Gabapentin attenuates intestinal inflammation: Role of PPAR-gamma receptor.

Gabapentin is an anticonvulsant drug that is also used for post-herpetic neuralgia and neuropathic pain. Recently, gabapentin showed anti-inflammatory effect. Nuclear factor kappa B (NFκB) is a regulator of the inflammatory process, and Peroxisome Proliferator-activated Receptor gamma (PPAR-gamma) is an important receptor involved in NFκB regulation. The aim of the present work was to study the potential role of PPAR-gamma receptor in gabapentin-mediated anti-inflammatory effects in a colitis experimental model. We induced colitis in rats using trinitrobenzenosulfonic acid and treated them with gabapentin and bisphenol A dicyldidyl ether (PPAR-gamma inhibitor). Macroscopic lesion scores, wet weight, histopathological analysis, mast cell count, myeloperoxidase, malondialdehyde acid, glutathione, nitrate/nitrite, and interleukin levels in the intestinal mucosa were determined. In addition, western blots were performed to determine the expression of Cyclooxygenase-2 (COX-2) and NFκB; Nitric Oxide Inducible Synthase (iNOS) and Interleukin 1 beta (IL-1ß) levels were also determined. Gabapentin was able to decrease all inflammatory parameters macroscopic and microscopic in addition to reducing markers of oxidative stress and cytokines such as IL-1ß and Tumor Necrosis Factor alpha (TNF-α) as well as enzymes inducible nitric oxide synthase and cyclooxygenase 2 and inflammatory genic regulator (NFκB). These effect attributed to gabapentin was observed to be lost in the presence of the specific inhibitor of PPAR-gamma. Gabapentin inhibits bowel inflammation by regulating mast cell signaling. Furthermore, it activates the PPAR-gamma receptor, which in turn inhibits the activation of NFκB, and consequently results in reduced activation of inflammatory genes involved in inflammatory bowel diseases.

Polysaccharide from Gracilaria caudata protects the human esophageal mucosal barrier: A differential topical effect and structural dependence.

This study aimed to evaluate the in vitro protective effect of topical treatment with a native sulfated polysaccharide of G. caudata (SP-Gc), hydrolyzed (H-SP-Gc), or desulfated (D-SP-Gc) polysaccharide of Gracilaria caudata in esophageal biopsies obtained from GERD patients. Biopsies were obtained from nonerosive reflux disease (NERD) patients and from erosive esophagitis patients. Then, the biopsies were mounted in an Ussing chamber to measure the basal transepithelial electrical resistance (TEER). The effect of mucosal exposure to an acid solution on TEER was analyzed with or without different concentrations (1, 0.3 or 1%) of SP-Gc, H-SP-Gc, or D-SP-Gc, precoated on the mucosa. Basal esophageal mucosal electrical resistance was significantly lower in erosive esophagitis than from NERD. Mucosal samples precoated with native SP-Gc (1%) significantly prevented TEER drop induced by an acidic solution in NERD, but this effect was not observed in erosive esophagitis. Topical application of D-SP-Gc showed no difference compared to native SP-Gc. However, when treated with chemically-modified SP-Gc, the protective effect observed with native SP-Gc was lost. The present study indicated that SP-Gc protects the human esophageal mucosal barrier in NERD patients. This effect is dependent on the structure but is independent of the presence of sulfate.

Galactomannan from the seeds of Caesalpinia pulcherrima prevents indomethacin-induced gastrointestinal damage via neutrophil migration.

