Indomethacin-induced Gastric Ulcer In Mice Research Articles

Molecular docking, characterization, ADME/toxicity prediction, and anti-ulcer activity of new quercetin derivatives on indomethacin-induced gastric ulcer in mice

Gastric ulcer (GU) is a serious upper gastrointestinal tract disorder that affects people worldwide. The drugs now available for GU treatment have a high rate of relapses and drug interactions, as well as mild to severe side effects. As a result, new natural therapeutic medications for treating GU with fewer negative side effects are desperately needed. Because of quercetin's (QCT) diverse pharmacological effects and unique structural features, we decided to semi-synthesize new QCT derivatives and test them for antiulcer activity. Docking assays were performed on the synthesized compounds to determine their affinity for TLR-4/MD-2, MyD88/TIR, and NF-κB domains, an important inflammatory pathway involved in GU development and progression. Mice were given oral famotidine (40 mg/kg/day), QCT, QCT pentamethyl (QPM), or QCT pentaacetyl (QPA) (50 mg/kg/day) for 5 days before GU induction by a single intraperitoneal injection of indomethacin (INDO; 18 mg/kg). QPM and QPA have a stronger binding affinity for TLR-4/MD-2, MyD88/TIR and NF-κB domains than QCT. In comparison, they demonstrated the greatest reduction in ulcer score and index, gastric MDA and nitric oxide (NO) contents, MyD88 and NF-κB expressions, and gastric TLR-4 immunostaining. They also enhanced the levels of GSH, CAT, COX-1, and COX-2 in the gastric mucosa, as well as HO-1 and Nrf2 expression, with histological regression in gastric mucosal lesions, with QPA-treated mice demonstrating the best GU healing. QPA is safe against all of the target organs and adverse pathways studied, with good ADME properties. However, further in vitro experiments are necessary to demonstrate the inhibitory effects of QPM and QPA on the protein targets of interest. In addition, preclinical research on its bioavailability and safety is essential before clinical management can be undertaken. Overall, the new QPA derivative could one day serve as the basis for a new class of potential antiulcer drugs.

Anti-Ulcerogenic Evaluation of Torilis Leptophylla Plant Extract on Indomethacin Induced Mice Gastric Ulcer

Introduction: Despite conventional anti-ulcer therapies for peptic ulcer diseases, medicinal plants might provide effective new anti-ulcer compounds or, alternatively, as adjuncts to existing therapies. Aims & Objectives: To evaluate the effects of Torilis leptophylla on indomethacin-induced gastric ulcer in mice. Place and duration of study: It was an experimental study carried out in the Department of Pharmacology, University of Health Sciences, Lahore, from March to December 2016. Material & Methods: Thirty six (36) adult healthy male BALB/C mice were divided equally in 6 groups and assigned as group I (control), group II (positive control), group III–V (TLM low, medium and high dose) and group VI (omeprazole). Gastric ulcers were induced by oral ingestion of indomethacin in groups II -VI. Acute oral toxicity of the plant was also tested. Antiulcer effect was assessed by measuring body weight, amount and pH of gastric juice, ulcer count, severity of gastric lesion, ulcer index, percentage (%) inhibition of ulcer and histopathology of gastric tissue. Results were analyzed by SPSS 20.0, P-value<0.05 was considered significant. Results: Gastric ulcer reduced the body weight in indomethacin induced animals (28 ± 2.53, 29.66 ± 3.88, 29.66 ± 2.33, 31 ± 3.52,32 ± 3.099 g in group II, III, IV, V and VI respectively) at day 3. Omeprazole and TLM treated groups reduced the gastric volume and pH as compared to positive control. Ulcer index (18.83, 5.14, 3.42, 1.71, 1.76 of the group II, III, IV, V and VI respectively) depicted significant reduction by treatment groups. Ulcer's percentage inhibition (72.7, 81.8, 90.88, 90.65 of low, median and high dose of TLM and standard drug respectively) was increased. Histopathological observations were remarkably reversed by TLM treated groups. Conclusion: Torilis leptophylla could significantly protect gastric mucosa from damage by indomethacin.

