期刊
ANNALS OF NEUROLOGY
卷 76, 期 3, 页码 393-402出版社
WILEY-BLACKWELL
DOI: 10.1002/ana.24220
关键词
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资金
- NIH (NINDS)
- NIH (NIA) [R01NS039913, R01NS05425, R01AG033679, R21AG030320, R01NS37688, R01NS058714, RO1 NS075321]
- Larry L. Hillblom Foundation
- Selma I. Hartke bequest
- American Parkinson Disease Association (APDA) Center for Advanced PD Research at Washington University
- Greater St Louis Chapter of the APDA
- McDonnell Center for Higher Brain Function
- Barnes-Jewish Hospital Foundation
Objective: We evaluated the efficacy of the potent antioxidant C-3 to salvage nigrostriatal neuronal function after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure in nonhuman primates. C-3 is a first-in-class functionalized water-soluble fullerene that reduces oxygen radical species associated with neurodegeneration in in vitro studies. However, C-3 has not been evaluated as a neuroprotective agent in a Parkinson model in vivo. Methods: Macaque fascicularis monkeys were used in a double-blind, placebo-controlled study design. MPTP-lesioned primates were given systemic C-3 (n = 8) or placebo (n = 7) for 2 months starting 1 week after MPTP. Outcomes included in vivo behavioral measures of motor parkinsonism using a validated nonhuman primate rating scale, kinematic analyses of peak upper extremity velocity, positron emission tomography imaging of 6-[F-18]fluorodopa (FD; reflects dopa decarboxylase) and [C-11]dihydrotetrabenazine (DTBZ; reflects vesicular monoamine transporter type 2), ex vivo quantification of striatal dopamine, and stereologic counts of tyrosine hydroxylase-immunostained neurons in substantia nigra. Results: After 2 months, C-3-treated monkeys had significantly improved parkinsonian motor ratings, greater striatal FD and DTBZ uptake, and higher striatal dopamine levels. None of the C-3-treated animals developed any toxicity. Interpretation: Systemic treatment with C-3 reduced striatal injury and improved motor function despite administration after the MPTP injury process had begun. These data strongly support further development of C-3 as a promising therapeutic agent for Parkinson disease.
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