Experimental Ulcerative Colitis In Rats Research Articles

Effect of Tamarindus indica L. fruit pulp and seed extracts on experimental ulcerative colitis in rats.

Tamarindus indica L. which has anti-inflammatory, radical scavenging, and ulcer healing effects can be useful for the alleviation of inflammatory bowel disease (IBD). Therefore, the effects of T. indica fruit pulp (TIPE) and seed extracts (TISE) were investigated on experimental colitis. TIPE and TISE (125, 250, and 500 mg/kg) were made by maceration (ethanol/water: 80/30) and administered to male Wistar rats with acetic acid-induced colitis. Prednisolone (4 mg/kg) and mesalazine (100 mg/kg) were used as reference drugs. The colon tissues were examined for macroscopic and pathologic parameters and myeloperoxidase (MPO) and malondialdehyde (MDA) values. The total phenols were 45.7 ± 1.1 and 453.0 ± 3.3 mg/g in terms of gallic acid for TIPE and TISE, respectively. Both of the extracts significantly improved most of the investigated parameters including body weight loss, the weight of colons, indices of ulcers, and total colitis. MPO activity and MDA in the treatment groups (except for TIPE at 125 mg/Kg) significantly decreased compared to the control. Both TIPE and TISE were effective in the treatment of colitis however it seems that the effective ingredients were more concentrated in seeds rather than pulp extract so the highest dose of seed extract had a competitive effect with reference drugs. More studies are needed to introduce T. indica as a suitable complementary medicine or food for patients with IBD.

Mimosa pudica leaf aqueous extract attenuates experimental ulcerative colitis in rats via suppression of MPO and IL-1β signaling pathways and improvement of the oxidative status

BackgroundColitis for so many years had been considered a disease exclusive only to developed countries; surprisingly, its incidence is now increasing worldwide. This study investigated Mimosa pudica leaf water extract anti-colitis potential on acetic acid-induced colitis in rats. MethodsFollowing 24 h fasting, 36 rats (both sexes) intrarectally received acetic acid (4%, 1 mL) to induce colitis. Afterward, they were separated into groups and treated twice a day (for 9 days) with distilled water; Mimosa pudica (25, 50, or 100 mg/kg); and Prednisolone (5 mg/kg). Body weight and quantity of feces were recorded. On day 9, animals were sacrificed, colon ulcerations number and weight/length ratio; GSH and MDA levels; MPO activity, and IL-1β were determined. ResultsColitis caused a significant drop in animals’ body weight - 30% decrease in colitis control against + 27% increase in the neutral control rats. Mimosa pudica at 25 mg/kg on day 9 brought a + 7% increase. Colitis led to an increase in the weight of feces in colitis rats with 14.28 ± 0.98 g (day 8). On this same day, the extract reduced feces weight (4.42 ± 0.31 g at 100 mg/kg), the number of colon ulcerations, and the mean colon weight/length ratio (P < 0.001). Colitis conditions increased MDA and decreased GSH. Mimosa pudica reversed these biomarkers. Colitis caused a marked increase in MPO activity and IL-1β concentration in colitis rats. This was reversed by the extract. ConclusionsOverall, our results proved the beneficial effects of Mimosa pudica leaf extract in protecting animals against colitis.

Inhibition of TLR4, NF-κB, and INOS pathways mediates ameliorative effect of syringic acid in experimental ulcerative colitis in rats.

