178-181 Implications of pathogenesis for neuroprotective therapy Current, understanding of the pathogenesis of PD implies that appropriate neuroprotective therapies aimed at reducing oxidative

or proteolytic stress, blocking the putative toxic effects of microglial activation, or promoting neuronal growth and repair, should be effective in preventing, slowing, or reversing Inhibitors,research,lifescience,medical both the underlying neurodegenerative process and the natural progression of the disease. Such therapies could include antioxidants, anti-inflammatory agents, neuronal growth factor infusions, and neural “transplant” procedures, as well as potential gene therapies and pharmacological interventions targeting enhancement of intracellular protein clearance or suppression of PCD pathways. To date, Inhibitors,research,lifescience,medical these approaches have had little success in achieving the intended outcomes. We still have no proven neuroprotective or restorative therapies that prevent, slow, or reverse the neurodegeneration or progression of PD, despite concerted efforts to develop such measures

over the past two decades.182,183 It remains uncertain, therefore, whether any of the pathogenic mechanisms proposed to date has a primary role in disease initiation, although it does seem likely that all, when present, could contribute to Inhibitors,research,lifescience,medical disease progression. This suggests that current models of the pathogenesis of PD remain incomplete. Such is the case especially for those predisposing factors that may be selective for nigral DA neurons. The roles of iron and NM, and Inhibitors,research,lifescience,medical the toxic effects of DA metabolism in SNc neurons, do not explain the similar pathology in other cell groups such as dorsal glossopharyngeus-vagus complex or the intermediolateral column of spinal cord. Various experimental strategies – including

Inhibitors,research,lifescience,medical pharmacological and gene-based therapies aimed at reducing oxidative or proteolytic stress or inflammation or reversing defective neurogenesis – do protect against genetic or toxin-induced parkinsonism in certain animal models.184 Such protection, however, often requires that the therapy has been in place at or before the time of toxic exposure or expression of toxic alleles. This may account in part for the lack of effective neuroprotective strategics in human PD, as these can only be tested in subjects if they already have the disease.182,185 Nonetheless, until we are able to intervene directly in the neurodegenerative process by blocking Phosphoprotein phosphatase one or more of the implicated pathogenic pathways, the causative role of these mechanisms in human disease will remain uncertain. Pathophysiology of motor dysfunction While the neurodegenerative process in PD affects multiple neuromodulator systems and diverse groups of Cabozantinib cost neurons at many levels of the neuraxis (Table I), the characteristic motor impairments in this disorder appear to result primarily, if not exclusively, from depletion of striatal DA caused by selective degeneration of nigrostriatal neurons.