pro-inflammatory cytokines (Yan et al., 2011).

Gallic acid is one of the major phenolic compounds of T. pratensis (Kucekova et al., 2011). Gallic acid protects against indomethacin-and also diclofenac-induced gastric ulcer in rat. Moreover, it demonstrated healing effect on indomethacin-induced gastric ulcer. Mechanism of its antiulcer activity is blocking the oxidative stress and lipid peroxidation. It showed in vitro antioxidant activity and suppressed gastric mucosal cell apoptosis (Pal et al., 2010).

Zizyphus spina-christi L.: There is no scientific report confirming anti-PU activity of fruits. Although, the leaves showed antioxidant properties in various in vitro models (Abalaka et al., 2011) and stem bark demonstrated antidiarrheal activity and reduced intestinal transit in rat (Adzu et al., 2003).

CONCLUSION

Current stalemates of modern medicine in the management of various ailments incline research tendencies to traditional medicine. In this respect, traditional medicine has introduced good protocols for treatment of various gastrointestinal disorders including inflammatory bowel disease (Rahimi et al., 2010; Rastegarpanah et al., 2011), irritable bowel disease (Rahimi and Abdollahi, 2012a), hemorrhoids (Rahimi and Abdollahi, 2012b; Rahimi and Abdollahi, 2013) and peptic ulcer as presented in this article. All of the remedies presented here had adequate evidence from traditional or scientific source for their efficacy in management of PU. As shown in Table 1, the plants used in TIM for management of PU are from different families and there is no exact relationship between the family of plants investigated and their efficacy. For many of these herbs, various studies which demonstrating their usefulness on PU were found. These studies were mainly in vitro and in vivo which are summarized in details in the Table 2 and 3, respectively.

As shown in Table 4, only 4 clinical trials were found; 2 on Symphytum x uplandicum (Barna et al., 2007; Barna et al., 2012) and 2 on Pistacia l entiscus (Al-Habbal et al., 1984; Dabos et al., 2010). As shown in Table 5, these remedies have shown their effectiveness on PU via several mechanisms of action including prostaglandin enhancement, modulation of inflammatory mediators and antioxidant, anti H. pylori, wound healing, cytoprotective and antisecretory activities. For some of these plants including Zizyphus spina-christi, Alisma plantago-aquatica, Rosa species, Cupressus sempervirens, Acacia Arabica, Cyperus species, Bambusa arundinacea, Althaea officinalis and Dolichos lablab, just one or two study on the efficacy and relevant mechanisms has been carried out. Advanced scientific studies for evaluation of these herbs on PU and their possible mechanisms are suggested. In comparison, some of these plants such as Boswellia carterii and B. serrata, Melissa officinalis, Myrtus communis, Polygonum species and Tragopogon graminifolius show their beneficial effects in PU by affecting various associated mechanisms. According to published investigations, these medicinal plants probably are more effective in the management of PU than the other ones. As mentioned above, despite many in vitro and in vivo evidences, there are few supportive clinical findings. Therefore, conducting clinical trials on the efficacy and safety of mentioned medicinal plants in the management of PU is recommended.

Table 1: Medicinal plants used for the treatment of peptic ulcer in traditional Iranian medicine
Image for - An Evidence-based Review on Medicinal Plants used for the Treatment of Peptic Ulcer in Traditional Iranian Medicine

Table 2: In vitro studies on plants used in traditional Iranian medicine for the treatment of peptic ulcer
Image for - An Evidence-based Review on Medicinal Plants used for the Treatment of Peptic Ulcer in Traditional Iranian Medicine

Table 3: In vivo studies on plants used in traditional Iranian medicine for the treatment of peptic ulcer
Image for - An Evidence-based Review on Medicinal Plants used for the Treatment of Peptic Ulcer in Traditional Iranian Medicine
NO: Nitric oxide, eNOS: Endothelial NO synthase, iNOS: Inducible NO synthase, GSH: Glutathione, GPx: Glutathione peroxidase SOD: Superoxide dismutase, TNF-α: Tumor necrosis factor-alpha, EGF: Endothelial growth factor, VEGF: Vascular endothelial growth factor, HGF: Hepatocyte growth factor, COX1: Cyclooxygenase-1, PGE2: Prostaglandin-E2, MPO: Myeloperoxidase, IL-1β: Interleukine-1ί, MDA: Malondialdehyde, HB-EGF: Heparin binding epidermal-growth-factor-like growth factor, TBARS: Thiobarbituric acid reactive substances

Table 4: Clinical studies on plants used in traditional Iranian medicine for the treatment of peptic ulcer
Image for - An Evidence-based Review on Medicinal Plants used for the Treatment of Peptic Ulcer in Traditional Iranian Medicine
PU: peptic ulcer; tid: three time a day

Table 5: Mechanisms of action of the plants used for the treatment of peptic ulcer disease in traditional Iranian medicine
Image for - An Evidence-based Review on Medicinal Plants used for the Treatment of Peptic Ulcer in Traditional Iranian Medicine
PG: Prostaglandin, NO: Nitric oxide, H. pylori: Helicobacter pylori

Moreover, combination of many of the mentioned herbs according to the protocols of TIM sources can be assumed to obtain more efficacious complementary and alternative treatment for PU.

ACKNOWLEDGMENT

This study is the outcome of an in-house financially non-supported study. Authors thank INSF.

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