Numerous therapeutics and pharmacological properties have been reported in syringic acid (SA). In this study, we aimed to evaluate effect of SA in ulcerative colitis (UC) in rats considering effect on TLR4, NF-κB, and INOS pathways. 48 Wistar rats were randomly designated into six groups (n = 8). UC was induced via intra-rectal administration of 7% acetic acid (0.8ml). SA at doses of 10, 25, 50mg/kg was administrated through gavage, and dexamethasone (2mg/kg) administrated intra-peritoneally for 5 consecutive days. The macroscopic and histopathological damages as well as expression of inflammatory and apoptotic genes along with superoxide dismutase (SOD) and catalase (CAT) activities, total antioxidant capacity (TAC), nitric oxide (NO), and malondialdehyde (MDA) levels in the colon tissue were assessed. UC led to an increase in the apoptotic and inflammatory genes, NO and MDA levels as well as decrease in TAC level, and SOD and CAT activities (p < 0.05). UC also caused severe damage, edema, inflammation, and necrosis in the colon. SA significantly reduced gene expressions of INOS, TLR4, IL-6, IL-1β, NF-κB, Caspase-3, Caspase-8, and Bax. SA ameliorated negative macroscopic and histopathologic effects of UC. SA significantly reduced MDA and NO levels, and increased TAC level and CAT activity in the colon tissue in comparison to the UC rats without treatment (p < 0.05). SA via attenuation of the TLR4-NF-κB, NF-κB-INOS-NO pathways, oxidative stress, inflammation, and apoptosis of UC in rats.

Protective effect of Arum maculatum against dextran sulfate sodium induced colitis in rats

ABSTRACT Ulcerative colitis (UC) is an inflammatory disease of the large intestine that is characterized by diarrhea, bloody stools, abdominal pain and mucosal ulceration. UC is treated with nonsteroidal anti-inflammatory drugs, corticosteroids or immunosuppressants, but long-term use of these drugs can cause adverse effects. Arum maculatum is used as a traditional treatment for digestive system disorders, but its use for treatment of UC has not been investigated rigorously. We investigated the possible protective effect of a methanol extract of A. maculatum against dextran sulfate sodium (DSS) induced experimental UC in rats. Total phenolic and flavonoid contents of the extract were 32.919 ± 1.125 mg gallic acid equivalent (GAE)/g and 52.045 ± 7.902 µg rutin equivalent (RE)/mg, respectively. The half-maximal inhibitory concentration (IC50) for the extract was 105.76 µg/ml according to the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity assay. Effects of A. maculatum extract on UC induced by DSS were assessed both macroscopically and histologically. We also investigated effects of A. maculatum extract on malondialdehyde (MDA) levels and the oxidative stress index (OSI) in normal rats and rats with UC. We found that treatment with A. maculatum extract protected the colon against DSS induced UC in a dose-dependent manner.

Curcumin-Loaded Microspheres Are Effective in Preventing Oxidative Stress and Intestinal Inflammatory Abnormalities in Experimental Ulcerative Colitis in Rats.

Curcumin’s role in the treatment of ulcerative colitis (UC) has been proven by numerous studies, but its preventive administration, with the aim of reducing the remission episodes that are characteristic of this disease, must be further investigated. This study investigates the effects of a novel curcumin-loaded polymeric microparticulate oral-drug-delivery system for colon targeting (Col-CUR-MPs) in an experimental model of UC. Male Wistar rats (n = 40) were divided into five groups (n = 8), which were treated daily by oral gavage for seven days with a 2% aqueous solution of carboxymethylcellulose sodium salt (CMCNa) (healthy and disease control), free curcumin powder (reference), Col-CUR-MPs (test) and prednisolone (reference) prior to UC induction by the intrarectal administration of acetic acid (AA), followed by animal sacrification and blood and colonic samples’ collection on the eighth day. Col-CUR-MPs exhibited an important preventive effect in the severity degree of oxidative stress that resulted following AA intrarectal administration, which was proved by the highest catalase (CAT) and total antioxidant capacity (TAC) levels and the lowest nitrites/nitrates (NOx), total oxidative status (TOS) and oxidative stress index (OSI) levels. Biochemical parameter analysis was supported by histopathological assessment, confirming the significant anti-inflammatory and antioxidant effects of this novel colon-specific delivery system in AA-induced rat models of UC. Thus, this study offers encouraging perspectives regarding the preventive administration of curcumin in the form of a drug delivery system for colon targeting.

