Effects of Melatonin on Brain's Glymphatic System and Cell Hypoxia in Mice with a Genetically Determined Model of Type II Diabetes Mellitus

Diabetes mellitus and its complications rank among the top ten leading causes of mortality worldwide. The need for effective treatments is urgent due to the numerous side effects associated with current diabetes medications. The progression of type 2 diabetes (T2D) is linked to reduced melatonin levels due to the reciprocal melatonin-insulin relationship. Exogenous melatonin therapy has shown effectiveness in alleviating T2D complications in cell lines, laboratory animals, and patients. In this study, we investigated the effects of melatonin on brain hypoxia and glymphatic system function in db/db mice, a genetic model of obesity and T2D. We observed intensive immunohistochemical HIF-1α staining in the brain sections of db/db mice, primarily in the cytoplasm of neurons and glial cells, particularly in the placebo group. Melatonin administration reduced HIF-1α expression and concentration compared to the placebo and control groups. This reduction indicates melatonin's potential to mitigate stress-induced hypoxia. Additionally, LYVE1 staining in the control group showed prominent capillary and lymphatic endothelial cell expression in brain parenchyma, with pathological Virchow-Robin space enlargement. Melatonin-treated mice exhibited no hydrocephalus cases, unlike control and placebo groups, and showed reduced Virchow-Robin space enlargement, suggesting decreased interstitial fluid accumulation. Morphometric analysis indicated a slight reduction in LYVE1 expression area in melatonin-treated db/db mice, while LYVE1 concentration in the glymphatic system remained comparable to control and placebo groups. These findings suggest melatonin's potential in addressing T2D-related neurological complications through its effects on brain hypoxia and glymphatic function.