Continuous MPTP intoxication in the göttingen minipig results in chronic parkinsonian deficits

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder, resulting from progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Neuroprotective therapies in PD are still not available, perhaps because animal models do not imitate the chronic and progressive nature of the clinical state of PD. To address this, we performed a feasibility study aimed at establishing a chronic non-primate large animal PD model in Göttingen minipigs based on continuous infusion of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Twelve female Göttingen minipigs were divided into groups of 2–4 animals and implanted with infusion pumps for continuous intramuscular MPTP delivery of 4–24 mg MPTP/day for 11 weeks. The animals showed parkinsonian symptoms with bradykinesia, rigidity, coordination and chewing difficulties. Symptoms were stable in the 12 and 18 mg MPTP/day groups, whereas the remaining groups showed partial or full behavioral recovery. Digital gait analysis, high performance liquid chromatography (HPLC) measurements and stereological counts of tyrosine hydroxylase-positive (TH+) neurons in the SNc revealed a dose-related decrease in gait velocity, striatal metabolite levels and neuron numbers with increasing doses of MPTP. No neuronal inclusions were observed, but alpha-synuclein staining intensified with increased cumulative MPTP dosages. We conclude that this large-animal model of chronic MPTP administration in Göttingen minipigs shows trends of stable parkinsonian deficits at 18 mg MPTP/day in all modalities examined. This PD model shares many of the characteristics seen in patients and, although preliminary, holds considerable promise for future pre-clinical trials of neuroprotective therapies.