Therapeutic Versus Preventative Use of Ginkgo biloba Extract (EGb 761) against Indomethacin-Induced Gastric Ulcer in Mice

The main bioactive constituents in the standardized Ginkgo biloba leaf extract (EGb 761) are the terpene lactones and flavonoid glycosides. EGb 761’s antioxidant and anti-inflammatory properties have previously been demonstrated. Indomethacin-induced gastric ulcers have a multifactorial etiology and represent a major restriction to its therapeutic utility. The underlying ulcerogenic process involves oxidative and inflammatory biomolecular insults. This study was performed to explore the curative and preventative benefits of EGb 761 in experimentally-induced ulcers. To develop gastric ulcers in mice, indomethacin (40 mg/kg) was administered orally. EGb 761 (200 mg/kg) was given by gavage for 7 days before (preventative) and after (therapeutic) indomethacin administration. The histological alterations and macroscopic mucosal lesions were assessed. In gastric tissue homogenates, malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), and inflammatory cytokines were measured. The expressions of cyclooxygenase-2 (COX-2), cytokines, and proliferating cell nuclear antigen (PCNA) in the stomach mucosa were also investigated. The ulcer index, histological alterations, gastric oxidants, and inflammatory biomarkers were all significantly increased by indomethacin. In stomach specimens, it increased COX-2 and PCNA expression. EGb 761 treatments, both prophylactic and therapeutic, resulted in significant reductions in ulcer lesions, nitrosative and oxidative damage, and inflammatory markers, along with the lowering of COX-2 and PCNA expressions. Furthermore, in the fight against stomach ulcers, EGb 761 treatment was found to be more efficient than prevention.

Chinese sumac (Rhus chinensis Mill.) fruits alleviate indomethacin-induced gastric ulcer in mice by improving oxidative stress, inflammation and apoptosis

Ethnopharmacological relevanceAccording to traditional Chinese medicine and a previous literature, many parts of Chinese sumac (Rhus chinensis Mill.), including fruits, are used as traditional herb to prevent or cure many diseases, such as inflammation, diarrhea, malaria, and other acute or chronic gastrointestinal diseases. However, the effects of the fruits on the prevention of gastric ulcer and the underlying mechanisms have not been reported.Aim of the study: This experiment aimed to investigate the preventive effect of ethanol extract (RM) from Chinese sumac fruits on indomethacin-induced gastric ulcer in mice and the underlying mechanisms. Materials and methodsA single gavage of indomethacin was used to induce a gastric ulcer model in Kunming male mice. According to the results of histopathological analysis, immunohistochemistry and immunofluorescence analysis, as well as the expression of prostaglandin E−2, antioxidant enzymes and cytokines, the protective effect of RM on indomethacin-induced gastric ulcer was evaluated. The expression levels of several key proteins involved in oxidative stress, inflammation and apoptosis in gastric tissue were detected to illuminate the underlying mechanisms. ResultsRM significantly reduced the ulcer index and pepsin activity, improved the microstructure of gastric mucosa and the prostaglandin E−2 content, restored the levels of glutathione and superoxide dismutase, and decreased the contents of malondialdehyde, advanced oxidation protein products, TNF-α, IL-1 β and IL-6. Further experimental results showed that RM could improve the expression levels of HO-1 and NQO1 by activating the Nrf2 protein pathway to alleviate oxidative stress in gastric tissue. At the same time, RM significantly down-regulated the expressions of p-NF-κB, p-IκBα and iNOS to relieve inflammatory response, and inhibited the cellular apoptosis of gastric tissue by up-regulating Bcl-2 and down-regulating Bax and cleaved Caspase-3. ConclusionsThe current work clarified that the ethanol extract from Chinese sumac fruits can improve the oxidative stress level, inflammatory response and cell apoptosis in gastric tissue by interfering with the expressions of several key regulatory proteins to prevent indomethacin-induced gastric ulcer in mice. This study may provide some insights and scientific evidence on the application of Chinese sumac fruits as a traditional herb to prevent or alleviate gastric ulcer.

Sildenafil attenuates nonsteroidal anti-inflammatory-induced gastric ulceration in mice via antioxidant and antigenotoxic mechanisms.

