Menthol: elucidating its gastroprotective mechanisms of action

AL Rozza, CH Pellizzon. UNESP, Morphology 18618-970, Brazil

(-)-Menthol (ME) demonstrated significant gastroprotective properties in our previous studies. Prostaglandin E2 (PGE2) is directly involved in gastroprotection through mucus production, and can be inhibited by non-steroidal antiinflammatory drugs like indomethacin. This study aimed to evaluate if the gastroprotection conferred by ME is directly related to PGE2 and mucus production and to an antisecretory effect.

Male Wistar rats (n=7) weighing 200-250 g were used in all bioassays. To investigate the ME gastroprotection against indomethacin, the rats were orally treated with vehicle, cimetidine 100 mg/kg or ME 50 mg/kg and after 30 minutes received indomethacin 100 mg/kg. After 5 h, the rats were euthanized, the stomachs were removed and the ulcer area (mm2 ) was determined by the software AVSoft BioView. For PGE2 measurement, besides the sham group, 2 groups of male rats (n=7) were orally treated with vehicle and 2 with ME 50 mg/kg. Two of these groups were treated with indomethacin (30 mg/kg s.c). After the rats were euthanized, PGE2 in the stomach mucosa was measured (ng/ml) with an immunoassay kit. The gastric juice parameters were evaluated by pylorus ligature model. After oral or intraduodenal administration of vehicle, cimetidine 100 mg/kg or ME 50 mg/kg, the pylorus ligature was performed. Four hours later, the rats were euthanized and the total acid content of gastric secretion was determined by titration using a digital burette. To determine the mucus adhering to the gastric wall, the rats orally received vehicle, carbenoxolone 200 mg/kg or ME 50 mg/kg and were submitted to pylorus ligature. After 4 hours, the animals were euthanized and the stomachs were immersed in alcian blue solution for the mucus quantification procedure. Mean ± s.e.m. ANOVA, Dunnett test, ap<0.01. All assays were approved by the UNESP Institutional Animal Care and Use Committee.

ME presented 77.88% of gastroprotection against indomethacin, presenting ulcer area of 8.42 ± 1.67a, while the positive control presented ulcer area of 3.20 ± 0.98a (91.59% of gastroprotection) and the vehicle 38.06 ± 8.02. ME was able to maintain the PGE2 levels (17.72 ± 0.67) near to that of sham group (20.74 ± 0.34), even with indomethacin administration (15.16 ± 0.50). The oral treatment with ME was able to diminish the H+ concentration (mEquiv/mL/4h) in the gastric juice (5.90 ± 0.67a) in comparison to vehicle group (9.60 ± 0.95) without modifying its volume (mL) (3.39 ± 0.63, vehicle 2.93 ± 0.36). Otherway, ME intraduodenally administrated was not able to significantly decrease the H+ concentration (9.05 ± 0.32, vehicle 10.23 ± 0.44) but to diminish the gastric juice volume (2.95 ± 0.15a, vehicle 5.08 ± 0.21). There was a significant increase in the gastric mucus adhering to the stomach (µg/g) in the ME group (3582.00 ± 89.73a) in comparison to vehicle group (1633.42 ± 43.73).

The gastroprotective effect of ME 50 mg/kg is related to the maintenance of PGE2 levels in the gastric mucosa, to an increase in mucus production and to an antisecretory effect.

Financial Support: CAPES and FAPESP