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:
https://lup.lub.lu.se/record/133040
- author
- Carlsson, Thomas
LU
; Winkler, Christian
LU
; Burger, Corinna
; Muzyczka, Nicholas
; Mandel, Ronald J
; Cenci Nilsson, Angela
LU
; Björklund, Anders
LU
and Kirik, Deniz
LU
- organization
- publishing date
- 2005
- 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
- 2016-04-01 12:13:47
- date last changed
- 2022-01-27 00:44:09
@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}},
keywords = {{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}},
doi = {{10.1093/brain/awh374}},
volume = {{128}},
year = {{2005}},
}