Diosmetin attenuate experimental ulcerative colitis in rats via suppression of NF-κB, TNF-α and IL-6 signalling pathways correlated with down-regulation of apoptotic events

Introduction Ulcerative colitis (UC) is a chronic inflammation of colon in which the innermost tissue of colon and rectum develops deep-rooted inflammation. Diosmetin is the aglycone of the flavonoid glycoside diosmin, commonly found in citrus fruits. Therapeutically diosmetin is indicated to demonstrate anticancer, antimicrobial, antioxidant, oestrogenic and anti-inflammatory activity. Methods In this research, we studied the action of diosmetin on TNBS (2,4,6-trinitrobenzene sulfonic acid)-induced UC in rats. Male Wister rats were anesthetised with pentobarbital and TNBS introduced by performing an enema. Diosmetin treatment was provided through oral gavage for the next 28 days. Animals were sacrificed on the 29th day and colon tissues were collected for further examinations. Results Diosmetin treatment decreased colonic ulceration dramatically and decreased the percentage of inflammation in the colonic mucosa. Depletion of the TNBS assisted of superoxide dismutase and catalase was substantially restricted, while lipid peroxidation was recorded in the colonic tissue as malondialdehyde content was also decreased. After treatment with diosmetin, the occurrence of TNF-α, IL-6and NF-κB was considerably lowered and the number of apoptotic cells observed was significantly reduced. Conclusion Taken together, these observations demonstrated the potential of diosmetin against ulcer formation and development.

Flos lonicerae flavonoids attenuate experimental ulcerative colitis in rats via suppression of NF-κB signaling pathway.

This study sought to isolate active Flos lonicerae flavonoids and evaluate their anti-oxidative and anti-inflammatory effects as well as investigate the molecular mechanistic action of these flavonoids in the rat model of ulcerative colitis (UC). Total flavonoids and three flavonoids (hyperoside, lonicerin, and luteolin) were isolated from honeysuckle and purified via column purification. Rat model of UC was established via 2,4,6-trinitrobenzene sulfonic acid (TNBS) intoxication. The anti-oxidative and anti-inflammatory effects of the three flavonoids against TNBS-induced UC were evaluated by measuring appropriate biomarkers via assay kit. The effects of hyperoside, lonicerin, and luteolin on the regulation of nuclear factor-kappa B (NF-κB) pathway were investigated using Western blot (WB) and real-time polymerase chain reaction (RT-PCR) while their protective effects on UC were also elucidated. Pretreatment with flavonoids (hyperoside, lonicerin, and luteolin at 25-100mg/kg) and sulfasalazine (SSZ, positive control at 100mg/kg) substantially attenuated TBNS-induced UC. Also, the flavonoids significantly reduced the levels of respective serum oxidative and proinflammatory markers such as superoxide dismutase (SOD), myeloperoxidase (MPO), malondialdehyde (MDA), prostaglandins E2 (PGE2), tumor necrosis factor-alpha (TNF-α), interleukin-beta (IL-β), and C-reactive protein (CRP). In addition, the flavonoids remarkably inhibited the expression of NF-κB signaling pathway. F. lonicerae flavonoids (hyperoside, lonicerin, and luteolin) demonstrated potent anti-UC activities in TBNS-induced UC rat model via anti-oxidative and anti-inflammatory effects through the inhibition of NF-κB signaling pathway.

Beneficial effect of Amorphophallus paeoniifolius tuber on experimental ulcerative colitis in rats

Context: The tuber of Amorphophallus paeoniifolius (Dennst.) Nicolson (Araceae), commonly called Suran or Jimmikand, has high medicinal value and is used ethnomedicinally for the treatment of different gastrointestinal and inflammatory disorders. Objective: The present study evaluated the effects of extracts of Amorphophallus paeoniifolius tubers on acetic acid-induced ulcerative colitis (UC) in rats. Materials and methods: Wistar rats were orally administered methanol extract (APME) or aqueous extract (APAE) (250 and 500 mg/kg) or standard drug, prednisolone (PRDS) (4 mg/kg) for 7 days. On 6th day of treatment, UC was induced by transrectal instillation of 4% acetic acid (AA) and after 48 h colitis was assessed by measuring colitis parameters, biochemical estimations and histology of colon. Results: APME or APAE pretreatment significantly (p < .05–.001) prevented AA-induced reduction in body weight and increase in colitis parameters viz. stool consistency, colon weight/length ratio and ulcer score, area and index. Extracts treatment attenuated (p < .001) increase in alkaline phosphatase and lactate dehydrogenase in serum and myeloperoxidase activity and cytokines in colon tissue due to AA administration. Extracts treatment prevented AA-induced elevation in lipid peroxidation and decline in activities of superoxide dismutase and catalase and reduced-glutathione content (p < .05–.001) along with histopathological alterations. PRDS also showed similar ameliorative effect on colitis. Discussion and conclusion: APME and APAE showed a preventive effect on UC, and ameliorated inflammation and oxidative damage in colon. The effects may be attributed to presence of phytochemicals, betulinic acid, β-sitosterol, and glucomannan. In conclusion, the tuber of Amorphophallus paeoniifolius exhibited an anticolitic effect through anti-inflammatory and antioxidant action.

