Intranigral transplantation in Parkinsonian Monkeys

Project: Research project

Project Details

Description

Dopamine secreting heterotopic fetal ventral mesencephalic (FVM) tissue grafts into the striatum that provide synaptic
connectivity between the graft and the host have been shown to improve parkinsonism but at the risk of causing delayed
disabling dyskinesias. We have shown that dopa secreting striatal grafts of human retinal pigment epithelial cells
(hRPEC) that do not cause synaptic connectivity between the graft and the host ameliorate parkinsonism without
causing dyskinesias. Dual dopaminergic grafts into the substantianigra (SN) and the striatum may provide better
recovery of function and restoration of basal ganglia neurophysiologywith reduced risk for dyskinesias in Parkinson's
disease (PD). We propose to compare the effects of transplanting FVM grafts versus hPvPEC grafts into the SN and the
striatum and to assess the effects of such grafts on drug induced dyskinesias in animal models of PD. All animals will
be treated with levodopa to induce drug induced dyskinesias and periodically tested using a behavioral battery of tests
(BBT) to assess parkinsonism and drug induced dyskinesias. In specific aim 1 (SA1), one group of hemiparkinsonian
(HP) rats will receive FVM transplants into the SN and into the striatum and compared to HP rats that receive FVM
grafts into the striatum alone and additional control groups. In SA2, a group of HP rats will receive nigral and striatal
grafts of hRPEC while another group of HP rats will receive hRPEC grafts into the striatum alone. These 2 groups will
be compared to controls. Microelectrode recordings of neuronal activity from the basal ganglia, differences in BBT
scores and imrnunohistochernistry will be outcome measures. To further delineate basal ganglia neurophysiology during
dyskinesias and to assess the effects of dual grafts on complex motor behavior and disease progression, we propose to
test the ameliorative qualities of dopaminergic dual transplants in the MPTP treated monkey. In SA3, bilaterally
parkinsonian monkeys "primed" to have drug induced dyskinesias will receive dopaminergic dual grafts of either FVM
or hRPEC and periodically challenged with chronic levodopa exposure to assess the neurophysiological correlates of
drug induced dyskinesias. These studies will test 2 separate but linked questions regarding synaptic connectivity
between the host and the graft and the role of dual nigral and striatal dopaminergic grafts in modulating drug induced
dyskinesias. Proposed studies will better delineate the pathophysiology of PD and drug induced dyskinesias and
potentially bring us close to the ideal of complete restoration of the nigrostriatal dopaminergic pathway in PD.
StatusFinished
Effective start/end date4/1/011/31/13

Funding

  • National Institute of Neurological Disorders and Stroke: $355,629.00
  • National Institute of Neurological Disorders and Stroke: $330,792.00
  • National Institute of Neurological Disorders and Stroke: $377,825.00
  • National Institute of Neurological Disorders and Stroke: $355,629.00
  • National Institute of Neurological Disorders and Stroke: $333,000.00
  • National Institute of Neurological Disorders and Stroke: $355,629.00
  • National Institute of Neurological Disorders and Stroke: $77,550.00
  • National Institute of Neurological Disorders and Stroke: $10,524.00
  • National Institute of Neurological Disorders and Stroke: $352,073.00
  • National Institute of Neurological Disorders and Stroke: $343,588.00
  • National Institute of Neurological Disorders and Stroke: $267,750.00

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