Combined Effect of Melatonin and Metformin in Mitigating Anxiety and Depression-Related Behaviors in Diabetic Mice Under Immobility Stress: Role of Oxidative Stress
Combined Effect of Melatonin and Metformin in Mitigating Anxiety and Depression-Related Behaviors in Diabetic Mice Under Immobility Stress: Role of Oxidative Stress
Idrissi Ouedrhiri Housna1, Bikri Samir1,2*, Benloughmari Douae1, Aboussaleh Youssef1
ABSTRACT
Previous epidemiological findings indicate an association between type 2 diabetes mellitus (T2DM) and behavioral alterations, with stress recognized as a factor contributing to psychiatric disorders. Melatonin (MEL), known for its potent antioxidant properties and various benefits against hyperglycemia and stress-related complications, is particularly intriguing. The primary objective of this study was to investigate whether combining Melatonin and Metformin (MET) could ameliorate biochemical and behavioral changes associated with persistent hyperglycemia, specifically by reducing lipid peroxidation (LPO), a key marker of oxidative stress (OS), in T2DM mice exposed to chronic immobilization stress (CIS).Mice were divided into four groups: normal-control (NC), diabetic treated with MET (D-Met), stressed diabetic treated with MET (D-Ims-Met), and stressed diabetic treated with a combination of MET and MEL (D-Ims-Met-Mel). T2DM was induced experimentally by exposing mice to fructose for 14 days followed by a single intraperitoneal injection of streptozotocin (STZ). Stress symptoms were induced using the chronic immobilization stress paradigm. Anxiety and depression-related behaviors were evaluated using three behavioral tests after treatment periods of 30 days (T1) and 60 days (T2), respectively. Blood samples collected post-sacrifice were analyzed to assess lipid parameters and corticosterone (CORT) levels. Additionally, organs (pancreas and brain) were dissected to measure LPO levels as indicators of OS. The data underwent a one-way analysis of variance, followed by Bonferroni’s post hoc test for inter-group comparisons.The results revealed that combining MET with MEL alleviated OS in the brain and pancreas of diabetic mice subjected to CIS for two months by reducing LPO accumulation (P<0.05). This combination treatment effectively regulated CORT levels, improved lipid profiles, and reduced the atherogenic index in these mice (P<0.05). Moreover, the combined therapy significantly improved depression-related behaviors in this mouse model (P<0.001). These findings suggest that the combination of MEL and MET could be promising as a potential antioxidant supplement for patients with T2DM. By mitigating oxidative stress and metabolic disorders, this combination could improve disease management and the quality of life for patients.
Keywords | Diabetes, Melatonin, Oxidative stress, Metformin, Anxiety and depression
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