Galactomannans are neutral polysaccharides isolated from the endosperm of some Leguminosae seeds. They consist of a (1 → 4) linked ß-mannopyranosyl backbone partially substituted at O-6 with α-d-galactopyranosyl side groups. C. pulcherrima have anti-inflammatory and muco-adhesive proprieties. Acute gastritis is an inflammatory disease triggered by use of non-steroidal anti-inflammatory drugs. We investigated the gastroprotective effect of galactomannan obtained from the seeds of Caesalpinia pulcherrima L. (GM-CP) in acute gastritis model induced by indomethacin. Gastritis was induced with indomethacin (30 mg/kg, P.·O.) in female Swiss mice. Animal groups (n = 7) were pretreated with saline-dissolved GM-CP (3 mg/kg, 10 mg/kg, 30 mg/kg, P.O.) or vehicle 1 h before gastritis induction. Mice were euthanized seven hours after the induction. The stomach and blood samples were collected for analysis. At 10 mg/kg, GP-CP reduced the extension of macroscopic lesion and the loss of superficial cells by alleviating inflammatory symptoms (neutrophil infiltration, migration and adhesion of mesenteric leukocytes, production of TNF-α and thiobarbituric acid reactive species (TBARS) and helping to maintain mucin labeling of the tissue. Thus, the findings of the study suggest that GM-CP exhibits gastroprotective effects.

An Overview on the Anti-inflammatory Potential and Antioxidant Profile of Eugenol.

The bioactive compounds found in foods and medicinal plants are attractive molecules for the development of new drugs with action against several diseases, such as those associated with inflammatory processes, which are commonly related to oxidative stress. Many of these compounds have an appreciable inhibitory effect on oxidative stress and inflammatory response, and may contribute in a preventive way to improve the quality of life through the use of a diet rich in these compounds. Eugenol is a natural compound that has several pharmacological activities, action on the redox status, and applications in the food and pharmaceutical industry. Considering the importance of this compound, the present review discusses its anti-inflammatory and antioxidant properties, demonstrating its mechanisms of action and therapeutic potential for the treatment of inflammatory diseases.

Neutrophils contribute to the pathogenesis of hemorrhagic cystitis induced by ifosfamide.

Ifosfamide (IFO) is an antineoplastic drug that is commonly used to treat gynecological and breast cancers. Hemorrhagic cystitis (HC) is a common side effect associated with IFO injection, which courses with neutrophil accumulation and affects 6-50% of patients depending on dose intensity. Here, we investigated the role of neutrophils in this inflammatory process. Female Swiss mice (n = 8/group) were injected with saline, IFO (400 mg/kg, i.p.), fucoidan (a P- and L-selectins inhibitor, 100 mg/kg, i.v.) or IFO + fucoidan (1-100 mg/kg) alone or combined with mesna (80 mg/kg i.p.). Another group of mice received anti-Ly6G antibody (500 µg/mouse, once daily for 2 days) for neutrophil depletion before IFO injection. In another experimental setting, animals received granulocyte colony-stimulating factor (G-CSF, 400 µg/kg), IFO (200 mg/kg), G-CSF (25-400 µg/kg, for 5 days) + IFO (200 mg/kg, i.p.) or fucoidan + G-CSF + IFO. Bladder injury was evaluated 12 h after IFO injection. IFO 400 mg/kg significantly increased visceral hyperalgesia, bladder edema, hemorrhage, vascular permeability, MPO, IL-1ß and IL-6 tissue levels, and COX-2 immunostaining and expression versus the saline group (P < 0.05). Conversely, fucoidan (100 mg/kg) significantly attenuated these parameters compared to IFO-injected mice (P < 0.05). Additionally, fucoidan potentiated mesna protective effect when compared with IFO + mesna group (P < 0.05). Accordingly, neutrophil depletion with anti-Ly6G reduced inflammatory parameters and bladder injury compared to IFO (P < 0.05). In contrast, G-CSF enhanced IFO (200 mg/kg)-induced HC, which was significantly attenuated by treatment with fucoidan (P < 0.05). Therefore, neutrophils contribute to the pathogenesis of HC.

The polysaccharide-rich tea of Ximenia americana barks prevents indomethacin-induced gastrointestinal damage via neutrophil inhibition.

