A quantitative approach to developing Parkinsonian monkeys (Macaca fascicularis) with intracerebroventricular 1-methyl-4-phenylpyridinium injections

Abstract

Background: Non-human primate Parkinson's disease (PD) models are essential for PD research. The most extensively used PD monkey models are induced with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, the modeling processes of developing PD monkeys cannot be quantitatively controlled with MPTP. Therefore, a new approach to quantitatively develop chronic PD monkey models will help to advance the goals of "reduction, replacement and refinement" in animal experiments.

New method: A novel chronic PD monkey models was reported using the intracerebroventricular administration of 1-methyl-4-phenylpyridinium (MPP(+)) in Cynomolgus monkeys (Macaca fascicularis).

Results: This approach successfully produced stable and consistent PD monkeys with typical motor symptoms and pathological changes. More importantly, a sigmoidal relationship (Y=8.15801e(-0.245/x); R=0.73) was discovered between PD score (Y) and cumulative dose of MPP(+) (X). This relationship was then used to develop two additional PD monkeys under a specific time schedule (4 weeks), with planned PD scores (7) by controlling the dose and frequency of the MPP(+) administration as an independent validation of the formula.

Comparison with existing method(s): We developed Parkinsonian monkeys within controlled time frames by regulating the accumulated dose of MPP(+) intracerebroventricular administered, while limiting side effects often witnessed in models developed with the peripheral administration of MPTP, makes this model highly suitable for treatment development.

Conclusions: This novel approach provides an edge in evaluating the mechanisms of PD pathology associated with environmental toxins and novel treatment approaches as the formula developed provides a "map" to control and predict the modeling processes.

Keywords: Dopaminergic cell loss; Intracerebroventricular administration; MPP(+); Non-human primate animal model; Parkinson's disease.