Larisse T. Lucetti

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/25g−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/KATP pathway.

Role of soluble guanylate cyclase activation in the gastroprotective effect of the HO-1/CO pathway against alendronate-induced gastric damage in rats

Our objective was to evaluate the role of soluble guanylate cyclase (sGC) activation in the gastroprotective effect of the HO-1/CO pathway against alendronate-induced gastric damage in rats. Rats were pretreated, once daily for 4 days, with saline, hemin (HO-1 inducer), or dimanganese decacarbonyl (DMDC, CO donor). Another group received zinc protoporphyrin IX (ZnPP IX, HO-1 antagonist) 1 h before hemin treatment or sGC inhibitor (ODQ) 30 min before hemin and DMDC treatment. After 30 min, gastric damage was induced by alendronate (30 mg/kg) by gavage. On the last day of treatment, 4 h after alendronate administration, the animals were killed. Gastric lesions were measured using a computer planimetry program, and gastric corpus pieces were assayed for malondialdehyde (MDA), glutathione (GSH), pro-inflammatory cytokines (tumor necrosis factor [TNF]-α and interleukin [IL]-1β), myeloperoxidase (MPO), or bilirubin. Another group was used to measure gastric mucus. HO-1 expression was determined after saline or alendronate administration by immunohistochemistry. Alendronate induced gastric damage, produced neutrophil accumulation, increased MDA levels and MPO activity, and reduced GSH and mucus in the gastric tissue. Alendronate also increased HO-1 immunoreactivity and the level of bilirubin in gastric mucosa. Pretreatment with hemin or DMDC reduced neutrophil infiltration and TNF-α, IL-1β, and MDA formation, and increased the levels of GSH and mucus in the gastric tissue. ODQ completely abolished the gastroprotective effect of hemin and DMDC and increased alendronate gastric damage. Our results suggest that the HO-1/CO pathway plays a protective role against alendronate-induced gastric damage through mechanisms that can be dependent on sGC activation.

Alendronate induces gastric damage by reducing nitric oxide synthase expression and NO/cGMP/KATP signaling pathway

Chronic use of alendronate has been linked to gastrointestinal tract problems. Our objective was to evaluate the role of the NO/cGMP/KATP signaling pathway and nitric oxide synthase expression in alendronate-induced gastric damage. Rats were either treated with the NO donor, sodium nitroprusside (SNP; 1, 3, and 10 mg/kg), or the NO synthase (NOS) substrate, L-arginine (L-Arg; 50, 100, and 200 mg/kg). Some rats were pretreated with either ODQ (a guanylate cyclase inhibitor; 10 mg/kg) or glibenclamide (KATP channels blocker; 10 mg/kg). In other experiments, rats were pretreated with L-NAME (non-selective NOS inhibitor; 10 mg/kg), 1400 W (selective inducible NOS [iNOS] inhibitor; 10 mg/kg), or L-NIO (a selective endothelial NOS [eNOS] inhibitor; 30 mg/kg). After 1 h, the rats were treated with alendronate (30 mg/kg) by gavage for 4 days. SNP and L-Arg prevented alendronate-induced gastric damage in a dose-dependent manner. Alendronate reduced nitrite/nitrate levels, an effect that was reversed with SNP or L-Arg treatment. Pretreatment with ODQ or glibenclamide reversed the protective effects of SNP and L-Arg. L-NAME, 1400 W, or L-NIO aggravated the severity of alendronate-induced lesions. In addition, alendronate reduced the expression of iNOS and eNOS in the gastric mucosa. Gastric ulcerogenic responses induced by alendronate were mediated by a decrease in NO derived from both eNOS and iNOS. In addition, our findings support the hypothesis that activation of the NO/cGMP/KATP pathway is of primary importance for protection against alendronate-induced gastric damage.

