Protective effect of boldine on oxidative mitochondrial damage in streptozotocin-induced diabetic rats.
Increased oxidative stress has been suggested to be involved in the pathogenesis and progression of diabetic tissue damage. Several antioxidants have been described as beneficial for oxidative stress-associated diseases. Boldine ([s]-2,9-dihydroxy-1, 10-dimethoxyaporphine) is a major alkaloid found in the leaves and bark of boldo (Peumus boldus Molina), and has been shown to possess antioxidant activity and anti-inflammatory effects. From this point 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: control, 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 with 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 of malondialdehydes and carbonyls and the activities of endogenous antioxidant enzymes (superoxide dismutase and glutathione peroxidase) in mitochondria of the pancreas, kidney and liver. The scavenging action of boldine on oxygen 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 levels of malondialdehyde (MDA) and carbonyls in liver, kidney and pancreas mitochondria were significantly increased in STZ-treated rats and decreased after boldine administration. The activities of mitochondrial manganese superoxide dismutase (MnSOD) in the liver, pancreas and kidney were significantly elevated in STZ-treated rats. Boldine administration decreased STZ-induced elevation of MnSOD activity in kidney and pancreas mitochondria, but not in liver mitochondria. In the STZ-treated group, glutathione peroxidase activities decreased in liver mitochondria, and were elevated in pancreas and kidney mitochondria. The boldine treatment restored the altered enzyme activities in the liver and pancreas, but not the kidney. Boldine attenuated both STZ- and iron plus ascorbate-induced MDA and carbonyl formation and thiol oxidation in the pancreas homogenates. Boldine decomposed superoxide anions, hydrogen peroxides and hydroxyl radicals in a dose-dependent manner. The alkaloid significantly attenuated the production of superoxide anions, hydrogen peroxide and nitric oxide caused by liver mitochondria. The results indicate that boldine may exert an inhibitory effect on STZ-induced oxidative tissue damage and altered antioxidant enzyme activity by the decomposition of reactive oxygen species and inhibition of nitric oxide production 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 diabetes mellitus.
Jang
Y Y
YY
Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, 156-756, Korea.
Song
J H
JH
Shin
Y K
YK
Han
E S
ES
Lee
C S
CS
D000818:Animals; D001060:Aporphines / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003920:Diabetes Mellitus / Q000139:chemically induced / Q000378:metabolism*; D004347:Drug Interactions; D005609:Free Radicals / Q000378:metabolism; D007501:Iron / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013311:Streptozocin; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
D001060:Aporphines; D001786:Blood Glucose; D005609:Free Radicals; D020011:Protective Agents; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D013311:Streptozocin; C011686:boldine; D007501:Iron; D013482:Superoxide Dismutase; D001205:Ascorbic Acid