Melatonin attenuates streptozotocin-induced Alzheimer-like features in hyperglycemic rats

Abstract

© 2019 Elsevier Ltd Diabetes mellitus (DM) is increasingly recognized as a risk for developing of Alzheimer's disease (AD). Accordingly, it has been reported that melatonin level is disturbed in both DM and AD which indicates its involvement in the pathophysiology of these diseases. In this study, the neuroprotective activities and relevant mechanisms of melatonin were evaluated in diabetic rat model. Rats were subcutaneously injected with melatonin (10 mg/kg) for 42 consecutive days. Single dose of streptozotocin (60 mg/kg STZ) was intraperitoneally injected. Morris water maze, Western blot and immunohistochemistry analysis of proteins in the hippocampus were measured. We found that melatonin was effective in protecting against memory impairment and decreased formation of Aβ42 peptide and phosphorylated tau in the hippocampus of STZ-treated rats. Melatonin significantly restored the reduction in phospho-insulin receptor β (p-IRβ) and ameliorated the increase of inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) in STZ-treated rats. Furthermore, it restored the phosphorylation of glycogen synthase kinase 3β (GSK3β), indicating a decreased activity of GSK3β. Melatonin prevented amyloidogenic processing of β-amyloid precursor protein (βAPP) by significantly inhibited β-site APP cleaving enzyme (BACE1), presenilin 1 (PS1), and β-cleaved C-terminal fragment (C99). In conclusion, melatonin ameliorates memory deficits in STZ-induced hyperglycemia rats by restoring insulin signaling pathway which is independent of its effects on blood glucose and insulin levels. Thus, melatonin might be a therapeutic option for helping patients suffering from diabetes and contributed to Alzheimer's disease.