Minocycline prevents depression-like behavior in streptozotocin-induced diabetic mice

Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia. Diabetic patients are known to have a higher prevalence and a higher risk of depression compared with the general population. The pathogenesis of diabetes-related depression is unclear, and the treatment is not well-established. Therefore, the prevention of diabetes-related depression is important for improving the quality of life of diabetic patients. Minocycline, a second-generation tetracycline antibiotic, has recently gained attention as a new agent for depression. In this study, we investigated the effect of minocycline on diabetes-related depression in a streptozotocin-induced mouse model of diabetes. Eight-week-old male C57BL/6 mice were injected with streptozotocin (200 mg/kg, i.p.). Seven days after injection, the mice received minocycline treatment through drinking water. We compared these mice with vehicle-treated control mice and diabetic mice not receiving minocycline treatment. On day 34, depression-like behavior was investigated using the forced swim test. On the following day, brain samples were collected, and formalin-fixed, paraffin-embedded specimens were prepared for immunohistochemistry. Compared with the control group, the diabetic mice not receiving minocycline treatment showed a prolonged duration of immobility in the forced swim test, the observation being interpreted as a depression-like behavior. Immunohistochemistry revealed an increase in microglia with an activated morphology in the diabetic mice without minocycline treatment. The expression of tumor necrosis factor alpha in microglia was increased. In addition, a decrease in the number of doublecortin-positive immature neurons was found in the hippocampus of diabetic mice. Minocycline treatment of diabetic animals prevented the depression-like behavior and microglial activation; however, minocycline did not reverse impaired hippocampal neurogenesis. These results indicate that minocycline has a preventive effect on diabetes-related depression. Inhibition of microglial activation would be a critical target for the antidepressant mechanism of minocycline. Impaired hippocampal neurogenesis was observed in diabetic mice; however, this may not be involved in the pathogenesis of depression.