Restoration of the Dopamine Transporter through Cell Therapy Improves Dyskinesia in a Rat Model of Parkinson's Disease.

D Tomas,D Stanic,W C Boon,K White,H K Chua,M Horne,Gilberto Fisone

doi:10.1371/journal.pone.0153424

Abstract

The dyskinesia of Parkinson's Disease is most likely due to excess levels of dopamine in the striatum. The mechanism may be due to aberrant synthesis but also, a deficiency or absence of the Dopamine Transporter. In this study we have examined the proposition that reinstating Dopamine Transporter expression in the striatum would reduce dyskinesia. We transplanted c17.2 cells that stably expressed the Dopamine Transporter into dyskinetic rats. There was a reduction in dyskinesia in rats that received grafts expressing the Dopamine Transporter. Strategies designed to increase Dopamine Transporter in the striatum may be useful in treating the dyskinesia associated with human Parkinson's Disease.

Highlights

The principle motor sign of Parkinson’s Disease (PD) arises because neurodegeneration of Substantia Nigra pars compacta (SNpc) neurones and their axons, results in failing dopamine (DA) neurotransmission in the dorsal striatum
This study examined whether reintroducing dopamine transporter (DAT) expression, by grafting cells that express DAT into the striatum of dyskinetic rats, would reduce dyskinesia
For this study we proposed that replacement of DAT would be effective in reducing dyskinesia as measured by AIMS scores in 6-OHDA lesioned rats treated with Levodopa

Summary

Introduction

The principle motor sign of Parkinson’s Disease (PD) arises because neurodegeneration of Substantia Nigra pars compacta (SNpc) neurones and their axons, results in failing dopamine (DA) neurotransmission in the dorsal striatum. At the onset of disease, treatment with levodopa improves motor function, but within 5 years this beneficial effect is marred by “wearing off” in about 50% of patients. “Wearing off” [1,2,3,4,5] refers to the increasingly shorter duration of efficacy of a single administration of levodopa, which eventually comes to mirror the plasma levels of levodopa [2,6]. The explanation provided for “wearing off” is that the physiological capacity to store DA, which is rapidly synthesised by Aromatic Amino Acid Decarboxylase (AADC), is eroded so that newly synthesised DA is immediately delivered into the synaptic space and is available for neurotransmission. Dyskinesia almost invariably accompanies “wearing off”, and the threshold and time-course for dyskinesia comes to parallel the anti-Parkinsonian effect of levodopa [1,7,8,9,10]

Methods

Results

Conclusion