Treatment with Mesna and n-3 polyunsaturated fatty acids ameliorates experimental ulcerative colitis in rats.

Oxidative damage is a central feature of ulcerative colitis. Here, we tested whether the antioxidant Mesna, when administered alone or in combination with n-3 polyunsaturated fatty acids (n-3 PUFAs), affects the outcome of dextran sodium sulphate (DSS)-induced ulcerative colitis in rats. After the induction of colitis, DSS-treated rats were further treated orally (p.o), intraperitoneally (i.p) or intrarectally (i.r) for either 7 or 14 days with Mesna, n-3 PUFAs or both. Rats were euthanized at the end of each treatment period. Clinical disease activity index was recorded throughout the experiment. At necropsy colorectal gross lesions were scored. Colitis was scored histologically, and the expression of myeloperoxidase (MPO), caspase-3, inducible nitric oxide synthase (iNOS) and nuclear factor κB (NF-κΒ) in colonic tissue was assessed by immunohistochemistry. Mesna alone was sufficient to significantly reduce colorectal tissue damage when administered orally or intraperitoneally. Orally coadministered n-3 PUFAs enhanced this effect, resulting in the significant suppression of DSS colitis after 7 days, and a remarkable recovery of colorectal mucosa was evident after 14 days of treatment. The amelioration of colon pathology co-existed with a significant decrease in MPO expression, overexpression of iNOS and reduction of nuclear NF-κB p65 in inflammatory cells, and the suppression of apoptosis in colonic epithelial cells. The simultaneous administration of Mesna and n-3 PUFAs is particularly effective in ameliorating DSS colitis in rats, by reducing oxidative stress, inflammation and apoptosis, probably through a mechanism that involves the inhibition of NF-κB and overexpression of iNOS.

Effects of Malva sylvestris and Its Isolated Polysaccharide on Experimental Ulcerative Colitis in Rats.

Malva sylvestris is an edible plant that is consumed as a herbal supplement for its antiulcer and colon cleansing properties in traditional Persian medicine. This study was designed to evaluate its effects on ulcerative colitis, which is a chronic gastrointestinal inflammation. Colitis was induced by rectal instillation of acetic acid solution. Rats in different groups received aqueous, n-hexane, or ethanolic fractions of the plant before induction of colitis. Isolated polysaccharide of plant was also tested in 2 groups before and after induction of colitis. Macroscopic and microscopic evaluation of colitis showed that the aqueous fraction was very effective in preventing the inflammation and efficacy was lower for ethanolic and n-hexane fractions. Polysaccharide was effective in reducing signs of inflammation, especially as pretreatment. These beneficial effects provide evidences that this plant can be suggested for patients with this disease to improve their health condition or to reduce adverse effects of their medication.

Targeting sphingosine kinase 1 (SphK1) and apoptosis by colon-specific delivery formula of resveratrol in treatment of experimental ulcerative colitis in rats