ETHNOPHARMACOLOGICAL RELEVANCE: Barks of Ximenia americana are used by the population to treat gastrointestinal inflammatory disorders. Indomethacin is a non-selective non-steroidal anti-inflammatory drug that induces marked gastrointestinal damage. AIMS OF THE STUDIES: To evaluate the gastroprotective activity of total polysaccharides contained in the extract (TPL-Xa) or tea (Tea-Xa) of Ximenia americana barks in the mice gastric damage induced by indomethacin. MATERIALS AND METHODS: TPL-Xa was obtained by a combination of NaOH extraction and ethanol precipitation. Tea-Xa was prepared in distilled water boiled during 5 min. Animals received p.o. 0.9% NaCl (saline - control group), TPL-Xa (1-90 mg/kg) or Tea-Xa 1 h before gastritis induction by indomethacin (20 mg/kg). Mice were sacrificed 7 h after gastritis induction and analyzed for the following parameters: stomach lesions measurement; histological evaluation; myeloperoxidase (MPO) activity; nitrate/nitrite and cytokine levels; leukocyte adhesion and rolling by intravital microscopy. RESULTS: TPL-Xa reduced macroscopic and microscopic damage, MPO activity (59%), leukocyte rolling (86%) and adhesion (84%), nitrite/nitrate ratio (100%) and IL-8 (69%), but increased IL-4 (50%). Tea-Xa (12.8 yield; 39.3% carbohydrate, including 25.8% uronic acid; 4% protein) reduced macroscopic damage (62%) and MPO activity (50%). CONCLUSION: TPL and Tea of Ximenia americana barks ameliorate the gastric injury induced by indomethacin in mice, an effect that was dependent on the reduction of neutrophil infiltration.

Proteins from the Rhinella schneideri parotoid gland secretion exhibit anti-nociceptive effect against nociception induced by inflammation.

As proteins isolated from the Rhinella schneideri parotoid gland secretion (RsPP) exhibit anti-inflammatory activity, the goal of this work was to investigate their anti-nociceptive effects using acetic acid-induced writhing, formalin, and hot-plate tests. The intraperitoneal administration of RsPP (2.5 or 5mg/kg) one hour prior to stimuli significantly reduced the abdominal constrictions induced by acetic acid (73.06 and 72.69% inhibition, respectively) and the inflammatory phase of paw licking time induced by formalin (69.3% inhibition, at 2.5mg/kg). However, RsPP (1, 2.5 or 5mg/kg) did not change the latency in response at the hot-plate test. The involvement of inflammatory mediators on the anti-nociceptive effect of RsPP was further demonstrated. RsPP (2.5mg/kg) significantly inhibited the inflammatory peak of paw edema induced by histamine (44.0%), bradykinin (51.3%), or prostaglandin E2 (53.7%). Our data indicate that RsPP may act on the pain process by inhibiting the effect of inflammatory mediators.

Physio-pharmacological Investigations About the Anti-inflammatory and Antinociceptive Efficacy of (+)-Limonene Epoxide.

D-limonene epoxidation generates (+)-limonene epoxide, an understudied compound in the pharmacologically point of view. Herein, we investigated the anti-inflammatory and antinociceptive potentialities of (+)-limonene epoxide and suggested a mechanism of action. The anti-inflammatory potential was analyzed using agents to induce paw edema, permeability, and myeloperoxidase (MPO) activity. Pro-inflammatory cytokines and cell migration of peritoneal cells were also assessed. Antinociceptive effects were evaluated by writhing test induced by acetic acid, formalin, and hot plate assays and contribution of opioid pathways. Pretreated animals with (+)-limonene epoxide showed reduced carrageenan-induced paw edema in all doses (25, 50, and 75 mg/kg) (P < 0.05). At 75 mg/kg, it suppressed edema provoked by compound 48/80, histamine, prostaglandin E2, and serotonin and reduced permeability determined by Evans blue and MPO activity. It also reduced leukocytes, neutrophils, and IL-1ß levels in the peritoneal cavity in comparison with carrageenan group (P < 0.05). (+)-Limonene epoxide diminished abdominal contortions induced by acetic acid (78.9%) and paw licking times in both 1 (41.8%) and 2 (51.5%) phases and a pretreatment with naloxone (3 mg/kg) reverted the antinociceptive action in morphine- and (+)-limonene epoxide-treated groups (P < 0.05). Additionally, it enlarged response times to the thermal stimulus after 60 and 90 min. In conclusion, (+)-limonene epoxide inhibited release/activity of inflammatory mediators, vascular permeability, migration of neutrophils and displayed systemic and peripheral analgesic-dependent effects of the opioid system.

