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

TLDR

Clinical trials of neural grafting for Parkinson’s disease have shown that grafted dopamine neurons can worsen dyskinesias, highlighting the need for a cost‑effective animal model to study this effect. The study aimed to examine how an embryonic ventral mesencephalic dopamine neuron graft influences levodopa‑induced dyskinesia in unilaterally 6‑hydroxydopamine‑lesioned rats. Rats received levodopa‑carbidopa (50:5 mg/kg) twice daily for six weeks after either a sham graft or a VM dopamine graft. While the graft prevented some levodopa‑induced rotations and dystonia, it markedly increased contralateral forelimb hyperkinesia, mirroring the pattern seen in grafted Parkinson’s patients and validating the model for preclinical mechanistic studies. © 2003 Movement Disorder Society.

Abstract

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. © 2003 Movement Disorder Society