Sildenafil (SIL) has potential as an interesting gastroprotective drug. However, the pathways of its protective effect still needs to be clarified, and its use as a potential gastroprotective agent validated. This study aims to evaluate the effects of SIL via modulation of oxidative stress in a NSAID-induced gastric lesion model. Male Swiss mice were divided into six groups: control (CON, water), nonsteroidal anti-inflammatory drug (NSAID, water), proton pump inhibitor (PPI, 30mg/kg of lansoprazole), SIL 5 (5mg/kg), SIL 25 (25mg/kg) and SIL 50 (50mg/kg). The animals were treated by gavage (a single dose) after 24hours of fasting, and gastric lesions were performed after 30minutes, with indomethacin (40mg/kg, by gavage). After 6h, the animals were killed and the stomach was removed to evaluate reactive oxygen species (ROS) production, oxidation of macromolecules, quantification of antioxidant enzymes, DNA fragmentation, apoptosis and macroscopic and histologic analysis of gastric lesions. SIL exerts a dose-dependent gastroprotective effect against NSAID-induced mucosal injury, also reducing cytoplasmic levels of ROS and consequent oxidative damage to macromolecules. In addition, SIL increases nitric oxide bioavailability, antioxidant enzymes and gastric cellular viability, as well as restoring important factors involved in gastroprotection. Our results demonstrate that different doses of SIL prevent indomethacin-induced gastric ulcer in mice via different, but complementary antioxidant, antigenotoxic and antiapoptotic mechanisms.

Avocado seeds (Persea americana Mill.) prevents indomethacin-induced gastric ulcer in mice

The long-term use of anti-inflammatory drugs is the most common cause of gastric ulcer disease, one of the major gastrointestinal disorders affecting people worldwide. Persea americana Mill. (avocado) seed is a by-product generally discarded as waste, but can be used to treat gastric disorder due to its anti-inflammatory, antioxidant and antimicrobial activities. The aim of the present study was to evaluate the potential protective effects of the ethyl acetate fraction of avocado seeds (SEAP) extracts against indomethacin-induced gastric ulcer in mice. It was found that SEAP were effective in mitigating oxidative stress through a decrease on the oxidized products levels (reduction of 90% in lipid peroxidation in plasma) and increasing superoxide dismutase enzyme (SOD) activity (4.25-fold increase compared to the indomethacin group), also preventing the rise in ulcer and lesions areas (92% of protection) and histological changes induced by indomethacin. Chemical analysis using mass spectrometry by (−)-ESI-FT-ICR MS revealed the presence of (−)-epicatechin and (+)-catechin, confirmed by HPLC-DAD, and other important phenolic compounds in avocado seeds, such as caffeoylquinic acid, flavonoids, phenylpropanoids and tannins, substances that promote inhibition of pathways involved in gastric ulcer formation. Thus, avocado seeds extract may be a suitable natural source for the prevention and treatment of gastric ulcer.

1-Deoxynojirimycin (DNJ) Ameliorates Indomethacin-Induced Gastric Ulcer in Mice by Affecting NF-kappaB Signaling Pathway.

Gastric ulcer (GU) is a main threat to public health. 1-Deoxynojirimycin (DNJ) has antioxidant and anti-inflammatory properties and may prevent GU but related mechanism remains unclear. DNJ was extracted from the supernatants of Bacillus subtilis by using ethanol and purified by using CM-Sepharose chromatography. A GU mouse model was induced by indomethacin. The functional role of DNJ in GU mice was explored by measuring the main molecules in the NF-KappaB pathway. After the model establishment, 40 GU mice were evenly assigned into five categories: IG (received vehicle control), LG (10 μg DNJ daily), MG (20 μg DNJ daily), HG (40 μg DNJ daily), and RG (0.5 mg ranitidine daily). Meanwhile, eight healthy mice were assigned as a control group (CG). After 1-month therapy, weight and gastric volume were investigated. The levels of serum inflammatory cytokines (IL-6 and TNF-α), antioxidant indices [superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH)], and oxidant biomarker malondialdehyde (MDA) were examined via ELISA. Meanwhile, inflammatory cytokine (IL-6 and TNF-α) levels, and key molecules (NF-κB p65), cyclooxygenase 1 (COX-1 and COX2) involved in NF-κB pathway, were analyzed by using Western Blot. COX-1 and COX-2 levels were further measured by immunohistochemistry. The effects of DNJ on gastric functions were explored by measuring the changes of Motilin (MOT), Substance P (SP), Somatostatin (SS), and Vasoactive intestinal peptide (VIP) in GU mouse models with ELISA Kits. The results indicated that DNJ prevented indomethacin-caused increase of gastric volume. DNJ improved histopathology of GU mice when compared with the mice from IG group (P < 0.05). DNJ consumption decreased the levels of IL-6 and TNF-α (P < 0.05). DNJ increased antioxidant indices of GU mice by improving the activities of SOD, CAT and reduced GSH, and reduced MDA levels (P < 0.05). DNJ increased the levels of prostaglandin E2, COX-1, COX2, and reduced the levels of and NF-κB p65 (P < 0.05). DNJ showed protection for gastric functions of GU mice by reducing the levels of MOT and SP, and increasing the levels of SS and VIP. DNJ treatment inactivates NF-κB signaling pathway, and increases anti-ulceration ability of the models.

