Chronic exposure to MPTP as a primate model of progressive parkinsonism: a pilot study with a free radical scavenger.
The development of a validated primate model of progressive parkinsonism is a critical step in the evaluation of drugs that might halt or slow progression of Parkinson's disease. In this pilot study, we gradually exposed 14 cynomolgus monkeys to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), at a weekly dose of 0.5 mg/kg s.c. for 10 weeks, to determine their probability of not reaching a predetermined endpoint on a disability scale by Kaplan-Meier analysis. Four other MPTP-exposed animals were coadministered the potent free radical scavenger 7-hydroxy-1-[4-(3-methoxyphenyl)-1-piperazinyl]acetylamino-2,2,4,6- tetramethylindan (OPC-14117) as a single oral daily dose of 0.6 g/kg, starting 2 weeks before MPTP initiation. The risk of reaching endpoint by week 10 was 79% and mean time before reaching endpoint was 6 weeks. Global motor activity, recorded in a subset of animals using a portable activity monitor, declined following the first MPTP dose and never recovered. Several cerebrospinal fluid indices of central monoamine metabolism collected by suboccipital puncture at 0, 5, and 10 weeks, including HVA, DOPAC, and tetrahydrobiopterin but not MHPG, were found to be "trait" markers for MPTP exposure, whereas CSF DOPAC and tetrahydrobiopterin constituted potential "state" markers for reaching endpoint. The antioxidant OPC-14117 did not protect against MPTP-induced parkinsonism. Further attempts to validate this incremental model of neurotoxin-induced parkinsonism as a predictor of patient responses to putative neuroprotective agents appear warranted.
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
P J
PJ
Blanchet
S
S
Konitsiotis
K
K
Hyland
L A
LA
Arnold
K D
KD
Pettigrew
T N
TN
Chase
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015102:3,4-Dihydroxyphenylacetic Acid / Q000134:cerebrospinal fluid; D000818:Animals; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001708:Biopterins / Q000031:analogs & derivatives / Q000134:cerebrospinal fluid; D004195:Disease Models, Animal; D005260:Female; D016166:Free Radical Scavengers / Q000097:blood / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid; D007189:Indans / Q000097:blood / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000134:cerebrospinal fluid; D009043:Motor Activity / Q000187:drug effects*; D010302:Parkinson Disease, Secondary / Q000134:cerebrospinal fluid / Q000503:physiopathology*; D010865:Pilot Projects; D010879:Piperazines / Q000097:blood / Q000494:pharmacology*
D015415:Biomarkers; D016166:Free Radical Scavengers; D007189:Indans; D010879:Piperazines; D015102:3,4-Dihydroxyphenylacetic Acid; D001708:Biopterins; C074852:OPC 14117; D008734:Methoxyhydroxyphenylglycol; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C003402:sapropterin; D006719:Homovanillic Acid