Intranigral Transplantation in Parkinsonian Monkeys

Project: Research project

Project Details

Description

DESCRIPTION: (Adapted from the Investigator's Abstract): Recent investigations
indicate that dopaminergic (DArgic) neurons in the substantia nigra (SN)
secrete dopamine not only in their axonal terminals within the striatum but
also via their dendrites within the SN pars reticulata (SNr) and that loss of
dopamine in the SNr may have a role in the development of parkinsonism in
primates. As a corollary, restoration of both nigral and striatal dopamine
inputs may produce better recovery of function in Parkinson's disease than
restoration of dopamine inputs in the striatum alone. Therefore, the PI
proposes to examine the effects of combined DArgic fetal ventral mesencephalic
(FVM) cell transplantation into the SN and the striatum in 1-methyl-4-phenyl-1,
2, 3, 6-tetrahydropyridine (MPTP)-treated hemiparkinsonian (HP) monkeys and
compare the results with FVM transplants in the striatum or SN alone. Animals
will be periodically assessed by investigators blinded to the type of
transplantation using a behavioral battery of tests (BBT). All animals will be
treated with intracarotid MPTP injections to cause a stable HP state and
briefly treated with oral levodopa to verify responsiveness to DArgic therapy
prior to randomization into 4 equal groups (1-4). Microelectrode recordings of
neuronal activity and magnetic resonance imaging (MRI) will be used to guide
all transplantation procedures. In specific aim 1 (SA 1), group 1 animals will
receive simultaneous FVM transplants into both striatum and the SN, group 2
animals will receive striatal FVM transplants, group 3 animals will receive FVM
transplants into the SN and group 4 animals will receive "control" fetal tissue
transplants into the SN. Periodic BBT assessments and immunochemical assessment
of the transplanted animals compared across groups 1-4 will be used to test the
hypothesis that combined striatal and nigral FVM transplants ameliorates
parkinsonism to a greater extent than striatal FVM or nigral FVM transplants
alone. In SA 2, neuronal recordings will be obtained before and after tissue
transplantation from all 4 groups of animals from the SNr and the subthalamic
nucleus (STN) and compared. This experiment will examine the hypothesis that
striatal FVM transplantation will alter neuronal discharge patterns in both SNr
and in the STN, while nigral FVM transplantation will alter neuronal discharge
patterns in the SNr only. In SA 3, dopamine levels will be measured in vivo
using microdialysis before and after nigral FVM transplantation from the SN and
STN in group 3 and group 4 animals. This experiment will test the hypothesis
that nigral FVM transplants restore dopamine content in the SN but do not
effect dopamine content in the STN. These 3 experiments will objectively
evaluate the role of restoring DArgic inputs into the SN in addition to
restoring DArgic inputs into the striatum to ameliorate parkinsonian behavioral
signs in primates and will help to understand the role of SNr in the
pathophysiology of primate parkinsonism.
StatusFinished
Effective start/end date4/1/013/31/02

Funding

  • National Institute of Neurological Disorders and Stroke: $330,792.00

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