Phytochemical Characterisation and Effects of the Native Plant Tabernanthe iboga in Models of Diabetes

Preparations of the root bark of Gabonese plants, T. iboga and G. tessmannii have long been used in Central and West African traditional medicine for the treatment of diabetes. In this thesis phytochemical characterisation of T. iboga aqueous extract revealed the presence of 23 unknown alkaloids and 7 already known alkaloids, including ibogaine, the main indole alkaloid found in T. iboga. For the first time, phenolic compounds have been identified in significant quantity in T. Iboga, the most prevalent being 3-O-CQA. The therapeutic potential of these constituents in diabetes remains to be determined. The aqueous extracts of these Gabonese plants for the potential to improve insulin release was examined. T. iboga (1 μg/ml) and G. tessmannii (70 μg/ml) demonstrated insulinotropic effects in isolated rat pancreatic islets at non-stimulatory and stimulatory glucose concentrations (2.8 and 11.1 mM, for T. iboga and 2.8 to 16.7 mM, for G. tessmannii), similar to the insulin secretagogue, tolbutamide (200 μM). An additive effect on glucose-induced insulin release was observed for both plant aqueous extracts in the presence of tolbutamide (200 μM). The mechanism of action of the insulinotropic effect of T. iboga (1 μg/ml) was explored through the use of a σ2 receptor antagonist, SM-21 (1 and 10 μM) which significantly blocked T. iboga (1 μg/ml) insulin potentiation at non-stimulatory and stimulatory glucose concentrations (2.8 and 11 mM) indicating these effects were seen to be partly through σ2 receptors. T. iboga (50, 100 and 200 mg/kg) when administered daily over 28 days demonstrated no observable toxicity and exerted hypoglycaemic activity on glucose tolerance in healthy rats. Feeding a 10% fructose solution over 2 weeks combined with a low intraperitoneal dose of streptozotocin (STZ, 40 mg/kg) to rats led to the development of a T2D compared with T1D rats over 4 weeks. T. iboga at the lowest daily dose of 50 mg/kg significantly improved hyperglycaemia after 3 and 4 weeks of treatment compared with glibenclamide. After 2 and 4 weeks daily administration of T. Iboga (50 and 200 mg/kg) glucose tolerance over a 2 hour fasted glucose load was improved compared with T2D rats treated with vehicle alone. Feeding a high fat diet (HFD) to mice for 10 weeks produced manifestations of metabolic syndrome and T2D, as compared to mice fed a low-fat diet (LFD). Supplementation of HFD with T. iboga aqueous extract at ibogaine doses of 0.83 (low) and 2.07 (high) mg/kg/day did not improve these HFD-induced metabolic effects except for a reduction of plasma MCP-1 in the low dose group, indicative of an anti-inflammatory effect. Overall, T. iboga and G. tessmannii aqueous extracts have demonstrated insulin potentiation, hypoglycaemic and anti-hyperglycaemic activities. However, further investigations are needed to validate their safe use for the management of DM in Gabon