Lysophosphatidic acid in medicinal herbs enhances prostaglandin E2 and protects against indomethacin-induced gastric cell damage in vivo and in vitro

Lysophosphatidic acid (LPA) is a bioactive phospholipid that induces diverse biological responses. Recently, we found that LPA ameliorates NSAIDs-induced gastric ulcer in mice. Here, we quantified LPA in 21 medicinal herbs used for treatment of gastrointestinal (GI) disorders. We found that half of them contained LPA at relatively high levels (40–240 μg/g) compared to soybean seed powder (4.6 μg/g), which we previously identified as an LPA-rich food. The LPA in peony (Paeonia lactiflora) root powder is highly concentrated in the lipid fraction that ameliorates indomethacin-induced gastric ulcer in mice. Synthetic 18:1 LPA, peony root LPA and peony root lipid enhanced prostaglandin E2 production in a gastric cancer cell line, MKN74 cells that express LPA2 abundantly. These materials also prevented indomethacin-induced cell death and stimulated the proliferation of MKN74 cells. We found that LPA was present in stomach fluids at 2.4 μM, which is an effective LPA concentration for inducing a cellular response in vitro. These results indicated that LPA is one of the active components of medicinal herbs for the treatment of GI disorder and that orally administered LPA-rich herbs may augment the protective actions of endogenous LPA on gastric mucosa.

Chrysophyllum cainito (apple-star): a fruit with gastroprotective activity in experimental ulcer models.

The gastroprotective potential of the methanolic extracts from peels (MEPe), seeds (MESe) and pulp (MEPu) of Chrysophyllum cainito L. (Sapotaceae) fruits was evaluated in mice using ethanol/HCl- and indomethacin-induced ulcer, as well as the antiulcer effect of the juice and flour from this fruit. The lowest oral gastroprotective dose of MEPe, MESe and MEPu against ethanol/HCl was 3, 3 and 10mg/kg, respectively. Moreover, all extracts increased mucin secretion at 176, 198 and 193%. Intraperitoneal administration of MEPe (0.3mg/kg), MESe (0.3mg/kg) and MEPu (1mg/kg) also promoted gastroprotection against ethanol/HCl. In addition, MEPe (3mg/kg, p.o), MESe (3mg/kg, p.o) and MEPu (10mg/kg, p.o) reduced indomethacin-induced gastric ulcer in mice by 78, 70 and 50%, respectively. Regarding the mode of action, the gastroprotective effect of MEPe was decreased by the pre-administration of N-ethylmaleimide (NEM, a sulfhydryl group chelator, 10mg/kg, i.p), glibenclamide (a potassium channel blocker, 10mg/kg, i.p), yohimbine (10mg/kg, i.p, an alpha-adrenergic receptor antagonist, 10mg/kg, i.p) and indomethacin (a cyclooxygenase inhibitor, 10mg/kg, i.p). The gastroprotective effect of MESe was reduced by the pre-administration of NEM, glibenclamide, N-Nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor, 70mg/kg, i.p) and yohimbine, while MEPu had the gastroprotective effect decreased in animals pretreated with NEM and L-NAME. However, the extracts did not reduce gastric acid secretion. The supplementation with the flour from C. cainito fruit at 10% by 7days, but not the juice intake, displayed gastroprotective potential, evidencing the fruit as a promising functional food. Together, the antiulcer effect of extracts of the C. cainito fruit in different experimental models was confirmed by the favoring of mucosal protective mechanisms among different, but complementary, modes of action. In parallel, the gastroprotective effects of the flour from C. cainito fruit were also described.