Ulcerative colitis (UC) is a chronic inflammatory bowel disorder (IBD) that has an elevated risk of developing into colon cancer. In trials to develop new therapeutic alternatives for UC, it is important to fulfill modifying effects on pathogenic targets and to reach the colon in a high concentration. Thus, the current work has investigated a colon-specific delivery formula of resveratrol in targeting sphingosine kinase 1 (SphK1) and apoptotic pathways to control pathogenesis and its progression to any expected neoplasm. This work was conducted on 40 Wister albino rats equally divided into 4 groups where group I served as the normal control group. The untreated oxazolone-induced colitis in group II exhibited significant increase in SphK1 activity as well as activity of both myeloperoxidase (MPO) and caspase-3 with concomitant mild DNA fragmentation in colonic tissue. Colonic SphK1 activity showed significant positive correlation with the disease activity index (DAI) and histopathological score in this group. Comparable with treatment by the native resveratrol formula, nRes (group III), treatment by the colon-specific delivery resveratrol formula, cRes (group IV) caused significant decrease in the activity of SphK1 and MPO with massive DNA fragmentation in colonic tissue and non significant change in caspase-3 activity. The lowest DAI and histopathological score have been recorded in the group treated by the colon-specific delivery resveratrol formula. In conclusion, the anti-inflammatory and apoptotic effects of resveratrol could be attributed to its inhibitory effect on sphingosine kinase 1 (SphK1) providing a useful therapeutic tool to break the link between inflammation and carcinogenesis risk in ulcerative colitis.

Sa1811 Mechanistic and Pharmacologic Roles of Stromal Cell-Derived Factor-1 and Its Receptor CXCR4 in Experimental Ulcerative Colitis in Rats

Sa1811 Mechanistic and Pharmacologic Roles of Stromal Cell-Derived Factor-1 and Its Receptor CXCR4 in Experimental Ulcerative Colitis in Rats

Mechanistic and pharmacologic role of placental growth factor in experimental ulcerative colitis in rats

We demonstrated that vascular endothelial growth factor accelerated the healing of experimental duodenal ulcer but aggravated ulcerative colitis (UC), probably because of the differences in ulcer healing. Since placental growth factor (PlGF) enhances abnormal (“pathologic”) angiogenesis, we measured its expression and role in experimental UC. Groups of rats were given iodoacetamide (IA) to cause UC and they were euthanized at 0.5, 2, 6, 12, 24, 48, and 84 hr after IA. Additional groups of rats were given neutralizing anti‐PlGF antibody, IgG (50ug/rat, i.m.) or saline on 2nd and 5th days and euthanized 7th day after IA when the extent of UC was evaluated macroscopically and by microscopy. Mucosal scrapings of distal colon were obtained at autopsy. Expression of PlGF was measured by Western blotting.ResultsExpression of PlGF protein was enhanced at 2 hr, with further increases (+50–80%) until 7 days. Inhibition of PlGF significantly reduced the levels of colonic PlGF, i.e., 2‐ to 3‐folds compared to control. Colonic lesions were also decreased from 323.2±44.1 (controls) to 209.8±31.2 mm2 (anti‐PlGF) (p &lt; 0.05).Conclusions1) The sustained increase in expression of PlGF in UC may indicate an abnormal (pathologic) angiogenesis occurring in the development of UC. 2) Inhibition of PlGF attenuated experimental UC development. 3) Thus, PlGF may play a pathogenic &amp; therapeutic role in the development &amp; healing of UC.(This work was supported by the Veterans Health Administration Merit Review Grants to Zs. Sandor and S. Szabo)

Early endothelial damage and increased colonic vascular permeability in the development of experimental ulcerative colitis in rats and mice

The role of endothelial damage and increased vascular permeability (VP) in the pathogenesis of ulcerative colitis (UC) has not been investigated. We examined using functional, morphologic, and molecular biologic studies whether and to what extent the endothelial barrier dysfunction precedes enhanced epithelial permeability (EP) and the development of mucosal lesions during the early stages of experimental UC. We showed that in rats with iodoacetamide (IA)-induced UC increased colonic VP occurs early (ie, 2.6-fold increase at 15 min, P<0.01) preceding changes in epithelial barrier permeability. EP was unchanged at 15 and 30 min after IA administration and was increased 1.9-fold at 1 h and 6.7-fold at 2 h (both P<0.001) after IA. In the dextran sodium sulfate-induced slowly developing UC, colonic VP was significantly increased in 2 days (P<0.05) and EP only in 4 days (P<0.05). Mucosal endothelial injury led to hypoxia (P<0.05) of colonic surface epithelial cells 30 min after IA administration that was associated with increased expressions of transcription factors hypoxia-inducible factor-1α and early growth response-1. Electron and light microscopy demonstrated areas of colonic mucosa with perivascular edema covered by intact layer of surface epithelial cells in both rat and mouse models of UC. This is the first demonstration in four models of UC that endothelial damage, increased colonic VP, perivascular edema, and epithelial hypoxia precede epithelial barrier dysfunction that is followed by erosions, ulceration, and inflammation in UC.

