Rotating minipigs: large animal model of Parkinson’s disease
based on 6-hydroxydopamine lesioning
The following abstract was presented at
Society for Neuroscience 2012 in New Orleans
For many decades the rotating 6-hydroxydopamine (6-OHDA) rat model has been important when developing new treatment strategies for Parkinson’s disease (PD). To optimize surgical techniques and therapeutic efficacy before translation to human use large animal models are, however, required as an intermediate step. With its large gyrated brain the Göttingen minipig is suitable for MRI-guided stereotactic procedures and is hereby a commendable alternative to non-human primates in translational PD research.
The aim of this study was to create a symptomatic model of PD in the Göttingen minipig by unilaterally injecting 6-OHDA into the nigrostriatal pathway, leading to rotational behavior.
Using an MRI-based stereotactic procedure, ten female Göttingen minipigs were injected with 6-OHDA in the right nigrostriatal pathway. Postoperatively the animals were injected with amphetamine and apomorphine given at various intervals, and observed for rotation and other differences in behavior. After a survival period of three months in which we performed T2-weighted MRIs in order to verify the site of the lesion, the brains were removed and immunohistochemically stained for tyrosine hydroxylase (TH), hereby visualizing the dopaminergic fibers.
The animals showed rotational motor behavior towards and away from the side of the lesion when given amphetamine and apomorphine, respectively. Not all pigs rotated with the same frequency, however, each pig showed a consistent response to the drugs. The T2-weighted MRIs showed lesions in the nigrostriatal pathway in all animals rotating. TH staining showed a marked decrease in the number of dopaminergic fibers in the substantia nigra pars compacta, the ventral tegmental area and the nigrostriatal pathway on the lesioned side.
Göttingen minipigs are susceptible to dopaminergic nerve degeneration when injected with 6-OHDA in the nigrostriatal pathway. They display a well-defined rotational response to amphetamine and apomorphine, and lesions can furthermore be verified in vivo using MRI. In the future the model will be useful in treatment studies including transplantation of stem cells, injection of viral vectors and gene therapy.
We gratefully acknowledge the work of Dora Zeidler and Michael Geneser at CFIN, Aarhus University Hospital (AUH); Albert Meier and Trine W. Mikkelsen at the Institute of Biomedicine, Aarhus University (AU) as well as Lise M. Fitting at the Department of Neurosurgery, AUH and the staff at Paaskehoejgaard, AU.