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Reversal of dyskinesias in an animal model of Parkinson's disease by continuous L-DOPA delivery using rAAV vectors.

Carlsson, Thomas LU ; Winkler, Christian LU ; Burger, Corinna; Muzyczka, Nicholas; Mandel, Ronald J; Cenci Nilsson, Angela LU ; Björklund, Anders LU and Kirik, Deniz LU (2005) In Brain 128(3). p.559-569
Abstract
Dyskinesias are a major complication of long-term l-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease, and are believed to result from the intermittent and pulsatile supply of L-DOPA. Daily injections of L-DOPA can prime similar abnormal involuntary movements of the limb, orolingual and axial muscles in rats rendered parkinsonian by destruction of the nigrostriatal dopamine (DA) neurons. In this study we used 33 rats with severe nigrostriatal dopamine depletion and showed that in vivo gene transfer of the DA-synthetic enzymes tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) using recombinant adeno-associated virus vectors can provide a constant source of DOPA production locally in the striatum, at a level that... (More)
Dyskinesias are a major complication of long-term l-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease, and are believed to result from the intermittent and pulsatile supply of L-DOPA. Daily injections of L-DOPA can prime similar abnormal involuntary movements of the limb, orolingual and axial muscles in rats rendered parkinsonian by destruction of the nigrostriatal dopamine (DA) neurons. In this study we used 33 rats with severe nigrostriatal dopamine depletion and showed that in vivo gene transfer of the DA-synthetic enzymes tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) using recombinant adeno-associated virus vectors can provide a constant source of DOPA production locally in the striatum, at a level that is effective in reducing L-DOPA-induced dyskinesias by >85%, and reverse lesion-induced motor impairments. Furthermore, the abnormal expression of DeltaFosB, prodynorphin and preproenkephalin mRNA within the striatal projection neurons normally seen in dyskinetic animals was completely reversed by TH-GCH1 gene transfer. These findings form a strong basis for replacing, or supplementing, conventional systemic L-DOPA therapy by continuous intrastriatal DOPA using in vivo gene transfer in the treatment of patients with advanced Parkinson's disease. (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
dyskinesia, gene therapy, GTP cyclohydrolase 1, Parkinson's disease, tyrosine hydroxylase
in
Brain
volume
128
issue
3
pages
559 - 569
publisher
Oxford University Press
external identifiers
  • pmid:15659429
  • wos:000227127800015
  • scopus:15044365742
ISSN
1460-2156
DOI
10.1093/brain/awh374
language
English
LU publication?
yes
id
af2c7922-c5da-4c4b-bcfb-d5dd68ff3bda (old id 133040)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15659429&dopt=Abstract
date added to LUP
2007-07-11 09:59:55
date last changed
2017-08-20 03:41:11
@article{af2c7922-c5da-4c4b-bcfb-d5dd68ff3bda,
  abstract     = {Dyskinesias are a major complication of long-term l-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease, and are believed to result from the intermittent and pulsatile supply of L-DOPA. Daily injections of L-DOPA can prime similar abnormal involuntary movements of the limb, orolingual and axial muscles in rats rendered parkinsonian by destruction of the nigrostriatal dopamine (DA) neurons. In this study we used 33 rats with severe nigrostriatal dopamine depletion and showed that in vivo gene transfer of the DA-synthetic enzymes tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) using recombinant adeno-associated virus vectors can provide a constant source of DOPA production locally in the striatum, at a level that is effective in reducing L-DOPA-induced dyskinesias by >85%, and reverse lesion-induced motor impairments. Furthermore, the abnormal expression of DeltaFosB, prodynorphin and preproenkephalin mRNA within the striatal projection neurons normally seen in dyskinetic animals was completely reversed by TH-GCH1 gene transfer. These findings form a strong basis for replacing, or supplementing, conventional systemic L-DOPA therapy by continuous intrastriatal DOPA using in vivo gene transfer in the treatment of patients with advanced Parkinson's disease.},
  author       = {Carlsson, Thomas and Winkler, Christian and Burger, Corinna and Muzyczka, Nicholas and Mandel, Ronald J and Cenci Nilsson, Angela and Björklund, Anders and Kirik, Deniz},
  issn         = {1460-2156},
  keyword      = {dyskinesia,gene therapy,GTP cyclohydrolase 1,Parkinson's disease,tyrosine hydroxylase},
  language     = {eng},
  number       = {3},
  pages        = {559--569},
  publisher    = {Oxford University Press},
  series       = {Brain},
  title        = {Reversal of dyskinesias in an animal model of Parkinson's disease by continuous L-DOPA delivery using rAAV vectors.},
  url          = {http://dx.doi.org/10.1093/brain/awh374},
  volume       = {128},
  year         = {2005},
}