Abstract
Although intrastriatal transplantation of fetal cells for the treatment of Parkinson’s disease had shown encouraging results in initial open-label clinical trials, subsequent double-blind studies reported more debatable outcomes. These studies highlighted the need for greater preclinical analysis of the parameters that may influence the success of cell therapy. While much of this has focused on the cells and location of the transplants, few have attempted to replicate potentially critical patient centered factors. Of particular relevance is that patients will be under continued L-DOPA treatment prior to and following transplantation, and that typically the grafts will not be immunologically compatible with the host. The aim of this study was therefore to determine the effect of chronic L-DOPA administered during different phases of the transplantation process on the survival and function of grafts with differing degrees of immunological compatibility. To that end, unilaterally 6-OHDA lesioned rats received sham surgery, allogeneic or xenogeneic transplants, while being treated with L-DOPA before and/or after transplantation. Irrespective of the L-DOPA treatment, dopaminergic grafts improved function and reduced the onset of L-DOPA induced dyskinesia. Importantly, although L-DOPA administered post transplantation was found to have no detrimental effect on graft survival, it did significantly promote the immune response around xenogeneic transplants, despite the administration of immunosuppressive treatment (cyclosporine). This study is the first to systematically examine the effect of L-DOPA on graft tolerance, which is dependent on the donor-host compatibility. These findings emphasize the importance of using animal models that adequately represent the patient paradigm.
Highlights
There has been a longstanding debate regarding the potential toxicity of the mainstay therapy for the neurodegenerative movement disorder Parkinson’s disease (PD), L-DOPA
Both allogeneic and xenogeneic transplanted cells survived well (1675 ± 133 and 1603 ± 193 average of TH positive cell bodies respectively). These data are comparable to previous study that reported a survival of syngeneic transplanted ventral mesencephalon (VM) ranging between 0.7% and 1.5% (Steece-Collier et al, 2009; Heuer et al, 2013; Tamburrino et al, 2015)
There was no significant difference between the numbers of TH positive cell bodies in the allogeneic versus xenogeneic transplanted groups (Fig. 2a–d; F2,115 = 34.33; Sidak’s post hoc test p = 0.999)
Summary
There has been a longstanding debate regarding the potential toxicity of the mainstay therapy for the neurodegenerative movement disorder Parkinson’s disease (PD), L-DOPA. Having shown encouraging results in preclinical studies and open-label clinical trials, US-led double-blind placebo controlled studies failed to demonstrate consistent benefit from the graft (Lindvall et al, 1990a; Kordower et al, 1995; Hauser et al, 1999; Hagell and Brundin, 2001) These studies, alongside the retrospective video analysis of the London-Lund-Marburg open label study, blew the field into disarray with the discovery of motor side effects persisting after the withdrawal of L-DOPA, termed graft-induced dyskinesias (GID) (Hagell et al, 2002; Olanow, 2003). In the search to understand inconsistency in transplant efficacy and the source of the motor side effects, it is important to consider factors that are present in patients but absent in models of transplantation in PD (generally the 6-hydroxydopamine (6-OHDA) lesioned rat)
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