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Brain Advance Access originally published online on July 18, 2008
Brain 2008 131(8):2106-2126; doi:10.1093/brain/awn149
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A multitarget basal ganglia dopaminergic and GABAergic transplantation strategy enhances behavioural recovery in parkinsonian rats

K. Mukhida1, M. Hong1, G.B. Miles2, T. Phillips1, B.A. Baghbaderani3, M. McLeod1, N. Kobayashi1, A. Sen3, L.A. Behie3, R.M. Brownstone2 and I. Mendez1

1Cell Restoration Laboratory, 2Motor Control Laboratory, Departments of Anatomy & Neurobiology and Surgery (Neurosurgery), Dalhousie University, Halifax, Nova Scotia, Canada and 3Pharmaceutical Production Research Facility, Schulich School of Engineering, University of Calgary, Calgary, Alberta, Canada

Correspondence to: Dr I. Mendez, MD PhD, Division of Neurosurgery, Queen Elizabeth II Health Sciences Centre, Room 3806, 1796 Summer Street, Halifax, Nova Scotia B3H 3A7 E-mail: mendez{at}dal.ca

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.

Key Words: Parkinson's disease; subthalamic nucleus; transplantation; GABA

Abbreviations: ChAT, choline acetyltransferase; DARPP-32, dopamine and cyclic AMP-regulated phosphoprotein; DBS, deep brain stimulation; FSP, foetal striatal primordia; FVM, foetal ventral mesencephalic; GABA, gamma-aminobutyric acid; GFAP, glial fibrillary acidic protein; hNPCs, human neural precursor cells; MAP2, microtubule-associated protein; SN, substantia nigra; SNr, substantia nigra pars reticulata; ST, striatum; STN, subthalamic nucleus; TUJ1, β-III tubulin

Received November 30, 2007. Revised June 4, 2008. Accepted June 16, 2008.


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