RESUMO
The purpose of this study is to investigate the effect of montelukast on lipopolysaccharide (LPS)-induced pancreatitis. Adult male Wistar rats were divided into 5 groups: normal control, control montelukast, LPS group, and two LPS + montelukast-treated groups. Acute pancreatitis (AP) was induced by a single dose of LPS (6 mg/kg, i.p.), while montelukast was given in two different doses (10 and 20 mg/kg/day) for 3 consecutive days prior to the injection of LPS. AP was demonstrated by significant increases in serum levels of lactate dehydrogenase (LDH) and pancreatic enzymes lipase and amylase. Proinflammatory response activation was evident by elevated serum levels of nitric oxide (NO) and increased pancreatic concentrations of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1ß), and intercellular adhesion molecule-1 (ICAM-1). The activity of myeloperoxidase (MPO), a neutrophil infiltration marker, has also been increased. Oxidative stress was confirmed by significant increases in the concentrations of lipid peroxides measured as thiobarbituric acid reactive substances (TBARS) and decreases in the concentrations of reduced glutathione (GSH) in the pancreatic tissues of animals treated with LPS. Histological examination confirmed the biochemical alterations. Montelukast treatment reversed all these biochemical indices and histopathological changes that LPS induced. Montelukast reduced the increase in serum levels of lipase, amylase, LDH, total nitrite/nitrate, TNF-α, IL-1ß, and ICAM-1. MPO activities and TBARS concentrations were also suppressed while GSH content was increased in pancreatic tissues. These results show that montelukast may be a beneficial pharmacological agent in protection against LPS-induced oxidative pancreatic injury by inhibiting neutrophil infiltration, counteracting oxidative stress, and suppressing inflammatory mediators.
RESUMO
Gastric ulcer is a serious disease that affects millions of individuals worldwide. Alcohol consumption is a major contributor to the disease pathogenesis and ethanol-induced ulcer in rats closely recapitulates the clinical pathology of ulcer. In this study, rats were pretreated with carvacrol (CAR,50 and 100 mg/kg, orally) 1 h before absolute ethanol administration to induce gastric ulcer. CAR prevented ethanol-induced increases in gastric volume and acidity while restored mucin content. The gastro-protective activity of CAR, particularly the higher dose (100 mg/kg), was further supported by histopathological examination, as manifested by reduced gastric lesions. Interestingly, oxidative stress is linked to early stages of ulcer development and progression. In this study, ethanol administration upregulated the levels of ROS-producing enzymes, NADPH oxidase homologs 1 and 4 (Nox1 and Nox4) and lipid peroxides while depleting the antioxidant defense mechanisms, including GSH, Glutathione Peroxidase (GPX) and catalase. Interestingly, these alterations were significantly ameliorated by CAR pretreatment. Additionally, CAR possesses anti-inflammatory and anti-apoptotic activities. Pretreatment with CAR blunted ethanol-induced increases in inflammatory cytokines (NF-κB and TNF-α) and rectified the apoptosis regulator (Bax/Bcl2 ratio) in gastric tissue. Moreover, the docking simulation of CAR illustrated good fitting and interactions with GPX, Nox1 and TNF-α through the formation of hydrogen and hydrophobic (pi-H) bonds with conservative amino acids, thus, further supporting the anti-inflammatory and antioxidant effects underlying the gastroprotective effects of CAR. In conclusion, this study elucidates, using in silico and in vivo models, that the gastroprotective activity of CAR is attributed, at least in part, to its mucin-secretagogue, antioxidative, anti-inflammatory, and anti-apoptotic mechanisms.