Advanced

The functional impact of the intrastriatal dopamine neuron grafts in parkinsonian rats is reduced with advancing disease

Breysse, Nathalie LU ; Carlsson, Thomas LU ; Winkler, Christian LU ; Björklund, Anders LU and Kirik, Deniz LU (2007) In Journal of Neuroscience 27(22). p.5849-5856
Abstract
Clinical trials involving intrastriatal transplants of human embryonic mesencephalic tissue have provided proof-of-principle that nigral dopamine (DA) neurons can survive and functionally integrate into the host neural circuitry. However, the degree of graft-induced symptomatic relief differs significantly between the patients. This variability has led to investigations aimed at identifying factors that could affect the clinical outcome. The extent and pattern of dopaminergic denervation in the brain may be one of the major determinants of the functional outcome after intrastriatal DA cell grafts. Here, we report that in animals subjected to an intrastriatal 6-hydroxydopamine lesion of the striatal dopaminergic afferent, the integrity of... (More)
Clinical trials involving intrastriatal transplants of human embryonic mesencephalic tissue have provided proof-of-principle that nigral dopamine (DA) neurons can survive and functionally integrate into the host neural circuitry. However, the degree of graft-induced symptomatic relief differs significantly between the patients. This variability has led to investigations aimed at identifying factors that could affect the clinical outcome. The extent and pattern of dopaminergic denervation in the brain may be one of the major determinants of the functional outcome after intrastriatal DA cell grafts. Here, we report that in animals subjected to an intrastriatal 6-hydroxydopamine lesion of the striatal dopaminergic afferent, the integrity of the host dopaminergic innervation outside the areas innervated by the graft is critical for optimal function of DA neurons placed in the striatum. Established graft-induced functional recovery, as assessed in the stepping and cylinder tests, was compromised in animals in which the dopaminergic lesion was extended to include also the medial and ventral striatum as well as the cortical and limbic DA projections. Poor clinical outcome after transplantation may, thus, at least in part, be caused by dopaminergic denervation in areas outside the graft-innervated territories, and similarly beneficial effects initially observed in patients may regress if the degeneration of the host extrastriatal DA projection systems proceeds with advancing disease. This would have two implications: first, patients with advanced disease involving the ventral striatum and/ or nonstriatal DA projections would be unlikely to respond well to intrastriatal DA grafts and, second, to retain the full benefit of the grafts, progression of the disease should be avoided by, for example, combining cell therapy with a neuroprotective approach. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Female, Dopamine: physiology, Corpus Striatum: physiology, Disease Progression, Fetal Tissue Transplantation: methods, Mesencephalon: transplantation, Neurons: physiology, Brain Tissue Transplantation: methods, Parkinson Disease, Animals, Secondary: physiopathology, Secondary: surgery, Rats, Sprague-Dawley
in
Journal of Neuroscience
volume
27
issue
22
pages
5849 - 5856
publisher
Society for Neuroscience
external identifiers
  • wos:000247048700004
  • scopus:34249801477
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.0626-07.2007
language
English
LU publication?
yes
id
4fc15351-9b88-458f-931b-358131b7b757 (old id 650792)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17537955&dopt=Abstract
date added to LUP
2007-12-11 15:58:11
date last changed
2017-02-26 04:08:16
@article{4fc15351-9b88-458f-931b-358131b7b757,
  abstract     = {Clinical trials involving intrastriatal transplants of human embryonic mesencephalic tissue have provided proof-of-principle that nigral dopamine (DA) neurons can survive and functionally integrate into the host neural circuitry. However, the degree of graft-induced symptomatic relief differs significantly between the patients. This variability has led to investigations aimed at identifying factors that could affect the clinical outcome. The extent and pattern of dopaminergic denervation in the brain may be one of the major determinants of the functional outcome after intrastriatal DA cell grafts. Here, we report that in animals subjected to an intrastriatal 6-hydroxydopamine lesion of the striatal dopaminergic afferent, the integrity of the host dopaminergic innervation outside the areas innervated by the graft is critical for optimal function of DA neurons placed in the striatum. Established graft-induced functional recovery, as assessed in the stepping and cylinder tests, was compromised in animals in which the dopaminergic lesion was extended to include also the medial and ventral striatum as well as the cortical and limbic DA projections. Poor clinical outcome after transplantation may, thus, at least in part, be caused by dopaminergic denervation in areas outside the graft-innervated territories, and similarly beneficial effects initially observed in patients may regress if the degeneration of the host extrastriatal DA projection systems proceeds with advancing disease. This would have two implications: first, patients with advanced disease involving the ventral striatum and/ or nonstriatal DA projections would be unlikely to respond well to intrastriatal DA grafts and, second, to retain the full benefit of the grafts, progression of the disease should be avoided by, for example, combining cell therapy with a neuroprotective approach.},
  author       = {Breysse, Nathalie and Carlsson, Thomas and Winkler, Christian and Björklund, Anders and Kirik, Deniz},
  issn         = {1529-2401},
  keyword      = {Female,Dopamine: physiology,Corpus Striatum: physiology,Disease Progression,Fetal Tissue Transplantation: methods,Mesencephalon: transplantation,Neurons: physiology,Brain Tissue Transplantation: methods,Parkinson Disease,Animals,Secondary: physiopathology,Secondary: surgery,Rats,Sprague-Dawley},
  language     = {eng},
  number       = {22},
  pages        = {5849--5856},
  publisher    = {Society for Neuroscience},
  series       = {Journal of Neuroscience},
  title        = {The functional impact of the intrastriatal dopamine neuron grafts in parkinsonian rats is reduced with advancing disease},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.0626-07.2007},
  volume       = {27},
  year         = {2007},
}