Tamarixetin 3-O-β-d-Glucopyranoside from Azadirachta indica Leaves: Gastroprotective Role through Inhibition of Matrix Metalloproteinase-9 Activity in Mice.

Neem (Azadirachta indica) is a well-known medicinal and insecticidal plant. Although previous studies have reported the antiulcer activity of neem leaf extract, the lead compound is still unidentified. The present study reports tamarixetin 3-O-β-d-glucopyranoside (1) from a methanol extract of neem leaves and its gastroprotective activity in an animal model. Compound 1 showed significant protection against indomethacin-induced gastric ulceration in mice in a dose-dependent manner. Moreover, ex vivo and circular dichroism studies confirmed that 1 inhibited the enzyme matrix metalloproteinase-9 (MMP-9) activity with an IC50 value of ca. 50 μM. Molecular docking and dynamics showed the binding of 1 into the pocket of the active site of MMP-9, forming a coordination complex with the catalytic zinc, thus leading to inhibition of MMP-9 activity.

Gastroprotective Effect of Nanocurcumin Particles against Indomethacin-induced Gastric Ulcer in Mice

Gastroprotective Effect of Nanocurcumin Particles against Indomethacin-induced Gastric Ulcer in Mice

Antiulcerative effect of sacran on indomethacin-induced gastric ulcer in mice

Antiulcerative effect of sacran on indomethacin-induced gastric ulcer in mice

Protective effects of escin against indomethacin-induced gastric ulcer in mice

Escin, a natural mixture of triterpenoid saponin isolated from the seed of the horse chestnut, is reported to have a potent antiulcer activity against ethanol-induced gastric mucosal lesions. This study investigated the possible mechanisms underlying the gastroprotective effect of escin against indomethacin-induced gastric ulcer in mice. Gastric ulceration was induced by a single intragastric administration of indomethacin (18 mg/kg). The mice underwent intragastric treatment with escin at doses of 0.45, 0.9 or 1.8 mg/kg. Gastric lesion was estimated morphometrically and histopathologically 6 h after the indomethacin administration. The antioxidative parameters in gastric mucosa were measured. Moreover, the activity of myeloperoxidase and the contents of TNF-α, P-selectin and VCAM-1 in gastric tissues were determined. The results showed that escin protected gastric tissues against indomethacin-induced gastropathy as demonstrated from a reduction in the ulcer index and an attenuation of histopathologic changes. Escin caused significant reductions of the contents of malondialdehyde, TNF-α, P-selectin, VCAM-1 and myeloperoxidase activity. The altered activities of superoxide dismutase, catalase and glutathione peroxidase in the stomach tissues were also ameliorated by escin treatment. The present study demonstrated that escin had a protective effect against indomethacin-induced gastric ulcer in mice, not only by virtue of its antioxidant potential, but also due to its anti-inflammatory effect.

Molecular mechanism of the anti-inflammatory activity of a natural diarylnonanoid, malabaricone C

