Abstract
Background: (-)-Carveol (p-Mentha-6,8-dien-2-ol) is a monocyclic monoterpenic alcohol, present in essential oils of plant species such as Cymbopogon giganteus, Illicium pachyphyllum and in spices such as Carum carvi (cumin). Pharmacological studies report its antitumor, antimicrobial, neuroprotective, vasorelaxant, antioxidant and anti-inflammatory activity.Hypothesis/Purpose: The objective of this study was to evaluate the acute non-clinical oral toxicity, gastroprotective activity of monoterpene (-)-Carveol in animal models and the related mechanisms of action.Methods: Acute toxicity was assessed according to OECD guide 423 in mice. Ethanol, stress, NSAIDs and pylorus ligation-induced gastric ulcer models were used to investigate antiulcer properties. The related mechanisms of action were using the ethanol-gastric lesions protocol.Results: (-)-Carveol has low toxicity, with a lethal dose 50% (LD50) equal to or greater than 2,500 mg/kg according to OECD guide nº 423. In all gastric ulcer induction methods evaluated, (-)-Carveol (25, 50, 100 and 200 mg/kg, p.o.) significantly reduced the ulcerative lesion in comparison with the respective control groups. To investigate the mechanisms involved in the gastroprotective activity, the antisecretory or neutralizing of gastric secretion, cytoprotective, antioxidant and immunoregulatory effects were evaluated. In the experimental protocol of pylorus ligation-induced gastric ulcer, (-)-Carveol (100 mg/kg) reduced (p < 0.001) the volume of gastric secretion in both routes (oral and intraduodenal). The previous administration of blockers NEM (sulfhydryl groups blocker), L-NAME (nitric oxide synthesis inhibitor), glibenclamide (KATP channel blocker) and indomethacin (cyclo-oxygenase inhibitor), significantly reduced the gastroprotection exercised by (-)-Carveol, suggesting the participation of these pathways in its gastroprotective activity. In addition, treatment with (-)-Carveol (100 mg/kg) increased (p < 0.001) mucus adhered to the gastric wall. Treatment also increased (p < 0.001) levels of reduced glutathione (GSH), superoxide dismutase (SOD) and interleukin-10 (IL-10). It also reduced (p < 0.001) malondialdehyde (MDA), myeloperoxidase (MPO), interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) levels.Conclusion: Thus, it is possible to infer that (-)-Carveol presents gastroprotective activity related to antisecretory, cytoprotective, antioxidant and immunomodulatory mechanisms.
Highlights
Peptic ulcer is a common disease of global incidence and prevalence, affecting millions of people worldwide and showing high rates of recurrence (Lanas and Chan, 2017)
The animals submitted to the administration of (-)-Carveol at doses of 300 and 2000 mg/kg (p.o.) did not show any behavioral
One-way analysis of variance (ANOVA): followed by Dunnett’s and Tukey’s test was performed using the software Graph Pad Prism. ***p < 0.001 compared to the control group (5% Tween 80). (n 8/per group)
Summary
Peptic ulcer is a common disease of global incidence and prevalence, affecting millions of people worldwide and showing high rates of recurrence (Lanas and Chan, 2017) This disease is of complex and multifactorial origin and develops from the loss of balance between aggressive (hydrochloric acid, continuous use of non-steroidal antiinflammatory drugs-NSAIDs, smoking, oxidative stress and the abusive ethanol intake) and protective agents (mucus, bicarbonate, prostaglandins, nitric oxide, growth factors and cell renewal) of the mucosa of the gastrointestinal tract (Yandrapu and Sarosiek, 2015; Malfertheiner and Schulz, 2020). Among the therapeutic options available for this condition are antacids, cytoprotectors, H2 histamine receptor antagonists, proton pump inhibitors (PPIs) and in cases where there is infection by Helicobacter pylori, it is necessary to use antimicrobial drugs (Sałaga and Mosińska, 2017). Many natural products have served as inspiration and starting points for medicinal chemistry and the development of new molecules and drugs (Barreiro, 2019)
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