Targeting brain insulin signaling pathway for modulation of cognitive impairment in a rat model of type II diabetes mellitus / By Muhammad Muneeb Muhammad Abdulazeem, (Bachelor degree of Pharmacy (2015), Teaching Assistant, Pharmacology, Toxicology & Biochemistry Department, Faculty of Pharmacy, Future University in Egypt (FUE)); Supervision of Dr. Samira Saleh Mostafa,(Professor of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Dr. Suzan Mohamed Mansour, Associate Professor of Pharmacology and Toxicology, Faculty of Pharmacy, Future University in Egypt, Dr. Reham Atef Muhamed, Faculty of Pharmacy, Cairo University).

Supervision of Dr. Samira Saleh Mostafa,(Professor of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Dr. Suzan Mohamed Mansour, Associate Professor of Pharmacology and Toxicology, Faculty of Pharmacy, Future University in Egypt, Dr. Reham Atef Muhamed, Faculty of Pharmacy, Cairo University)

Thesis (M.Sc.)-Cairo University, Faculty of pharmacy, Department of Pharmacology & Toxicology, 2022.

Includes bibliographical references.

The study aimed to explore the possible neuroprotective effects of VitD and/or RSV in T2DM-induced cognitive deficits. It investigates the crosstalk between insulin/AKT/GSK-3β and the canonical/non-canonical Wnt/β-catenin signaling in the hippocampus.
T2DM was induced by a fat sucrose diet and a single dose of streptozotocin (STZ). Diabetic rats were randomly allocated into 4 groups, a diabetic control and three groups treated for 5 weeks with RSV (15 mg/kg/day, PO), VitD (cholecalciferol, 500 IU/kg/day, PO) or their combination. A normal-control group was run concomitantly. We determined antineuropathic effects (cognitive function and histopathological examination), metabolic abnormalities (glucose, insulin, HOMA-IR, FFA and lipid profile), neuro-inflammation (IL-23, IL-27), Wnt/β-catenin signaling, canonical (ApoE-4, Wnt5a, pS9 GSK-3β, pS675 β-catenin, pS37 β-catenin) and non-canonical (RhoA, Rac1, p-Akt ), blood brain barrier integrity markers (Annexin A1, claudin 3 and VE-cadherin), dementia hallmarks (p-Tau and Aβ protein), and gene expression of insulin and α7nACh receptors.
Treatment with VitD and/or RSV significantly hampered T2DM-induced disturbances in metabolic profile and stimulated both canonical/noncanonical Wnt/β-catenin cassettes in the hippocampus with activation of their downstream molecules. They hindered hippocampal ApoE-4 content, Tau hyperphosphorylation and Aβ deposition. The amended pathways were reflected as improved performance in Morris water maze and novel object recognition tests besides restored histological architecture.
The current study provides evidence for expanding the use of VitD and RSV against T2DM-induced cognitive and memory impairment. The study also suggests a superior benefit of combining both treatments over either drug alone

Text in English, abstracts in English and Arabic.