The spice-derived phenolic, malabaricone C (mal C), has recently been shown to accelerate healing of the indomethacin-induced gastric ulceration in mice. In this study, we explored its anti-inflammatory activity and investigated the underlying mechanism of the action. Mal C suppressed the microvascular permeability and the levels of tumor necrosis factor-α, interleukin-1β, and nitric oxide in the lipopolysaccharide (LPS)-administered mice. At a dose of 10mg/kg, it showed anti-inflammatory activity comparable to that of omeprazole (5mg/kg) and dexamethasone (50mg/kg). It also reduced the expression and activities of inducible nitric oxide synthase, cyclooxygenase-2, as well as the pro- vs anti-inflammatory cytokine ratio in the LPS-treated RAW macrophages. Mal C was found to inhibit LPS-induced NF-kB activation in RAW 264.7 cells by blocking the MyD88-dependent pathway. Mal C suppressed NF-κB activation and iNOS promoter activity, which correlated with its inhibitory effect on IκB phosphorylation and degradation, and NF-κB nuclear translocation, in the LPS-stimulated macrophages. It also inhibited LPS-induced phosphorylation of p38 and JNK, which are also upstream activators of NF-κB, without affecting Akt phosphorylation. Mal C also effectively blocked the PKR-mediated activation of NF-κB. These findings indicate that mal C exerts an anti-inflammatory effect through NF-κB-responsive inflammatory gene expressions by inhibiting the p38 and JNK-dependent canonical NF-κB pathway as well as the PKR pathway, and is a potential therapeutic agent against acute inflammation.

Gallic Acid Enriched Fraction ofPhyllanthus emblicaPotentiates Indomethacin-Induced Gastric Ulcer Healing via e-NOS-Dependent Pathway

The healing activity of gallic acid enriched ethanolic extract (GAE) of Phyllanthus emblica fruits (amla) against the indomethacin-induced gastric ulceration in mice was investigated. The activity was correlated with the ability of GAE to alter the cyclooxygenase- (COX-) dependent healing pathways. Histology of the stomach tissues revealed maximum ulceration on the 3rd day after indomethacin (18 mg/kg, single dose) administration that was associated with significant increase in inflammatory factors, namely, mucosal myeloperoxidase (MPO) activity and inducible nitric oxide synthase (i-NOS) expression. Proangiogenic parameters such as the levels of prostaglandin (PG) E2, vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), von Willebrand Factor VIII, and endothelial NOS (e-NOS) were downregulated by indomethacin. Treatment with GAE (5 mg/kg/day) and omeprazole (3 mg/kg/day) for 3 days led to effective healing of the acute ulceration, while GAE could reverse the indomethacin-induced proinflammatory changes of the designated biochemical parameters. The ulcer healing activity of GAE was, however, compromised by coadministration of the nonspecific NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME), but not the i-NOS-specific inhibitor, L-N6-(1-iminoethyl) lysine hydrochloride (L-NIL). Taken together, these results suggested that the GAE treatment accelerates ulcer healing by inducing PGE2 synthesis and augmenting e-NOS/i-NOS ratio.

Black Tea and Theaflavins Assist Healing of Indomethacin‐Induced Gastric Ulceration in Mice by Antioxidative Action

The healing activities of black tea (BT) and the theaflavins (TF) against the indomethacin-induced stomach ulceration were studied in a mouse model. Indomethacin (18 mg/kg, p.o.) administration induced maximum ulceration in the glandular portion of the gastric mucosa on the 3rd day, accompanied by increased lipid peroxidation and protein oxidation, depletion of thiol-defense and mucin, as well as reduced expressions of cyclooxygenases (COX) and prostaglandin (PG) E synthesis in the gastric tissues, and plasma total antioxidant status of mice. Treatment with BT (40 mg/kg), TF (1 mg/kg), and omeprazole (3 mg/kg) produced similar (74%–76%) ulcer healing, as revealed from the histopathological studies. Treatment with all the above samples reversed the adverse oxidative effects of indomethacin significantly. BT and TF also enhanced the PGE synthesis by augmenting the expressions of COX 1 and 2, but did not modulate acid secretion.

Comparative healing property of kombucha tea and black tea against indomethacin-induced gastric ulceration in mice: possible mechanism of action

The healing activity of black tea (BT) and BT fermented with Candida parapsilosis and kombucha culture, designated as CT and KT respectively against the indomethacin-induced stomach ulceration has been studied in a mouse model. The KT sample (KT4) produced by fermenting BT for four days, showed the best DPPH radical scavenging capacity and phenolics contents. Hence the ulcer-healing activity of KT4 was compared with those of CT4 and BT. All the tea extracts (15 mg kg(-1)) could effectively heal the gastric ulceration as revealed from the histopathological and biochemical studies, with relative efficacy as KT4 > CT4 ∼ BT. The healing capacities of the tea extracts could be attributed to their antioxidant activity as well as the ability to protect the mucin content of the gastric tissues. In addition, the ability of KT4 to reduce gastric acid secretion might also contribute to its ulcer-healing activity. The tea preparation KT4 (15 mg kg(-1)) was as effective as the positive control, omeprazole (3 mg kg(-1)) in ulcer healing.

