RESCUE FROM NIGROSTRIATAL INJURY

Washington University, Saint Louis MO

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Parkinson disease (PD) affects nearly one million people in North America. Current treatment provides only symptomatic relief, but no proven intervention slows its progression. Such an intervention should be administered early in the course of the disease to minimize progressive neuronal injury, disability and its substantial economic impact. A new class of potent antioxidants, the carboxyfullerenes, has the potential to slow the progression of the disease and promote recovery since these drugs have produced significant protection from neurotoxic injuries on dopaminergic cells in vitro and recovery from nigrostriatal injury in rodent models of PD. Furthermore, these compounds appear to have minimal in vivo toxicity and can be administered systemically making them outstanding candidates for human therapy. To translate these basic discoveries into treatment, we must do the next critical step; evaluate efficacy and safety in nonhuman primates. This is essential since dosing can be markedly different between rodents and primates. Finding the proper dose for human trials may save millions of dollars on studies done with the wrong dose. To do this, we propose using unilateral intracarotid (i.c.) infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in monkeys to produce ipsilateral nigrostriatal injury and contralateral behavioral abnormalities. We hypothesize that systemic administration of carboxyfullerenes will prevent progression from early signs of nigrostriatal injury to chronic parkinsonism, reduce the severity of subsequent parkinsonism and induce recovery from neuronal injury. The C3 carboxyfullerene derivative will be chronically administered for two months in three doses to determine the most effective dose. Effectiveness will be quantified in vivo with positron emission tomographic measures of 18 Fluoro-L-DOPA [18FDOPA] uptake, behavioral measures of motor function and in vitro measures of nigrostriatal neurons with tyrosine hydroxylase immunoreactivity, cells counts and dopamine content. These studies represent the first attempt to treat nigrostriatal injury in primates with the antioxidant buckminsterfullerenes. Further, this multidisciplinary strategy provides the basis for testing other agents that may prevent progression or restore function in parkinsonism. If this strategy works, these results will provide the preliminary data for a proper trial of these promising drugs in humans.