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

Vitamin D and rosuvastatin are two well-known drugs that mediate beneficial effects in type 2 diabetes (T2D) complications, however, their anti-neuropathic potential is still debatable. Hence, we studied the possible neurotherapeutic effect & the possible underling mechanisms. Additionally, evaluating the merit of their combination using a high fat fructose diet/streptozotocin (HFFD/STZ) T2D model. In addition to the control group, rats with T2D-associated neuropathy (6 weeks post STZ) were allocated into untreated and treated with vitamin D (cholecalciferol, 3500 IU/kg/week), rosuvastatin (10 mg/kg/day), or both. After 2 months of treatment, the therapeutic effect on small/large nerves was investigated using tail flick test, electrophysiological examination and histological evaluation, which documented that long-term use of vitamin D and/or rosuvastatin regenerated neuronal function and architecture of the sciatic nerve. These treatment regimens also decreased neuronal inflammation and apoptosis verified by inhibiting neuron content of TNF-Ü and IL-18, as well as caspase-3 activity, while augmenting Bcl-2 content. On the molecular level, vitamin D and rosuvastatin abated the protein expression of NICD1, Wnt-10Ü, Ý-catenin and TGF-Ý, while augmented the sciatic nerve content of SMAD7. These effects were associated with an upturn in the neuronal mitochondrial function (NRF-1, TFAM, mtDNA, and ATP). In conclusion, vitamin D and/or rosuvastatin abridged diabetes-induced neuropathy via turning off Notch1, Wnt-10Ü/Ý-catenin and modulating TGF-Ý/SMAD7 signaling along with enhancing mitochondrial function, effects that lessened neuronal degeneration, demyelination and fibrosis

Issued also as CD