Thesis (M.Sc.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology

The study aimed to explore the possible neuroprotective effects of vitamin D3 (VitD3) and/or rosuvastatin (RSV) in type II diabetes mellitus (T2DM)-induced cognitive deficits. It investigates the crosstalk between insulin/protein kinase B (AKT)/glycogen synthase kinase 3Ý (GSK-3Ý) and the canonical/non-canonical Wnt/Ý-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), VitD3 (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, model assessment for insulin resistance, free fatty acids and lipid profile), neuro-inflammation (interleukins-23 and -27), Wnt/Ý-catenin signaling, canonical (Apolipoprotein E-4 (ApoE-4), wingless-type family member 5a, pS9 GSK-3Ý, pS675 Ý-catenin, pS37 Ý-catenin) andnon-canonical (ras homolog family member A, rac family small GTPase 1, p-Akt ), blood brain barrier integrity markers (Annexin A1, claudin-3 and vascular endothelial cadherin), dementia hallmarks (p-Tau and amyloid beta (AÝ) protein), and gene expression of insulin and alpha-7 nicotinic acetylcholine receptors Treatment with VitD3 and/or RSV significantly hampered T2DM-induced disturbances in metabolic profile and stimulated both canonical/noncanonical Wnt/Ý-catenin cassettes in the hippocampus with activation of their downstream molecules. They hindered hippocampal ApoE-4 content, Tau hyperphosphorylation and AÝ 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 VitD3 and RSV against T2DM-induced cognitive and memory impairment. The study also suggests a superior benefit of combining both treatments over either drug alone

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