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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4429632
- author
- Francardo, Veronica
LU
; Bez, Francesco
LU
; Wieloch, Tadeusz
LU
; Nissbrandt, Hans
; Ruscher, Karsten
LU
and Cenci Nilsson, Angela
LU
- organization
- publishing date
- 2014
- 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
- pmid:24755275
- 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
- 2016-04-01 10:42:18
- date last changed
- 2024-12-02 17:12:37
@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}},
doi = {{10.1093/brain/awu107}},
volume = {{137}},
year = {{2014}},
}