Parkinson's disease (PD) is a neurodegenerative condition that causes substantial disability in the nearly 1 million affected people in North America. Development of a treatment that could halt or slow its progression has the potential to minimize progressive neuronal injury, thereby reducing subsequent disability and the substantial economic impact of this disease. C3, a carboxyfullerene, is a newly synthesized potent antioxidant and superoxide dismutase mimetic. Preliminary studies demonstrate that C3 provides significant protection of dopamine neurons from neurotoxic injuries in vitro and in vivo. Thus, C3 has the potential to slow progression and promote neuronal recovery in human PD. C3 also appears to have minimal in vivo toxicity and can be given systemically making it an outstanding candidate for treating people. To translate these basic discoveries into human therapy, we must evaluate safety, efficacy and dosing in monkeys since results from rodent studies may not be directly applicable for development of a treatment strategy for people. Finding the proper dose in nonhuman primates may save millions of dollars in subsequent clinical trials. We will give MPTP via unilateral intracarotid infusion to selectively damage nigrostriatal neurons and produce contralateral motor deficits. We hypothesize that subcutaneous administration of C3 will reduce the severity of subsequent parkinsonism and damage to nigrostriatal dopaminergic neurons. In this project, we will determine the most effective dose of C3. Efficacy will be quantified with behavioral measures of motor function, with in vivo measures of nigrostriatal neurons with high resolution MicroPET and [11C]DTBZ (a marker of vesicular monoamine uptake transporter - VMAT2), and with ex vivo measures of nigrostriatal dopaminergic neurons with tyrosine hydroxylase immunoreactivity, cells counts and dopamine content. This multidisciplinary strategy combines state-of-the-art neuroimaging and quantitative behavioral measures to determine whether the carboxyfullerene C3 has the potential in a primate model of PD to prevent progression, restore function or both. These studies will provide a solid foundation for a clinical trial in humans with C3 and can potentially reduce the suffering and economic burden of PD.
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