Dietary supplementation of krill oil attenuates inflammation and oxidative stress in experimental ulcerative colitis in rats

Objective. To evaluate the effects of krill oil (KO) on inflammation and redox status in dextran sulfate sodium (DSS)-induced colitis in rats. Materials and methods. Thirty male Wistar rats were divided into three groups: Control, DSS, and DSS + KO 5% in a 4-week diet study. Colitis was induced by 5% DSS in the drinking water the last week of the experiment. Weight and disease activity index (DAI), colon length, histological combined score (HCS), colon levels of selected cytokines and prostaglandins, markers of protein oxidative damage, fatty acid profile, and expression of selected genes were measured. Results. Rats in the DSS group increased their DAI and HCS compared with healthy controls. The colon length was significantly preserved after KO diet. Tumor necrosis factor (TNF)-α and interleukin (IL)-1β were elevated in the DSS group compared with controls. Cytokines and HCS were nonsignificantly lower in the KO versus the DSS group. Prostaglandin (PG)E3 increased significantly in the KO versus the other groups. Peroxisome proliferator-activated receptor (PPAR)-γ expression was nonsignificantly increased while PPAR-γ coactivator 1α (Pparg1α) expression increased significantly after KO. The levels of protein oxidation markers decreased significantly. Conclusions. KO showed protective potential against DSS colitis based on the preservation of colon length, reduction of oxidative markers and the consistent beneficial changes of HCS, cytokine, and (PG)E3 levels, as well as PPAR-γ and Pparg1α expression compared with DSS alone. These findings indicate an anti-inflammatory and a protein antioxidant effect of KO.

Molecular Mechanisms of Basic Fibroblast Growth Factor Effect on Healing of Experimental Ulcerative Colitis in Rats

Molecular Mechanisms of Basic Fibroblast Growth Factor Effect on Healing of Experimental Ulcerative Colitis in Rats

Qingchang Suppository up-regulates the expression of tight junction proteins ZO-1 and occludin in experimental ulcerative colitis in rats

AIM: To observe the effect of Qingchang Suppository (QS) on the expression of tight junction proteins zonula occluden-1 (ZO-1) and occludin in the colon of rats with trinitrobenzenesulfonic acid (TNBS)-induced ulcerative colitis (UC). METHODS: Thirty-six SD rats were randomly and equally divided into six groups: normal control group, model group, SASP group, high-, mediumand low-dose QS groups. UC was induced in rats with TNBS. The expression of tight junction proteins ZO-1 and occludin in the colon was examined by immunofluorescence. RESULTS: The immunofluorescence signals of ZO-1 and occludin were irregularly distributed and appeared disrupted in rats with UC. The average optical density of ZO-1 and occludin immunofluorescence, as calculated using image analysis software, were decreased obviously in UC rats compared to normal controls (1.802 ± 1.304 vs 3.145 ± 0.110; 0.568 ± 0.063 vs 1.538 ± 0.220, both P < 0.01). Treatment with QS upregulated the expression of ZO-1 and occludin in rats with UC (both P < 0.01). CONCLUSION: QS exerts a beneficial effect against TNBS-induced UC in rats possibly by modulating intestinal mucosal barrier and decreasing increased intestinal permeability.

