Abstract
The current transplantation paradigm for Parkinson's disease that places foetal dopaminergic cells in the striatum neither normalizes neuronal activity in basal ganglia structures such as the substantia nigra (SN) and subthalamic nucleus (STN) nor leads to complete functional recovery. It was hypothesized that restoration of parkinsonian deficits requires inhibition of the pathological overactivity of the STN and SN in addition to restoration of dopaminergic activity in the striatum. To achieve inhibition, a multitargeted basal ganglia transplantation strategy using GABAergic cells derived from either foetal striatal primordia (FSP) cells or human neural precursor cells (hNPCs) expanded in suspension bioreactors was investigated. In hemiparkinsonian rats, transplantation of foetal rat dopaminergic cells in the striatum in conjunction with GABAergic grafts in the STN and/or SN promoted significant improvement in forelimb akinesia and motor function compared to transplantation of intrastriatal dopaminergic grafts alone or in conjunction with undifferentiated hNPCs. In culture, FSP cells exhibited neuronal electrophysiological properties. However, recordings from GABAergic hNPCs revealed limited ionic conductances and an inability to fire action potentials. Despite this, they were almost as efficacious as FSP cells in inducing functional recovery following transplantation, suggesting that such recovery may have been mediated by secretion of GABA rather than by functional integration into the host. Thus, restoration of dopaminergic activity to the striatum in concert with inhibition of the STN and SN by GABAergic grafts may be beneficial for improving clinical outcomes in patients with Parkinson's disease and potential clinical application of this strategy may be enhanced by the use of differentiated hNPCs.
Original language | English |
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Pages (from-to) | 2106-2126 |
Number of pages | 21 |
Journal | Brain |
Volume | 131 |
Issue number | 8 |
DOIs | |
Publication status | Published - Aug 2008 |
Bibliographical note
Funding Information:This project was supported by funding from the Capital Health Research Foundation (IM), Stem Cell Network (IM, LAB) and the Natural Sciences and Engineering Research Council (AS, LAB). KM was supported by fellowships from the Congress of Neurological Surgeons (Margot Anderson Foundation Fellowship in Brain Restoration Research), Dalhousie Medical Research Foundation (Clinical Research Fellowship), Parkinson Society Canada (Basic Research Fellowship) and Nova Scotia Health Research Foundation (Student Research Award) and a Killam Memorial Scholarship. The authors gratefully acknowledge the technical assistance of Alia Mukhida, Damaso Sadi, Ruperto Ulalia, Craig Moore and Dr. Amanda Wintink.
ASJC Scopus Subject Areas
- Clinical Neurology
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't