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mTOR Inhibition Alleviates L-DOPA-Induced Dyskinesia in Parkinsonian Rats

Decressac, Mickael LU and Björklund, Anders LU (2013) In Journal of Parkinson's Disease 3(1). p.13-17
Abstract
The development of dyskinesia upon chronic L-DOPA treatment is a major complication for the management of the motor symptoms in Parkinson's disease (PD) patients. Efforts are made to understand the underlying mechanisms and identify targets for the pharmacological alleviation of dyskinesia without affecting the therapeutic effect of L-DOPA. Previous studies have shown that the mTOR pathway is hyperactive in dyskinesia as a consequence of D1 receptor hypersensitivity. We investigated the effect of the FDA-approved mTOR inhibitor Temsirolimus (CCI-779), currently used in the clinic, on the development of LID and on the severity of already established LID in hemi-parkinsonian rats. Systemic delivery of CCI-779 prevented the development of LID... (More)
The development of dyskinesia upon chronic L-DOPA treatment is a major complication for the management of the motor symptoms in Parkinson's disease (PD) patients. Efforts are made to understand the underlying mechanisms and identify targets for the pharmacological alleviation of dyskinesia without affecting the therapeutic effect of L-DOPA. Previous studies have shown that the mTOR pathway is hyperactive in dyskinesia as a consequence of D1 receptor hypersensitivity. We investigated the effect of the FDA-approved mTOR inhibitor Temsirolimus (CCI-779), currently used in the clinic, on the development of LID and on the severity of already established LID in hemi-parkinsonian rats. Systemic delivery of CCI-779 prevented the development of LID and significantly alleviated the severity of dyskinesia in L-DOPA-primed animals. This was associated with a reduced activation of the mTOR pathway in striatal medium spiny neurons. Drugs with mTOR inhibiting activity that are actively developed in cancer research may be of interest for the management of LID in PD patients. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
mTOR inhibition, dyskinesia, Parkinson's disease
in
Journal of Parkinson's Disease
volume
3
issue
1
pages
13 - 17
publisher
IOS Press
external identifiers
  • wos:000319339700002
  • scopus:84880243271
ISSN
1877-718X
DOI
10.3233/JPD-120155
language
English
LU publication?
yes
id
ea5a7176-f2da-4153-87b1-0d23da77cdb2 (old id 3931331)
date added to LUP
2013-08-01 07:39:00
date last changed
2019-04-02 01:16:10
@article{ea5a7176-f2da-4153-87b1-0d23da77cdb2,
  abstract     = {The development of dyskinesia upon chronic L-DOPA treatment is a major complication for the management of the motor symptoms in Parkinson's disease (PD) patients. Efforts are made to understand the underlying mechanisms and identify targets for the pharmacological alleviation of dyskinesia without affecting the therapeutic effect of L-DOPA. Previous studies have shown that the mTOR pathway is hyperactive in dyskinesia as a consequence of D1 receptor hypersensitivity. We investigated the effect of the FDA-approved mTOR inhibitor Temsirolimus (CCI-779), currently used in the clinic, on the development of LID and on the severity of already established LID in hemi-parkinsonian rats. Systemic delivery of CCI-779 prevented the development of LID and significantly alleviated the severity of dyskinesia in L-DOPA-primed animals. This was associated with a reduced activation of the mTOR pathway in striatal medium spiny neurons. Drugs with mTOR inhibiting activity that are actively developed in cancer research may be of interest for the management of LID in PD patients.},
  author       = {Decressac, Mickael and Björklund, Anders},
  issn         = {1877-718X},
  keyword      = {mTOR inhibition,dyskinesia,Parkinson's disease},
  language     = {eng},
  number       = {1},
  pages        = {13--17},
  publisher    = {IOS Press},
  series       = {Journal of Parkinson's Disease},
  title        = {mTOR Inhibition Alleviates L-DOPA-Induced Dyskinesia in Parkinsonian Rats},
  url          = {http://dx.doi.org/10.3233/JPD-120155},
  volume       = {3},
  year         = {2013},
}