Carboxyfullerene neuroprotection postinjury in Parkinsonian nonhuman primates

Abstract

Objective We evaluated the efficacy of the potent antioxidant C3 to salvage nigrostriatal neuronal function after MPTP exposure in nonhuman primates. C3 is a first-in-class functionalized water-soluble fullerene which reduces oxygen radical species associated with neurodegeneration in in vitro studies. However, C3 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 C3 (n = 8) or placebo (n = 7) for two months starting one week after MPTP. Outcomes included in vivo behavioral measures of motor parkinsonism using a validated non-human primate rating scale, kinematic analyses of peak upper extremity velocity, PET imaging of 6-[18F]fluorodopa (FD, reflects dopa decarboxylase) and [11C]dihydrotetrabenazine (DTBZ; reflects vesicular monoamine transporter type 2), as well as ex vivo quantification of striatal dopamine (DA) and stereologic counts of tyrosine hydroxylase (TH) immunostained neurons in substantia nigra. Results After two months, C3 treated monkeys had significantly improved parkinsonian motor ratings, greater striatal FD and DTBZ uptake, and higher striatal dopamine levels. None of the C3 treated animals developed any toxicity. Interpretation Systemic treatment with C3 reduced striatal injury and improved motor function despite administration after the MPTP injury process had begun. These data strongly support further development of C3 as a promising therapeutic agent for PD.

Pharmacokinetics and Toxicology of the Neuroprotective e,e,e-Methanofullerene(60)-63-tris Malonic Acid [C3] in Mice and Primates

“…A group of 15 male M. fasciculari s monkeys (age 5–10 years) which were enrolled in a vehicle-controlled study testing C 3 in a model of Parkinson disease, using intracarotid 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP 0.25 mg/kg) injection [9], also served here as subjects to evaluate the effect of C 3 on hematology, blood chemistry, and heart function. Care was taken throughout the study to keep all investigators blinded to the treatment group.…”

“…Care was taken throughout the study to keep all investigators blinded to the treatment group. As we previously reported [9], monkeys were fasted overnight, anesthetized with ketamine, intubated and given inhaled isoflurane to maintain anesthesia. An 80 cm catheter was guided from the femoral artery into the internal carotid artery utilizing fluoroscopic guidance.…”

“…In addition, chronic oral administration of C 3 produced a modest increase in lifespan [3, 8] and prevented cognitive deficits [3] in aging mice, arguing against toxicity at therapeutic doses, even with long-term administration. In addition, chronic systemic treatment with C 3 in a non-human primate model of Parkinson’s disease for two months demonstrated significant behavioral and neuroanatomical improvement [9]. In that study, C3 treatment was started after degeneration of the nigral dopaminergic neurons was already in process.…”

Nanotechnology platforms in Parkinson’s Disease

“…In an in vitro cellular model of Parkinson's disease, significant protective effects as reflected by cell viability, mitochondrial function; levels of reactive oxygen species decreased and DNA and proteins damage were reduced with polyhydroxylated fullerenes [106]. Also, fullerenes in the form of carboxyfullerenes (C3) showed neuroprotection in Macaque fascicularis monkeys [107]. The technology leveraging the antioxidant properties of fullerenes in the treatment of Parkinson's disease is being commercialized and the leading companies involved are The Bronx Project, Inc. (TBP), Tego BioSciences Corporation (Tego) and Luna Innovations Incorporated (Luna) [108].…”

Physico-chemical properties of the water-soluble C70-tris-malonic solutions

“…Dugan et al determined that carboxy-fullerene is a first-inclass functionalized water-soluble fullerene that reduces oxygen radical species associated with neurodegeneration in in vitro studies. This fact can be used in the creation of medicinal drug against Parkinson disease [23]. Authors of [24,25] [28].…”