Nitric Oxide and Hydrogen Sulfide Interact When Modulating Gastric Physiological Functions in Rodents.

AIM: The objective was to evaluate the effects of nitric oxide (NO) and hydrogen sulfide (H2S) donors and possible interactions between these two systems in modulating gastric function. METHODS: Mice received saline, sodium nitroprusside (SNP), or sodium hydrosulfite (NaHS), and after 1 h, the animals were killed for immunofluorescence analysis of CSE or eNOS expressions, respectively. Other groups received saline, SNP, NaHS, Lawesson's reagent (H2S donor), PAG + SNP, L-NAME, L-NAME + NaHS, or L-NAME + Lawesson's reagent. Then, the gastric secretions (mucous and acid), gastric blood flow, gastric defense against ethanol, and gastric motility (gastric emptying and gastric contractility) were evaluated. RESULTS: SNP and NaHS increased the expression of CSE or eNOS, respectively. SNP or Lawesson's reagent did not alter gastric acid secretion but increased mucus production, and these effects reverted with PAG and L-NAME treatment, respectively. SNP or NaHS increased gastric blood flow and protected the gastric mucosa against ethanol injury, and these effects reverted with PAG and L-NAME treatments, respectively. SNP delayed gastric emptying when compared with saline, and PAG partially reversed this effect. NaHS accelerate gastric emptying, and L-NAME partially reversed this effect. SNP and NaHS alone induced gastric fundus and pylorus relaxation. However, pretreatment with PAG or L-NAME reversed these relaxant effects only in the pylorus but not in the gastric fundus. CONCLUSION: NO and H2S interact in gastric physiological functions, and this "cross-talk" is important in the control of mucus secretion, gastric blood flow, gastric mucosal defense, and gastric motility, but not in the control of basal gastric acid secretion.

Riparin B, a Synthetic Compound Analogue of Riparin, Inhibits the Systemic Inflammatory Response and Oxidative Stress in Mice.

The aim of our study was to evaluate the anti-inflammatory, anti-nociceptive, and anti-oxidant action of Riparin B in vivo. We performed experiments in which we induced paw edema by carrageenan and other mediators, carrageenan-induced peritonitis and the level of myeloperoxidase (MPO) activity, pro-inflammatory cytokines (TNF-α and IL-1ß), malondialdehyde (MDA) acid, and glutathione (GSH) from the peritoneal fluid. We also performed behavior tests such as acetic acid-induced writhing, formalin-induced linking, and the hot plate test. Among the doses tested of the Riparin B (1, 3, and 10 mg/kg), the dose of 10 mg/kg showed the strongest effect, and this dose was able to reduce the paw edema induced by carrageenan, dextran, histamine serotonin, bradykinin, 48/80, and PGE2. Similarly, the Riparin B in the same dose reduced cell migration and significantly decreased the nociception induced by formalin and acetic acid and reversed the parameters of the oxidative stress. Thus, we can infer that Riparin B exhibits anti-inflammatory, anti-nociceptive, and anti-oxidant actions in vivo.

Cyane-carvone, a synthetic derivative of carvone, inhibits inflammatory response by reducing cytokine production and oxidative stress and shows antinociceptive effect in mice.