The nitric oxide donor cis-[Ru(bpy)2(SO3)NO](PF6) increases gastric mucosa protection in mice – Involvement of the soluble guanylate cyclase/KATP pathway

Here, we have evaluated the protective effect of the NO donor cis-[Ru(bpy)2(SO3)NO](PF6) (FOR0810) in experimental models of gastric damage induced by naproxen or ethanol in mice, and the involvement of soluble guanylate cyclase (sGC) and ATP-sensitive K(+) channels (KATP) in these events. Swiss mice were pre-treated with saline, ODQ (a soluble guanylate cyclase inhibitor; 10 mg kg(-1)) or glibenclamide (a KATP channels blocker; 10 mg kg(-1)). After either 30 min or 1 h, FOR0810 (3 mg kg(-1)) was administered. At the end of 30 min, the animals received naproxen (300 mg kg(-1)) by gavage. After 6 h, the animals were sacrificed and gastric damage, myeloperoxidase (MPO) activity, and TNF-α and IL-1β gastric concentrations were evaluated. In addition, the effects of FOR0810 on naproxen-induced mesenteric leukocyte adherence were determined by intravital microscopy. Other groups, were pre-treated with saline, ODQ or glibenclamide. After either 30 min or 1 h, FOR0810 was administered. At the end of 30 min, the animals received 50% ethanol by gavage. After 1 h, the animals were sacrificed, and gastric damage, gastric reduced glutathione (GSH) concentration and malondialdehyde (MDA) levels were determined. In naproxen-induced gastric damage, FOR0810 prevented gastric injury, decreased gastric MPO activity and leukocyte adherence, associated with a decrease in TNFα and IL-1β gastric concentrations. FOR0810 also prevented ethanol-induced gastric damage by increase in GSH levels and decrease in MDA levels. ODQ and glibenclamide completely reversed FOR0810s ability to prevent gastric damage by either naproxen or ethanol. We infer that FOR0810 prevented gastric damage through the activation of both sGC and KATP channels, which triggered a decrease in both free radical and cytokine production via the blocking of neutrophil adhesion and infiltration.

Epiisopiloturine hydrochloride, an imidazole alkaloid isolated from Pilocarpus microphyllus leaves, protects against naproxen-induced gastrointestinal damage in rats

OBJECTIVE This study aimed to investigate the protective effect of epiisopiloturine hydrochloride (EPI), an imidazole alkaloid, on NAP-induced gastrointestinal damage in rats. METHODS Initially, rats were pretreated with 0.5% carboxymethylcellulose (vehicle) or EPI (3, 10 and 30mg/kg, p.o. or i.p., groups 3-5, respectively) twice daily, for 2days. After 1h, NAP (80mg/kg, p.o.) was given. The control group received only vehicle (group 1) or vehicle+naproxen (group 2). Rats were euthanized on 2nd day, 4h after NAP treatment. Stomachs lesions were measured. Samples were collected for histological evaluation and glutathione (GSH), malonyldialdehyde (MDA), myeloperoxidase (MPO), and cytokines levels. Moreover, gastric mucosal blood flow (GMBF) was evaluated. RESULTS EPI pretreatment prevented NAP-induced macro and microscopic gastric damage with a maximal effect at 10mg/kg. Histological analysis revealed that EPI decreased scores of damage caused by NAP. EPI reduced MPO (3.4±0.3U/mg of gastric tissue) and inhibited changes in MDA (70.4±8.3mg/g of gastric tissue) and GSH (246.2±26.4mg/g of gastric tissue). NAP increased TNF-α levels, and this effect was reduced by EPI pretreatment. Furthermore, EPI increased GMBF by 15% compared with the control group. CONCLUSION Our data show that EPI protects against NAP-induced gastric and intestinal damage by reducing pro-inflammatory cytokines, reducing oxidative stress, and increasing GMBF.

Topical protection of mice laryngeal mucosa using the natural product cashew gum

Evaluate the effect of in vitro exposure of mice laryngeal mucosa to solutions that simulated human gastric juice and to assess the topical protective effect of cashew gum on mice laryngeal mucosal integrity in vitro.