Metformin Protects the Brain Against the Oxidative Imbalance Promoted by Type 2 Diabetes

Abstract

We aimed to investigate whether metformin protects the brain against the oxidative imbalance promoted by type 2 diabetes. This study analyzed the effect of metformin on oxidative stress markers (thiobarbituric acid reactive substances (TBARS), malondialdehyde (MDA) and carbonyl groups), hydrogen peroxide (H(2)O(2)) levels, non-enzymatic antioxidant defenses [reduced (GSH) and oxidized (GSSG) glutathione and vitamin E] and enzymatic antioxidant defenses [glutathione peroxidase (GPx), glutathione reductase (GRed) and manganese superoxide dismutase (MnSOD)] in brain homogenates of diabetic GK rats, a model of type 2 diabetes. For this purpose we compared brain homogenates obtained from untreated GK rats versus GK rats treated with metformin during a period of 4 weeks. Brain homogenates obtained from Wistar rats were used as control. The MDA levels, GPx and GRed activities are significantly higher in untreated GK rats, while TBARS levels, carbonyl groups, glutathione content and vitamin E levels remain statistically unchanged when compared with control rats. In contrast, MnSOD activity and the levels of H(2)O(2) are significantly decreased in untreated GK rats when compared with control animals. However, metformin treatment normalized the majority of the parameters altered by diabetes. We observed that metformin, besides its antihyperglycemic action, induces a significant decrease in TBARS and MDA levels, GPx and GRed activities and a significant increase in GSH levels and MnSOD activity. These results indicate that metformin protects against diabetes-associated oxidative stress suggesting that metformin could be an effective neuroprotective agent.

Antidiabetic drug metformin (Glucophage R ) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription

“…This concern needs to be addressed by direct testing of the drug in animal models, in conjunction with learning, memory and behavioral tests. Although the precise mechanism of action of metformin in the CNS remains largely unknown, recent studies (39,40), together with ours, suggest that metformin crosses the blood brain barrier and exerts specific pharmacological effects in rodent brains upon chronic administration. Indeed, our study using a comparable dose (2 mg/mL is equivalent to a clinical dosage of 300 mg/kg/ day) indicates that systemically administrated metformin for 6 days increases brain AMPK activation and BACE1 protein levels (Fig.…”

Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation

“…In some models, antioxidative activity of metformin has been associated with its hypoglycemic effect, but in the presented study HFD-fed rats did not exhibit hyperglycemia. Numerous studies have demonstrated that both T1D (Type 1 diabetes) and T2D are associated with decreased activity and expression of antioxidant enzymes and that metformin treatment can restore normal conditions (13,19,62). In our experimental design, HFD-fed rats exhibited augmented markers of oxidative stress (lipoperoxides) accompanied by a significant decrease of liver GSH content and SOD activity and elevated catalase activity.…”

Metformin Normalizes Type 2 Diabetes-Induced Decrease in Cell Proliferation and Neuroblast Differentiation in the Rat Dentate Gyrus

“…It has been reported that AICAR exerts a protective effect against apoptosis in astrocytes induced by fatty acids [30] and by glucose deprivation in hippocampal neurons [31]. In addition, metformin treatment significantly decreases oxidative stress levels and increases the levels of anti-oxidants such as glutathione and Mn-superoxide dismutase in the brain [14].…”

“…In addition, metformin has anti-oxidative effects in diabetic brain [14] and neuroprotective effects induced by permeability transition pore opening [15].…”