Cyane-carvone (CC) was studied to elucidate its anti-inflammatory, antinociceptive, and antioxidant effects in Mus musculus. Anti-inflammatory (bradykinin, histamine, prostaglandin E2, serotonin, and carrageenan) and antinociceptive (acetic acid and formalin) models were utilized. Myeloperoxidase activity, interleukin (IL)-1ß, tumor necrosis factor alpha (TNF-α), and glutathione (GSH) levels were evaluated. Analysis of variance followed by Student-Newman-Keuls' test was done. Results were compared with control groups (significantly when p < 0.05). In bradykinin, histamine, prostaglandin E2, and serotonin tests, 75 mg/kg CC decreased significantly paw edema (t = 30, 60, 90, and/or 120 min). In carrageenan test, 50 and 75 mg/kg CC (t = 3 h and t = 4 h) and 25 mg/kg CC (t = 4 h) decreased significantly paw edema. CC (75 mg/kg) inhibited significantly mieloperoxidase activity and decreased IL-1ß and TNF-α, and all doses increased GSH levels. CC (75 mg/kg) decreased significantly the number of contortions of animals and time of licking (phase 2). CC showed anti-inflammatory, antinociceptive, and antioxidant effects in mice.

Antiinflammatory and antinociceptive effects in mice of a sulfated polysaccharide fraction extracted from the marine red algae Gracilaria caudata.

Many algal species contain relatively high concentrations of polysaccharide substances, a number of which have been shown to have anti-inflammatory and/or immunomodulatory activity. In this study, we evaluated the anti-inflammatory and antinociceptive effects in mice of a sulfated polysaccharide fraction (PLS) extracted from the algae Gracilaria caudata. The antiinflammatory activity of PLS was evaluated using several inflammatory agents (carrageenan, dextran, bradykinin, and histamine) to induce paw edema and peritonitis in Swiss mice. Samples of the paw tissue and peritoneal fluid were removed to determine myeloperoxidase (MPO) activity or TNF-α and IL-1ß levels, respectively. Mechanical hypernociception was induced by subcutaneous injection of carrageenan into the plantar surface of the paw. Pretreatment of mice by intraperitoneal administration of PLS (2.5, 5, and 10 mg/kg) significantly and dose-dependently reduced carrageenan-induced paw edema (p < 0.05) compared to vehicle-treated mice. Similarly, PLS 10 mg/kg effectively inhibited edema induced by dextran and histamine; however, edema induced by bradykinin was unaffected by PLS. PLS 10 mg/kg inhibited total and differential peritoneal leukocyte counts following carrageenan-induced peritonitis. Furthermore, PLS reduced carrageenan-increased MPO activity in paws and reduced cytokine levels in the peritoneal cavity. Finally PLS pretreatment also reduced hypernociception 3-4 h after carrageenan. We conclude that PLS reduces the inflammatory response and hypernociception in mice by reducing neutrophil migration and cytokines concentration.

Sulfated-polysaccharide fraction from red algae Gracilaria caudata protects mice gut against ethanol-induced damage.

The aim of the present study was to investigate the gastroprotective activity of a sulfated-polysaccharide (PLS) fraction extracted from the marine red algae Gracilaria caudata and the mechanism underlying the gastroprotective activity. Male Swiss mice were treated with PLS (3, 10, 30 and 90 mg·kg(-1), p.o.), and after 30 min, they were administered 50% ethanol (0.5 mL/25 g(-1), p.o.). One hour later, gastric damage was measured using a planimeter. Samples of the stomach tissue were also obtained for histopathological assessment and for assays of glutathione (GSH) and malondialdehyde (MDA). Other groups were pretreated with l-NAME (10 mg·kg(-1), i.p.), dl-propargylglycine (PAG, 50 mg·kg(-1), p.o.) or glibenclamide (5 mg·kg(-1), i.p.). After 1 h, PLS (30 mg·kg(-1), p.o.) was administered. After 30 min, ethanol 50% was administered (0.5 mL/25 g(-1), p.o.), followed by sacrifice after 60 min. PLS prevented-ethanol-induced macroscopic and microscopic gastric injury in a dose-dependent manner. However, treatment with l-NAME or glibenclamide reversed this gastroprotective effect. Administration of propargylglycine did not influence the effect of PLS. Our results suggest that PLS has a protective effect against ethanol-induced gastric damage in mice via activation of the NO/K(ATP) pathway.