Continuous MPTP intoxication in the Göttingen minipig results in chronic parkinsonian deficits.
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.
Department of Biomedicine, Center for Experimental Neuroscience (CENSE), Aarhus University, Aarhus, Denmark. metsloni@rm.dk.
Mette Slot
MS
Nielsen
Department of Biomedicine, Center for Experimental Neuroscience (CENSE), Aarhus University, Aarhus, Denmark; Department of Neurosurgery, Aarhus University Hospital, Aarhus, Denmark.
Andreas Nørgaard
AN
Glud
Center for Functionally Integrative Neuroscience (CFIN), Aarhus University Hospital, Aarhus, Denmark.
Arne
A
Møller
Hammel Neurocenter, Hammel, Denmark.
Poul
P
Mogensen
PET Center, Aarhus University Hospital, Aarhus, Denmark.
Dirk
D
Bender
Department of Neurosurgery, Aarhus University Hospital, Aarhus, Denmark.
Jens Christian
JC
Sørensen
Center for Functionally Integrative Neuroscience (CFIN), Aarhus University Hospital, Aarhus, Denmark.
Doris
D
Doudet
Department of Biomedicine, Center for Experimental Neuroscience (CENSE), Aarhus University, Aarhus, Denmark; Department of Neurosurgery, Aarhus University Hospital, Aarhus, Denmark.
Carsten Reidies
CR
Bjarkam
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems; D004435:Eating / Q000187:drug effects; D005260:Female; D007273:Injections, Intramuscular; D007980:Levodopa / Q000494:pharmacology / Q000627:therapeutic use; D009498:Neurotoxins / Q000008:administration & dosage* / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D012720:Severity of Illness Index; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors
D000978:Antiparkinson Agents; D009498:Neurotoxins; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine