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 parkinsoni sm is a critical step in the evaluation of drugs that might halt or sl ow progression of Parkinson's disease, In this pilot study, we gradual ly exposed 14 cynomolgus monkeys to 1-methyl-4-phenyl-1,2,3,6- tetrahy dropyridine (MPTP), at a weekly dose of 0.5 mg/kg s.c. for 10 weeks, t o determine their probability of not reaching a predetermined endpoint on a disability scale by Kaplan-Meier analysis. Four other MPTP-expos ed animals were coadministered the potent free radical scavenger -meth oxyphenyl)-1-piperazinyl]acetylamino-2,2,4,6- tetramethylindan (OPC-14 117)as a single oral daily dose of 0.6 g/kg, starting 2 weeks before M PTP initiation. The risk of reaching endpoint by week 10 was 79% and m ean time before reaching endpoint was 6 weeks. Global motor activity, recorded in a subset of animals using a portable activity monitor, dec lined following the first MPTP dose and never recovered. Several cereb rospinal fluid indices of central monoamine metabolism collected by su boccipital puncture at 0, 5, and 10 weeks, including HVA, DOPAC, and t etrahydrobiopterin but not MHPG, were found to be ''trait'' markers fo r MPTP exposure, whereas CSF DOPAC and tetrahydrobiopterin constituted potential ''state'' markers for reaching endpoint, The antioxidant OP C-14117 did not protect against MPTP-induced parkinsonism. Further att empts to validate this incremental model of neurotoxin-induced parkins onism as a predictor of patient responses to putative neuroprotective agents appear warranted.