Thesis (Ph.D.) - Cairo University - Faculty of Medicine - Department of

Background: Diabetes mellitus and sepsis are major causes of cognitive decline. Liraglutide (LIRA) is a Glucagon like peptide-1 (GLP-1) agonist used by many diabetic patients with potential beneficial effects on the central nervous system. Objective: The purpose of the present study is to investigate the possible effect of liraglutide on cognitive decline in diabetes and sepsis. Methods: Male albino rats were divided into nine groups: Control (C), Drug control (Cd), Diabetes (D) (High fat diet for 2 weeks, Streptozotocin 40 mg/kg, (i.p.), once), Sepsis (S) (Cecal ligation and perforation (CLP)), Diabetic-Septic (DS) (Diabetes, CLP), Diabetes-treated rats (D-ttt) (Diabetes, LIRA (200 og/kg; i.p.; once daily, 4 weeks)), Sepsis treated rats (S-ttt) (Sepsis, LIRA), Diabetes-Sepsis treated group (DS-ttt) (Diabetes, CLP, LIRA), Diabetes and sepsis prophylaxis group (DS-pro) (Diabetes, CLP, LIRA (8 weeks). At the end of experimental period cognitive functions were assessed; blood glucose, insulin and HOMA-IR were measured. Oxidative stress, synaptic plasticity, and insulin signaling markers were assessed. Microglia, astrocytes were examined, in addition to H & E stain and electron microscopy examination of the hippocampus.Results: The results of the present study revealed that blood glucose levels, insulin and HOMA-IR in D and DS groups were all significantly increased (P<0.05) compared to C and Cd groups. LIRA treatment reversed all these changes in treatment groups. In cognitive tests (Ymaze test), the percentage of correct alternations was decreased significantly (P<0.05) in D and DS groups compared to C and Cd groups and all treatment groups showed a significant increase (P<0.05) in % of correct alternations compared to D and DS groups, while in Novel Object Recognition (NOR) test, the discrimination index (DI) showed a significant decrease (P<0.05) in D, S and DS groups compared to C and Cd groups. LIRA in D-ttt group caused a significant increase (P<0.05) in DI compared to D, S and DS group. In the hippocampus, oxidative stress markers (Tumor necrosis factor (TNF)- Ü and Malondialdehyde (MDA)) increased, while markers for synaptic function (Cyclic-AMP Response Element Binding Protein (CREB) and synaptophysin) decreased significantly (P<0.05), in D, S, and DS groups compared to C and Cd groups. Hippocampal insulin signaling markers, phosphorylatedserine/ threonine-specific protein kinase (p-Akt) decreased, while phosphorylated Mammalian target of rapamycin (p-mTOR) increased significantly (P<0.05) in D, S, and DS groups compared to C and Cd groups. Hippocampal Ionized calcium-binding adapter molecule-1(Iba1) and glial fibrillary acidic protein (GFAP), the count of Iba-1 positive microglia and GFAPpositive astrocytes were increased significantly (P<0.05) in D, S, DS groups compared to C and Cd groups. LIRA treatment reversed all these abnormalities. On H & E staining and electron microscopy examination of the hippocampus, many degenerative changes in all hippocampal regions were noted in D, S, and DS groups. LIRA in all treatment groups improved all these changes

Issued also as CD