Protective effect of boldine on oxidative mitochondrial damage in streptozotocin-induced diabetic rats

Increased oxidative stress has been suggested to be involved in the pathoge nesis and progression of diabetic tissue damage. Several antioxidants have been described as beneficial for oxidative stress-associated diseases. Bold ine ([s]-2,9-dihydroxy-1,10-dimethoxyaporphine) is a major alkaloid found i n the leaves and bark of boldo (Peumus boldus Molina), and has been shown t o possess antioxidant activity and anti-inflammatory effects. From this poi nt of view, the possible anti-diabetic effect of boldine and its mechanism were evaluated. The experiments were performed on male rats divided into four groups: contr ol, boldine (100 mg kg(-1), daily in drinking water), diabetic [single dose of 80 mg kg(-1) of streptozotocin (STZ), i.p.] and diabetic simultaneously fed with boldine for 8 weeks. Diabetic status was evaluated periodically w ith changes of plasma glucose levels and body weight in rats. The effect of boldine on the STZ-induced diabetic rats was examined with the formation o f malondialdehydes and carbonyls and the activities of endogenous antioxida nt enzymes (superoxide dismutase and glutathione peroxidase) in mitochondri a of the pancreas, kidney and liver. The scavenging action of boldine on ox ygen free radicals and the effect on mitochondrial free-radical production were also investigated. The treatment of boldine attenuated the development of hyperglycemia and weight loss induced by STZ injection in rats. The lev els of malondialdehyde (MDA) and carbonyls in liver, kidney and pancreas mi tochondria were significantly increased in STZ-treated rats and decreased a fter boldine administration. The activities of mitochondrial manganese supe roxide dismutase (MnSOD) in the liver, pancreas and kidney were significant ly elevated in STZ-treated rats. Boldine administration decreased STZ-induc ed elevation of MnSOD activity in kidney and pancreas mitochondria, but not in liver mitochondria. In the STZ-treated group, glutathione peroxidase ac tivities decreased in liver mitochondria, and were elevated in pancreas and kidney mitochondria. The boldine treatment restored the altered enzyme act ivities in the liver and pancreas, but not the kidney. Boldine attenuated b oth STZ- and iron plus ascorbate-induced MDA and carbonyl formation and thi ol oxidation in the pancreas homogenates. Boldine decomposed superoxide ani ons, hydrogen peroxides and hydroxyl radicals in a dose-dependent manner. T he alkaloid significantly attenuated the production of superoxide anions, h ydrogen peroxide and nitric oxide caused by liver mitochondria. The results indicate that boldine may exert an inhibitory effect on STZ-ind uced oxidative tissue damage and altered antioxidant enzyme activity by the decomposition of reactive oxygen species and inhibition of nitric oxide pr oduction and by the reduction of the peroxidation-induced product formation . Boldine may attenuate the development of STZ-induced diabetes in rats and interfere with the role of oxidative stress, one of the pathogeneses of di abetes mellitus. (C) 2000 Academic Press.