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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039913-03
Application #
6619417
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Oliver, Eugene J
Project Start
2001-09-25
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2005-08-31
Support Year
3
Fiscal Year
2003
Total Cost
$404,757
Indirect Cost
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Hardt, Joshua I; Perlmutter, Joel S; Smith, Christopher J et al. (2018) Pharmacokinetics and Toxicology of the Neuroprotective e,e,e-Methanofullerene(60)-63-tris Malonic Acid [C3] in Mice and Primates. Eur J Drug Metab Pharmacokinet 43:543-554
Dugan, Laura L; Tian, LinLin; Quick, Kevin L et al. (2014) Carboxyfullerene neuroprotection postinjury in Parkinsonian nonhuman primates. Ann Neurol 76:393-402
Tabbal, Samer D; Tian, Linlin; Karimi, Morvarid et al. (2012) Low nigrostriatal reserve for motor parkinsonism in nonhuman primates. Exp Neurol 237:355-62
Gordon, Mollie; Markham, Joanne; Hartlein, Johanna M et al. (2007) Intravenous levodopa administration in humans based on a two-compartment kinetic model. J Neurosci Methods 159:300-7
Maraganore, Demetrius M; de Andrade, Mariza; Elbaz, Alexis et al. (2006) Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 296:661-70
Karimi, Morvarid; Carl, Juanita L; Loftin, Susan et al. (2006) Modified high-performance liquid chromatography with electrochemical detection method for plasma measurement of levodopa, 3-O-methyldopa, dopamine, carbidopa and 3,4-dihydroxyphenyl acetic acid. J Chromatogr B Analyt Technol Biomed Life Sci 836:120-3
Weiss, Elliott M; Hershey, Tamara; Karimi, Morvarid et al. (2006) Relative risk of spread of symptoms among the focal onset primary dystonias. Mov Disord 21:1175-81
Racette, Brad A; Good, Laura; Antenor, Jo Ann et al. (2006) [18F]FDOPA PET as an endophenotype for Parkinson's Disease linkage studies. Am J Med Genet B Neuropsychiatr Genet 141B:245-9
Perlmutter, Joel S; Mink, Jonathan W (2006) Deep brain stimulation. Annu Rev Neurosci 29:229-57
Sinha, Rashmi; Racette, Brad; Perlmutter, Joel S et al. (2005) Prevalence of parkin gene mutations and variations in idiopathic Parkinson's disease. Parkinsonism Relat Disord 11:341-7

Showing the most recent 10 out of 14 publications