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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050425-03
Application #
7224834
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Sieber, Beth-Anne
Project Start
2005-07-15
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
3
Fiscal Year
2007
Total Cost
$511,435
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
Tian, LinLin; Xia, Yuanxuan; Flores, Hubert P et al. (2015) Neuroimaging Analysis of the Dopamine Basis for Apathetic Behaviors in an MPTP-Lesioned Primate Model. PLoS One 10:e0132064
Liu, Hui; Jin, Hongjun; Yue, Xuyi et al. (2015) Preclinical evaluation of a promising C-11 labeled PET tracer for imaging phosphodiesterase 10A in the brain of living subject. Neuroimage 121:253-62
Perlmutter, Joel S; Norris, Scott A (2014) Neuroimaging biomarkers for Parkinson disease: facts and fantasy. Ann Neurol 76:769-83
Dugan, Laura L; Tian, LinLin; Quick, Kevin L et al. (2014) Carboxyfullerene neuroprotection postinjury in Parkinsonian nonhuman primates. Ann Neurol 76:393-402
Karimi, Morvarid; Tian, LinLin; Brown, Christopher A et al. (2013) Validation of nigrostriatal positron emission tomography measures: critical limits. Ann Neurol 73:390-6
Tabbal, Samer D; Tian, Linlin; Karimi, Morvarid et al. (2012) Low nigrostriatal reserve for motor parkinsonism in nonhuman primates. Exp Neurol 237:355-62
Tian, LinLin; Karimi, Morvarid; Loftin, Susan K et al. (2012) No differential regulation of dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) binding in a primate model of Parkinson disease. PLoS One 7:e31439
Brown, C A; Campbell, M C; Karimi, M et al. (2012) Dopamine pathway loss in nucleus accumbens and ventral tegmental area predicts apathetic behavior in MPTP-lesioned monkeys. Exp Neurol 236:190-7
Perlmutter, Joel S (2011) Expert testimony at the Food and Drug Administration: who wants the truth? Narrat Inq Bioeth 1:78-82

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