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The Neuroprotective Role of Nitric Oxide Synthase Inhibitors in in Vitro and in Vivo Models of Parkinson's Disease
註釋Nitric oxide has been linked with the neurodegenerative process in Parkinson's disease (PD). Studies in knockout mice suggest the involvement of either inducible (iNOS) or neuronal nitric oxide synthase (nNOS) and in vivo studies have reported neuroprotection with non-selective NOS inhibitors. However, the neuroprotective effect of selective iNOS or nNOS inhibition in PD has not been fully elucidated. For this reason, the aim of the studies reported in this thesis was to investigate the neuroprotective effect of nNOS or iNOS inhibitors on dopaminergic cell death in in vitro and in vivo models of cell death in Pb. -- A study on neuroblastoma cell lines with different expression levels of nNOS, showed that inhibition of nNOS by ARR17477 exhibited a neuroprotective effect against MPP+ and MG-132-induced cell death in cell lines that overexpress nNOS but not in those that endogenously express nNOS. In contrast, inhibition of iNOS by 1400W was ineffective in those cell lines following MPP+ and MG-132 treatment. To investigate whether this was due to the absence of glial cells, primary rat ventral mesencephalic (VM) cell cultures were used. Treatment of VM cell cultures with 1400W, but not ARR1477, protected dopaminergic neurones from MPP+ -induced cell death and reduced the accompanied activation of glial cells. Similarly, an in vivo study showed that 1400W but not ARR17477 protected dopaminergic neurones in the substantia nigra but not striatal dopamine depletion from 6-0HDA-induced retrograde neurodegeneration and reduced microgliamediated inflammatory response in rats. -- In conclusion, these studies showed that inhibition of iNOS but not nNOS is neuroprotective in experimental models of dopaminergic cell death suggesting iNOS as a potential target for neuroprotective strategies m PD.