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Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental parkinsonism.

Francardo, Veronica LU ; Bez, Francesco LU ; Wieloch, Tadeusz LU ; Nissbrandt, Hans; Ruscher, Karsten LU and Cenci Nilsson, Angela LU (2014) In Brain 137(Apr 22). p.1998-2014
Abstract
The sigma-1 receptor, an endoplasmic reticulum-associated molecular chaperone, is attracting great interest as a potential target for neuroprotective treatments. We provide the first evidence that pharmacological modulation of this protein produces functional neurorestoration in experimental parkinsonism. Mice with intrastriatal 6-hydroxydopamine lesions were treated daily with the selective sigma-1 receptor agonist, PRE-084, for 5 weeks. At the dose of 0.3 mg/kg/day, PRE-084 produced a gradual and significant improvement of spontaneous forelimb use. The behavioural recovery was paralleled by an increased density of dopaminergic fibres in the most denervated striatal regions, by a modest recovery of dopamine levels, and by an upregulation... (More)
The sigma-1 receptor, an endoplasmic reticulum-associated molecular chaperone, is attracting great interest as a potential target for neuroprotective treatments. We provide the first evidence that pharmacological modulation of this protein produces functional neurorestoration in experimental parkinsonism. Mice with intrastriatal 6-hydroxydopamine lesions were treated daily with the selective sigma-1 receptor agonist, PRE-084, for 5 weeks. At the dose of 0.3 mg/kg/day, PRE-084 produced a gradual and significant improvement of spontaneous forelimb use. The behavioural recovery was paralleled by an increased density of dopaminergic fibres in the most denervated striatal regions, by a modest recovery of dopamine levels, and by an upregulation of neurotrophic factors (BDNF and GDNF) and their downstream effector pathways (extracellular signal regulated kinases 1/2 and Akt). No treatment-induced behavioural-histological restoration occurred in sigma-1 receptor knockout mice subjected to 6-hydroxydopamine lesions and treated with PRE-084. Immunoreactivity for the sigma-1 receptor protein was evident in both astrocytes and neurons in the substantia nigra and the striatum, and its intracellular distribution was modulated by PRE-084 (the treatment resulted in a wider intracellular distribution of the protein). Our results suggest that sigma-1 receptor regulates endogenous defence and plasticity mechanisms in experimental parkinsonism. Boosting the activity of this protein may have disease-modifying effects in Parkinson's disease. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Brain
volume
137
issue
Apr 22
pages
1998 - 2014
publisher
Oxford University Press
external identifiers
  • pmid:24755275
  • wos:000338646800025
  • scopus:84903529679
ISSN
1460-2156
DOI
10.1093/brain/awu107
language
English
LU publication?
yes
id
86795dce-a00c-47fc-836a-83c7b6c31ce3 (old id 4429632)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24755275?dopt=Abstract
date added to LUP
2014-05-04 15:29:51
date last changed
2017-11-19 03:15:01
@article{86795dce-a00c-47fc-836a-83c7b6c31ce3,
  abstract     = {The sigma-1 receptor, an endoplasmic reticulum-associated molecular chaperone, is attracting great interest as a potential target for neuroprotective treatments. We provide the first evidence that pharmacological modulation of this protein produces functional neurorestoration in experimental parkinsonism. Mice with intrastriatal 6-hydroxydopamine lesions were treated daily with the selective sigma-1 receptor agonist, PRE-084, for 5 weeks. At the dose of 0.3 mg/kg/day, PRE-084 produced a gradual and significant improvement of spontaneous forelimb use. The behavioural recovery was paralleled by an increased density of dopaminergic fibres in the most denervated striatal regions, by a modest recovery of dopamine levels, and by an upregulation of neurotrophic factors (BDNF and GDNF) and their downstream effector pathways (extracellular signal regulated kinases 1/2 and Akt). No treatment-induced behavioural-histological restoration occurred in sigma-1 receptor knockout mice subjected to 6-hydroxydopamine lesions and treated with PRE-084. Immunoreactivity for the sigma-1 receptor protein was evident in both astrocytes and neurons in the substantia nigra and the striatum, and its intracellular distribution was modulated by PRE-084 (the treatment resulted in a wider intracellular distribution of the protein). Our results suggest that sigma-1 receptor regulates endogenous defence and plasticity mechanisms in experimental parkinsonism. Boosting the activity of this protein may have disease-modifying effects in Parkinson's disease.},
  author       = {Francardo, Veronica and Bez, Francesco and Wieloch, Tadeusz and Nissbrandt, Hans and Ruscher, Karsten and Cenci Nilsson, Angela},
  issn         = {1460-2156},
  language     = {eng},
  number       = {Apr 22},
  pages        = {1998--2014},
  publisher    = {Oxford University Press},
  series       = {Brain},
  title        = {Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental parkinsonism.},
  url          = {http://dx.doi.org/10.1093/brain/awu107},
  volume       = {137},
  year         = {2014},
}