Regulation of arginase/nitric oxide synthesis axis via cytokine balance contributes to the healing action of malabaricone B against indomethacin-induced gastric ulceration in mice

The role of the arginine-metabolism in the healing action of the Myristica malabarica phenol malabaricone B (mal B) and omeprazole against indomethacin-induced stomach ulceration in mouse was investigated. Indomethacin (18 mg kg − 1 ) was found to induce maximum stomach ulceration in Swiss albino mice on the 3rd day of its administration, which was associated with reduced arginase activity (30.8%, P < 0.01), eNOS expression, along with increased iNOS expression, total NOS activity (5.55 folds, P < 0.001), NO generation (2.19 folds, P < 0.001), and ratio of pro-/anti-inflammatory cytokines. Besides providing comparable healing as omeprazole (3 mg kg − 1 × 3 days), mal B (10 mg kg − 1 × 3 days, p. o.) shifted the iNOS/NO axis to the arginase/polyamine axis as revealed from the increased arginase activity (51.6%, P < 0.001), eNOS expression, and reduced iNOS expression, total NOS activity (~ 75%, P < 0.001), and NO level (50.6%, P < 0.01). These could be attributed to a favourable anti/pro inflammatory cytokines ratio, generated by mal B. The healing by omeprazole was however, not significantly associated with those parameters.

Biochemical Mechanism of Healing Activity of the Natural Phenolic, Allylpyrocatechol Against Indomethacin-Induced Gastric Ulceration in Mice

Indomethacin caused maximum stomach ulceration in mice on the 3rd day, which was associated with reduction of plasma total antioxidant status (TAS), COX-1, COX-2, mucosal PGE(2), VEGF, and vWF, along with an increase in endostatin levels. Treatment with the phytochemical allylpyrocatechol (5 mg/kg, p.o. for 3 days) provided significant ulcer healing by reversing these biochemical parameters, as well as increasing the EGF expression more than that observed due to ulceration. Omeprazole (3 mg/kg, p.o. for 3 days) provided a similar healing by improving TAS and mucin levels, without significantly altering the other parameters.

Healing properties of malabaricone B and malabaricone C, against indomethacin-induced gastric ulceration and mechanism of action

The healing activity of malabaricone B and malabaricone C, the major antioxidant constituents of the spice Myristica malabarica against the indomethacin-induced gastric ulceration in mice has been studied. The histological indices revealed maximum ulceration on the 3rd day after indomethacin administration, which was effectively healed by malabaricone B, malabaricone C (each 10 mg/kg body weight/day) and omeprazole (3 mg/kg body weight/day) for 3 days. Compared to the untreated ulcerated mice, treatment with malabaricone B, malabaricone C and omeprazole reduced the ulcer indices by 60.3% ( P < 0.01), 88.4% and 86.1% respectively ( P < 0.001). All the test samples accelerated ulcer healing than observed in natural recovery even after 7 days. Stomach ulceration reduced the total antioxidant status of plasma by 41% ( P < 0.05), which was significantly increased by malabaricone B (36%, P < 0.01), malabaricone C (61%, P < 0.001) and omeprazole (53%, P < 0.001). Compared to the ulcerated untreated mice, those treated with malabaricone B reduced the levels of thiobarbituric acid reactive substances and protein carbonyls by 17% and ∼ 34% respectively ( P < 0.05), while malabaricone C and omeprazole reduced the parameters almost equally (∼ 30%, P < 0.01, and ∼ 40%, P < 0.01 respectively). Likewise, all the test samples reduced the oxidation of protein and non-protein thiols significantly ( P < 0.05). The antioxidant activity of the test samples could partly account their healing capacities. However, the differential potency of them was explainable by considering their relative abilities to modulate mucin secretion, PGE 2 synthesis and expression of EGF receptor and COX isoforms, malabaricone C being most effective in controlling all these factors.