Embryonic mesencephalic grafts increase levodopa‐induced forelimb hyperkinesia in parkinsonian rats

Abstract

Recent observations from clinical trials of neural grafting for Parkinson's disease (PD) have demonstrated that grafted dopamine neurons can worsen dyskinesias in some graft recipients. This deleterious side effect reveals a new challenge for neural transplantation, that of elucidating mechanisms underlying these postgraft dyskinesias. One problem facing this challenge is the availability of a cost-effective and reliable animal model in which to pursue initial investigations. In the current study, we investigated the interaction of an embryonic ventral mesencephalic (VM) dopamine (DA) neuron graft on levodopa (LD)-induced dyskinetic movements in unilaterally 6-hydroxydopamine-lesioned rats. Rats were administered LD (levodopa-carbidopa, 50:5 mg/kg) twice daily for 6 weeks after either a sham graft or VM DA graft. Although a single solid graft of embryonic DA neurons can prevent progression of some lesioned-induced behavioral abnormalities such as LD-induced rotation and dystonia, it significantly increases hyperkinetic movements of the contralateral forelimb. This differential effect of grafted neurons on abnormal behavioral profiles is reminiscent of that reported in grafted patients with PD. Data from this study illustrate important similarities between this model of parkinsonism and PD in human patients that make it suitable for initial preclinical investigations into possible mechanisms underlying postgraft aggravation of dyskinetic movements.

Validation of a New Scoring Scale for Behavioral Assessment of L-Dopa-Induced Dyskinesia in the Rat: A New Tool for Early Decision-Making in Drug Development

“…However, we designed our scale to reflect as much contrast as possible within the different levels of AIM severity to increase its sensitivity. It is worth noting that such an approach, relying on assigning a severity coefficient depending on the features of the observed behavior has been used in previous validated scales 19 .…”

“…Furthermore, the clinical assessment of LID is highly subject to the placebo effect 28 . Similarly, in rat models of dyskinesia, various rating scales were developed and validated over the last decades 14,[16][17][18][19]21 . These methods rely on direct visual observation of a limited number of behavioral subtypes including orolingual/jaw movements (easily impacted by subjectivity) but only taking into account the severity level of AIM through frequency scores 14 or amplitude scores depending on the observation of parameters easily subjectively appreciated (e.g.…”

“…Interestingly, in this latter method, the score was assigned not only based on the duration of a behavior, but also on its features, in order to better reflect LID severity 19 .…”

Graft placement and uneven pattern of reinnervation in the striatum is important for development of graft-induced dyskinesia

“…Thus, the same cellular mechanisms, possibly involving abnormal activation of striatal cells in a specific sub-region, may be involved in the initiation of these abnormal involuntary movements. The study by Steece-Collier and collaborators has provided some evidence that DA neuron grafts might induce enhanced L-DOPA-induced forelimb hyperkinesia (Steece-Collier et al, 2003). However, in their study, the L-DOPA treatment was initiated already 24 hours after the grafting procedure.…”

Effects of ex vivo transduction of mesencephalic reaggregates with bcl-2 on grafted dopamine neuron survival

“…It was originally hypothesized that postoperative exacerbation of dyskinesias was due to graft overgrowth in the striatum and a generalized hyperdopaminergic effect. However, data from both clinical trials [26] and animal studies [28,44] suggest that non-homogeneous DA fiber reinnervation is more likely causative. The percentage of grafted fetal DA neurons that survive transplantation is extremely low (5-20%), further limiting the ability of these grafted cells to provide innervation.…”