As humans age, a recent large PD twin study indicates that physiological and toxic factors play major roles in causing typical PD, This progressive decline of dopamine (DA) terminals seen in idiopathic PD can be closely modeled in Macaca fascicularis by a low-dose exposure to the mitochondrial toxin, MPTP, over nine to fourteen months. The PET imaging of DA terminal and MRS data from such animals provide a physiological chart of degeneration and appearance of PD signs. This data profile enables the design of an experimental paradigm for realistically determining neuroprotection and regeneration in idiopathic PD. Based on our novel findings of neurophilin (V-10, 367) prevention of MPTP-induced toxicity in mice and DA degeneration in rat, we propose to examine 2 hypotheses. First, by delivering the neurophilin in parallel with MPTP, we can substantially delay the onset of PD signs. Second, by starting neurophilin treatment after PD signs (post-MPTP paradigm) we can prevent the continued DA and physiological decline and possibly reverse the parkinsonism. This project will generate unique data about the physiology of parkinsonism. This project will generate unique data about the physiology of parkinsonism and novel neurophilin prevention and reversal of DA degeneration seen in PD.
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