TY - JOUR
T1 - Dyskinesias do not develop after chronic intermittent levodopa therapy in clinically hemiparkinsonian rhesus monkeys
AU - Lieu, Christopher A.
AU - Deogaonkar, Milind
AU - Bakay, Roy A.E.
AU - Subramanian, Thyagarajan
N1 - Funding Information:
Authors acknowledge the assistance from Deanna Marchionini, PhD, John M. Hoffman, MD, Marijn Brummer, PhD, Walt Hubert, PhD, Lisa Nidert, Erin Gilbert, Patrick Redman, PhD, Gary Miller, PhD and Alan Levey, MD, PhD. The authors acknowledge and thank Kathy Steece-Collier, PhD, Marina Emborg, MD, PhD, Mark Hallett, MD, Mark Nolt, PhD and Jeffrey Kordower, PhD for their suggestions and critical review of this manuscript. Funded in part by the NIH NINDS RO1NS42402 , HRSA DIBTH0632 , PA Tobacco Settlement Funds Biomedical Research Grant, PSUHMC Movement Disorders Brain Repair Fund, and NCCAM R21 AT001607 to Thyagarajan Subramanian. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions.
PY - 2011/1
Y1 - 2011/1
N2 - The stable 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hemiparkinsonian (HP) rhesus monkey model of Parkinson's disease (PD) has been frequently used to test preclinical experimental therapeutics targeted to treat patients with advanced PD who suffer from motor fluctuations and drug-induced dyskinesias. We retrospectively analyzed data from 17 stable HP rhesus monkeys treated long-term with chronic intermittent dosing of levodopa (LD) in an attempt to induce choreoathetoid and dystonic dyskinesias. Rhesus monkeys in stable HP state for greater than 6 months as confirmed by multiple blinded behavioral ratings and 18F-dopa Positron Emission Tomography (PET) were treated with optimal doses of LD to provide maximal amelioration of unilateral clinical parkinsonism without any adverse effects. Thereafter, each animal was given chronic intermittent daily challenge with doses of LD up to 700 mg/day orally or with 300 mg/kg/day parenteral injections. LD treatments failed to induce choreoathetoid and dystonic dyskinesias in these animals despite chronic intermittent high dose administration. These results suggest that the stable strictly unilateral HP rhesus monkey model of PD may not be a suitable animal model to test experimental therapeutics targeted against dyskinesias, and that bilateral parkinsonian rhesus models that readily demonstrate drug-induced dyskinesias and clinically relevant motor fluctuations are more appropriate for preclinical experimental testing of therapies designed to treat patients with advanced PD.
AB - The stable 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hemiparkinsonian (HP) rhesus monkey model of Parkinson's disease (PD) has been frequently used to test preclinical experimental therapeutics targeted to treat patients with advanced PD who suffer from motor fluctuations and drug-induced dyskinesias. We retrospectively analyzed data from 17 stable HP rhesus monkeys treated long-term with chronic intermittent dosing of levodopa (LD) in an attempt to induce choreoathetoid and dystonic dyskinesias. Rhesus monkeys in stable HP state for greater than 6 months as confirmed by multiple blinded behavioral ratings and 18F-dopa Positron Emission Tomography (PET) were treated with optimal doses of LD to provide maximal amelioration of unilateral clinical parkinsonism without any adverse effects. Thereafter, each animal was given chronic intermittent daily challenge with doses of LD up to 700 mg/day orally or with 300 mg/kg/day parenteral injections. LD treatments failed to induce choreoathetoid and dystonic dyskinesias in these animals despite chronic intermittent high dose administration. These results suggest that the stable strictly unilateral HP rhesus monkey model of PD may not be a suitable animal model to test experimental therapeutics targeted against dyskinesias, and that bilateral parkinsonian rhesus models that readily demonstrate drug-induced dyskinesias and clinically relevant motor fluctuations are more appropriate for preclinical experimental testing of therapies designed to treat patients with advanced PD.
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U2 - 10.1016/j.parkreldis.2010.10.010
DO - 10.1016/j.parkreldis.2010.10.010
M3 - Article
C2 - 21074478
AN - SCOPUS:78651100065
SN - 1353-8020
VL - 17
SP - 34
EP - 39
JO - Parkinsonism and Related Disorders
JF - Parkinsonism and Related Disorders
IS - 1
ER -