Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Multiple Sclerosis is a chronic inflammatory neurodegenerative disease of the central nervous system which injures the myelin sheath.Telmisartan and nifedipine are antihypertensive drugs that recently showed neuroprotective properties against neurodegenerative diseases.This study evaluated the neuroprotective effect of telmisartan or nifedipine in cuprizone-induced demyelination in mice with examining the underlying mechanisms. C5B7/6 mice received a diet containing 0.7% (w/w) cuprizone for 7 days followed by 3 weeks on 0.2% cuprizone diet.Telmisartan (5 mg/kg/day, p.o.) or nifidipine (5 mg/kg/day, p.o.) were given for 3 weeks starting from the second week. Telmisartan or nifidipine improved locomotor activity and enhanced motor coordination as demonstrated by open field, rotarod and grip strength tests. Furthermore, treatment with telmisartan or nifedipine resulted in the restoration of myelin basic protein mRNA and protein expression and the increase in Luxol Fast Blue-staining intensity. Telmisartan or nifedipine attenuated cuprizone-induced oxidative stress and apoptosis by decreasing brain malondialdehyde and caspase-3 along with restoring reduced glutathione and brain derived neurotrophic factor levels.Telmisartan or nifidipine exerted an anti-inflammatory effect by reducing the expression of nuclear factor kappa B (NF-mB p65) as well as proinflammatory cytokines and elevating the expression of ImB-Ü. In parallel, telmisartan or nifedipine upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and the levels of heme oxygenase-1 and NADPH quinone oxidoreductase1 enzymes. In conclusion, the current study provides evidence for the protective effect of telmisartan and nifedipine in cuprizone-induced demyelination and behavioural dysfunction in mice possibly by modulating NF-mB and Nrf2 signalling pathways

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