Preparation and in vitro/in vivo evaluation of dextran matrix tablets of budesonide in experimental ulcerative colitis in rats

Budesonide is an anti-inflammatory drug of choice for treatment of ulcerative colitis which affects the rectum and a part of or the entire colon. Delivery of budesonide specifically to the colon would increase the efficacy of the drug and reduce the side-effects. The aim of this study was to develop an oral matrix system formulation for budesonide to deliver the major part of the drug to the colon for treatment of ulcerative colitis that has not been reported before. Directly compressed matrix tablets were prepared using different molecular weights of dextran and three ratios of drug-to-polymer. The physical properties of the tablets including weight variation, hardness, content uniformity, and release profile in HCl 0.1 N, phosphate buffer pH 7.4 and 6.8 containing 4% rat caecal and colonic contents were studied. The efficacy of the desired formulation was also evaluated against acetic acid-induced colitis in rats. Physical properties of the tablets were in the ranges recommended by official references. More than 10% of the drug was released in HCl 0.1 N and pH 7.4, while a very drastic increase was observed after exposure to pH 6.8 containing rat caecal contents. The efficacy of the selected formulation against rat-induced colitis was also increased in comparison to the non-targeted formulation of budesonide. In conclusion, matrix tablets with a 1:10 drug-to-dextran ratio with high molecular weight could deliver the drug specifically to the colon and are promising for treatment of ulcerative colitis.

Neutralizing Anti-Vascular Endothelial Growth Factor (VEGF) Antibody Reduces Severity of Experimental Ulcerative Colitis in Rats: Direct Evidence for the Pathogenic Role of VEGF

In ulcerative colitis (UC), an increased expression of vascular endothelial growth factor (VEGF) correlates with disease activity, but a causal relationship is unknown. We tested the hypothesis that VEGF plays a mechanistic role in the pathogenesis of experimental UC and that VEGF neutralization may exert therapeutic effect. UC was induced in Sprague-Dawley rats by 6% iodoacetamide given intracolonically. Neutralizing anti-VEGF antibody (50 microg/rat), nonspecific IgG, or saline (0.1 ml/rat) was injected intramuscularly on the 3rd and 5th days after iodoacetamide enema. Rats were euthanized on the 7th day. We examined the extent of macroscopic, histologic, and clinical features of colitis and colonic vascular permeability. Colonic VEGF mRNA and protein expressions increased as early as 0.5 h after iodoacetamide enema and remained elevated in the active phase of colitis. Treatment with anti-VEGF antibody markedly improved the clinical and morphologic features of UC. Colonic lesion area was significantly reduced from 370 +/- 140 or 311 +/- 170 mm(2) in saline- or IgG-treated groups to 122 +/- 57 mm(2) in the anti-VEGF-group (p < 0.05). Increased colonic vascular permeability was decreased by the anti-VEGF antibody (p < 0.05) and the Src inhibitor PP1 [pyrazolopyrimidine, 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]-pyrimidine] (p < 0.01). The number of acute and chronic inflammatory cells in the lesion area was significantly reduced in anti-VEGF-treated rats. In the anti-VEGF-treated group, mucosal levels of VEGF, platelet-derived growth factor, and basic fibroblast growth factor were also reduced. 1) Neutralizing anti-VEGF antibody significantly ameliorates experimental UC in rats in part by reducing excessive vascular permeability and decreasing inflammatory cells infiltration; and 2) VEGF seems to mediate increased colonic vascular permeability in experimental UC via the Src-dependent mechanism.

Butyrate Suppresses The Severity Of Acetic Acid-Induced Ulcerative Colitis In Rats

Short chain fatty acids are increasingly used as food additives due to the health benefits they have. Recently, they have been implicated in protecting patients against intestinal disorders but without a well-known mechanism. We explored the benefits of a major short chain fatty acid, butyrate on experimental ulcerative colitis in rats. The ulcerative colitis was induced by intrarectal instillation of 10% acetic acid after or without prior administration of 50 or 150 mg/kg butyrate intraperitoneally or intrarectally, respectively, for three consecutive days prior to exposure to acetic acid. After 24 hours of exposure to acetic acid, rats were sacrificed, postmortem examination done, intestinal sections fixed, processed and stained for histopathology in a routine manner. Acetic acid induced infiltration of inflammatory cells, loss of epithelium, crypt damage, and loss of goblet cells in the colon. These changes were significantly suppressed following butyrate treatment. We conclude that butyrate reduces the severity of acetic acid induced ulcerative colitis lesions in rats. This protective potency could be, at least in part, one of the mechanisms by which butyrate imparts its benefits to ulcerative colitis patients. Tanzania Veterinary Journal Vol. 25 (1) 2008: pp. 1-12