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3 Acta Neurobiologiae Experimentalis

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The application of iPSCs in Parkinson’s disease

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Nielson J. J. J. , Lillethorup T. P. , Glud A. N. , Sorensen J. C. H. , Orlowski D.

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The discovery and application of induced pluripotent stem cells (iPSCs) provide a novel treatment modality for diseases, which remain incurable. Particularly, in the treatment of neurodegenerative diseases such as Parkinson’s disease (PD), iPSC‑technology holds an interesting prospect for replacement therapy. Currently, the prognostic improvement of PD is limited and relies on symptomatic treatment. However, the symptomatic dopamine‑replacement therapies lose their long‑duration responses, and novel regenerative treatment modalities are needed. Animal models have provided valuable information and identified pathogenic mechanisms underlying PD but the lack of models that recapitulate the complex pathophysiology of the disease postpones further development of novel therapeutics. This review summarizes the possible uses of iPSCs in PD and discusses the future investigations needed for iPSCs as a possible treatment of PD patients.

Direct gene transfer in the Göttingen minipig CNS using stereotaxic lentiviral microinjections

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Glud A. N. , Hedegaard C. , Nielsen M. S. , Sorensen J. C. , Bendixen C. , Jensen P. H. , Larsen K. , Bjarkam C. R.

Acta Neurobiologiae Experimentalis

2010

tom 70

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We aim to induce direct viral mediated gene transfer in the substantia nigra (SN) of the Göttingen minipig using MRI guided stereotaxic injections of lentiviral vectors encoding enhanced green fluorescent protein (EGFP). Nine female Göttingen minipigs were injected unilaterally into the SN with 6×2.5 μl lentivirus capable of transducing cells and mediating expression of recombinant EGFP. The animals were euthanized after four (n=3) or twenty weeks (n=6). Fresh brain tissue from three animals was used for PCR. The remaining six brains were cryo- or paraffin-sectioned for fluorescence, Nissl-, and immunohistochemical EGFP visualization. EGFP was seen in nigral neurons, axons, glial cells, endothelial cells, and in nigral fibers targeting the striatum. PCR-based detection confirmed the presence of the transgene in SN, whereas all other examined brain areas were negative, indicating that the immunohistochemically detected EGFP in the striatum derived from transfected nigral cells.

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

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Nielsen M. S. , Glud A. N. , Moller A. , Mogensen P. , Bender D. , Sorensen J. C. , Doudet D. , Bjarkam C. R.

Acta Neurobiologiae Experimentalis

2016

tom 76

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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.