Abstract
Purpose : To evaluate the protective effect of melatonin on diabetes-induced cognitive dysfunction. Methods : Rats were fed a high-fat diet + streptozotocin (HFD + STZ) for 15 weeks to induce type 2 diabetes (HFD + STZ group). At the end of the 15-week induction of diabetes, cognitive function in the diabetic rats was estimated using a Morris water maze and an object recognition task. Next, the diabetic rats were treated with melatonin (10 mg/ kg, po) for 3 weeks. Thereafter, cognitive function was reevaluated in the melatonin-treated diabetic rats (melatonin group). Results : There was a significant (p < 0.01) decrease in the serum glucose and insulin in melatonintreated diabetes type 2 rats compared with that of diabetes type 2 rats exposed to only HFD + STZ. Treatment with melatonin (10 mg/kg, po) for 3 weeks in diabetic type 2 rats also caused a significant increase (p < 0.01) in the time spent in the target quadrant and preference index in diabetic rats compared with the HFD + STZ group. There were significant decreases in reactive oxygen species (ROS), oxido-nitrosative stress markers, including thiobarbituric acid reactive substances (TBARS), nitrite, and depleted glutathione (GSH) level in the hippocampus of melatonin-treated group, compared with the HFD + STZ-treated group. Moreover, the melatonin-treated group showed significant inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and reduction in the levels of proinflammatory cytokines. Conclusion : The results demonstrate that melatonin prevents cognitive dysfunction in type 2 diabetic rats by attenuating oxido-nitrosative stress and NF-κB-mediated neuroinflammation. This effect suggests that melatonin may be useful for the management of cognitive dysfunction in patients suffering from diabetes. Keywords : Cognitive dysfunction, Melatonin, Neuroinflammation, Nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB), Oxido-nitrosative stress, Type 2 diabetes
Highlights
EXPERIMENTALDiabetes is a metabolic disorder that results from inadequate action and secretion of insulin [1]
One-way analysis of variance (ANOVA) revealed that the diabetic rats failed to discriminate between familiar and unfamiliar objects placed in the Object recognition task (ORT) box
After 15 weeks of diabetes induction, type 2 diabetic rats had significantly increased body weight (p < 0.01) and showed marked (p < 0.01) elevation of serum glucose and insulin levels compared with the control group (Table 1)
Summary
Diabetes is a metabolic disorder that results from inadequate action and secretion of insulin [1]. Complications in several body systems, such as cranial and peripheral nerves, large vessels, eyes, kidney, and cardiovascular system, are associated with diabetes [2,3]. Cognitive deficits have been observed in both type 1 and type 2 diabetes patients. Previous studies suggest that hyperglycemia is associated with the cognitive decline seen in both types of diabetic patients [4]. Hyperglycemia alters multiple mechanisms, causing activation of protein kinase C activity and the polyol pathway, accumulation of sorbitol and advanced glycation end products, disturbances in Ca2+ homeostasis, and augmentation of reactive oxygen species (ROS) levels. Increased levels of ROS and free radical generation disturb oxidative metabolism balance, which leads to detrimental effects on cellular function [5]. The detrimental changes induced by ROS in the cell include depletion of endogenous antioxidants, energy insufficiency, mitochondrial dysfunction, protein and DNA damage, and inflammation
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