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

K. Mukhida, M. Hong, G.B. Miles, T. Phillips, B.A. Baghbaderani, M. McLeod, N. Kobayashi, A. Sen, L.A. Behie, R.M. Brownstone, I. Mendez
DOI: http://dx.doi.org/10.1093/brain/awn149 2106-2126 First published online: 18 July 2008

Summary

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.

  • Parkinson's disease
  • subthalamic nucleus
  • transplantation
  • GABA
  • Abbreviations:
    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
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