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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042402-09
Application #
7777248
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Sutherland, Margaret L
Project Start
2001-04-01
Project End
2013-01-31
Budget Start
2010-02-01
Budget End
2013-01-31
Support Year
9
Fiscal Year
2010
Total Cost
$352,073
Indirect Cost
Name
Pennsylvania State University
Department
Neurology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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Gilmour, Timothy P; Piallat, Brigitte; Lieu, Christopher A et al. (2011) The effect of striatal dopaminergic grafts on the neuronal activity in the substantia nigra pars reticulata and subthalamic nucleus in hemiparkinsonian rats. Brain 134:3276-89
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Gilmour, Timothy P; Subramanian, Thyagarajan (2011) Three-dimensional reconstruction of transcranial ultrasound images obtained through the temporal bone window using a helmet-mounted mechanical beam-steering device. Conf Proc IEEE Eng Med Biol Soc 2011:413-6
Gilmour, Timothy P; Subramanian, Thyagarajan (2011) Multiscale autoregressive identification of neuro-electrophysiological systems. Conf Proc IEEE Eng Med Biol Soc 2011:7071-4
Lieu, Christopher A; Kunselman, Allen R; Manyam, Bala V et al. (2010) A water extract of Mucuna pruriens provides long-term amelioration of parkinsonism with reduced risk for dyskinesias. Parkinsonism Relat Disord 16:458-65

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