Combination of Rheum ribes and Metformin Against Diabetes, Thermal Hyperalgesia, and Tactile Allodynia in a Mice Model.

CONTEXT

The prevalence of diabetes mellitus (DM) is increasing. Because of its progressive nature, therapeutic shifts and combinations are often required to reduce the risk of glucose toxicity and avoid serious side effects. To treat DM and its related complications, a combination therapy may offer a promising remedy to counteract those issues.

OBJECTIVES

The study was established to evaluate the phytochemical content of a standardized aqueous extract of Rheum ribes (RR) and to determine the antidiabetic, antihyperalgesic, and antimechanical allodynic effects of 50 mg/kg of RR alone, 25 mg/kg of metformin (MTF) alone, and a combination of the 2 substances (MTF+RR) in mice with alloxan-induced diabetes.

DESIGN

The research team designed an animal study.

SETTING

The study was performed at the facilities of the faculty of pharmacy at Beirut Arab University (Beirut, Lebanon).

ANIMALS

The animals were male, Swiss-Webster mice, weighing 22-30 g and aged 12-16 wk.

INTERVENTION

DM was induced in experimental animals by an IP injection of alloxan every 48 h for 3 injections at a total dose of 180 mg/kg. Substudy A measured the acute-0, 0.5, 2, and 6 h-and subchronic-1, 3, 5, and 8 d-effects of a water extract of the RR alone, of the MTF alone, and of the MTF+RR combination on blood-glucose levels (BGLs), body weights, and catalase (CAT) serum levels. The mice were divided into 6 groups of 7 mice each, and each group received various IP injections of the tested samples: (1) group 1, a vehicle control group of normal mice (NORM group) received sterile, cold, 0.9% saline; (2) group 2, a vehicle control group of diabetic mice (VEH group) received sterile, cold, 0.9% saline; (3) group 3, a positive control group of diabetic mice (GB group) received 5 mg/kg of glibenclamide; (4) group 4, an intervention group of diabetic mice (MTF group) received 25 mg/kg of MTF only; (5) group 5, an intervention group of diabetic mice (RR group) received 50 mg/kg of RR only; and (6) group 6, an intervention group (MTF+RR group) of diabetic mice received 25 mg/kg of MTF and 50 mg/kg of RR. Substudy B measured the subchronic-0, 2, 4, 6, and 8 wk-effects of the RR only, of the MTF only, and of the MTF+RR combination on the hot plate and tail flick latencies and on the von Frey paw withdrawal thresholds. Again, they were divided into 6 groups of 7 mice each (groups 7 through 12), and each group received various IP injections of the tested samples, with all of the groups receiving the same treatments as for substudy A, except that group 9, a positive control group of diabetic mice, received 10 mg/kg of tramadol.

OUTCOME MEASURES

The BGLs of the mice were monitored acutely for 6 h and subchronically for 8 d. Glycated hemoglobin (HbA1c), inhibition of α-glucosidase, and effects on serum insulin were evaluated. Using tail flick, hot plate latencies, and von Frey paw withdrawal thresholds, thermal hyperalgesia and tactile allodynia were assessed. Using a natural antioxidant, in vivo antioxidant activity was used to evaluate CAT and lipid peroxide (LPO) levels.

RESULTS

The reductions in blood glucose, HbA1c, α-glucosidase, and LPO were statistically significant for the MTF+RR. The body weight, serum insulin, tail flick, hot plate latencies, paw withdrawal thresholds, and CAT increased significantly in diabetic mice treated with the combination. Consequently, the combination's potent inhibitory effect on α-glucosidase and serum insulin elevation might be responsible for its hypoglycemic potential, whereas its antioxidant effects might be responsible for the amelioration of painful hyperalgesia and allodynia, suggesting that the combination has better antidiabetic and antinociceptive effects and fewer side effects than treatment with MTF alone. No adverse events were reported.

CONCLUSION

When combined with MTF, RR might be a promising adjuvant for amelioration of DM and related nociceptive complications.