Abstract
Transplantation of fetal human ventral mesencephalic (VM) dopaminergic neurons into the striatum is a promising strategy to compensate for the characteristic dopamine deficit observed in Parkinson’s disease (PD). This therapeutic approach, however, is currently limited by the high number of fetuses needed for transplantation and the poor survival and functional integration of grafted dopaminergic neurons into the host brain. Accumulating evidence indicates that contrasting inhibitory signals endowed in the central nervous system (CNS) might support neuronal regeneration. Hence, in the present study we aimed at improving survival and integration of grafted cells in the host brain by neutralizing Nogo-A, one of the most potent neurite growth inhibitors in the CNS. For that purpose, VM tissue cultures were transplanted into rats with a partial 6-hydroxydopamine (6-OHDA) lesion causing a hemi-PD model and concomitantly treated for 2 weeks with intra-ventricular infusion of neutralizing anti-Nogo-A antibodies. Motor behavior using the cylinder test was assessed prior to and after transplantation as functional outcome. At the end of the experimental period the number of dopaminergic fibers growing into the host brain, the number of surviving dopaminergic neurons in the grafts as well as graft size was examined. We found that anti-Nogo-A antibody infusion significantly improved the asymmetrical forelimb use observed after lesions as compared to controls. Importantly, a significantly three-fold higher dopaminergic fiber outgrowth from the transplants was detected in the Nogo-A antibody treated group as compared to controls. Furthermore, Nogo-A neutralization showed a tendency for increased survival of dopaminergic neurons (by two-fold) in the grafts. No significant differences were observed for graft volume and the number of dopaminergic neurons co-expressing G-protein-coupled inward rectifier potassium channel subunit two between groups. In sum, our findings support the view that neutralization of Nogo-A in the host brain may offer a novel and therapeutically meaningful intervention for cell transplantation approaches in PD.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder mainly characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) with a subsequent loss of dopamine innervation in the striatum
The analysis revealed that about 75% of the grafted tyrosine hydroxylase (TH) positive neurons co-expressed G-protein-coupled inward rectifier potassium channel subunit 2 (GIRK2), no significant differences were detected between groups (Figure 7)
The rats were transplanted with only half a ventral mesencephalon, which corresponds to a subtherapeutic treatment, since we have previously shown that transplantation of a whole ventral mesencephalon results in complete recovery (Meyer et al, 1998)
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder mainly characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) with a subsequent loss of dopamine innervation in the striatum. Numerous clinical trials showed functional improvement after transplantation of fetal human ventral mesencephalic (VM) dopaminergic neurons into the striatum of PD patients (Lindvall et al, 1989, 1990; Kordower et al, 1995; Hauser et al, 1999) even without the support of additional pharmacological treatment (Kefalopoulou et al, 2014) It became clear, that before cell replacement strategies can be used in clinical practice, the criteria for patient selection (Freed et al, 2001; Barker et al, 2013) as well as the collection, the pre-treatment and the storage of donor tissue have to be optimized and standardized (Petit et al, 2014). In line with this notion, it has been shown that mainly the dopaminergic sub-population expressing the G-protein-coupled inward rectifier potassium channel subunit 2 (GIRK2) innervate the host brain after transplantation (Mendez et al, 2005; Thompson et al, 2005; Gaillard et al, 2009; Grealish et al, 2010)
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