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Carboxyfullerene neuroprotection postinjury in Parkinsonian nonhuman primates
Author(s) -
Dugan Laura L.,
Tian LinLin,
Quick Kevin L.,
Hardt Josh I.,
Karimi Morvarid,
Brown Chris,
Loftin Susan,
Flores Hugh,
Moerlein Stephen M.,
Polich John,
Tabbal Samer D.,
Mink Jonathan W.,
Perlmutter Joel S.
Publication year - 2014
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24220
Subject(s) - mptp , parkinsonism , vesicular monoamine transporter , neuroprotection , dopamine , tyrosine hydroxylase , parkinson's disease , neurodegeneration , neuroscience , dopamine transporter , pharmacology , medicine , psychology , monoamine neurotransmitter , endocrinology , dopaminergic , serotonin , disease , receptor
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‐[ 18 F]fluorodopa (FD; reflects dopa decarboxylase) and [ 11 C]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. Ann Neurol 2014;76:393–402