Pridopidine Induces Functional Neurorestoration Via the Sigma-1 Receptor in a Mouse Model of Parkinson’s Disease
Francardo, Veronica LU ; Geva, Michal ; Bez, Francesco LU ; Denis, Quentin LU ; Steiner, Lilach ; Hayden, Michael R. and Cenci, M. Angela LU
(2019)
In Neurotherapeutics
16(2).
p.465-479
- Abstract
Pridopidine is a small molecule in clinical development for the treatment of Huntington’s disease. It was recently found to have high binding affinity to the sigma-1 receptor, a chaperone protein involved in cellular defense mechanisms and neuroplasticity. Here, we have evaluated the neuroprotective and neurorestorative effects of pridopidine in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of parkinsonism in mice. By 5 weeks of daily administration, a low dose of pridopidine (0.3 mg/kg) had significantly improved deficits in forelimb use (cylinder test, stepping test) and abolished the ipsilateral rotational bias typical of hemiparkinsonian animals. A higher dose of pridopidine (1 mg/kg) significantly improved only the... (More)
Pridopidine is a small molecule in clinical development for the treatment of Huntington’s disease. It was recently found to have high binding affinity to the sigma-1 receptor, a chaperone protein involved in cellular defense mechanisms and neuroplasticity. Here, we have evaluated the neuroprotective and neurorestorative effects of pridopidine in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of parkinsonism in mice. By 5 weeks of daily administration, a low dose of pridopidine (0.3 mg/kg) had significantly improved deficits in forelimb use (cylinder test, stepping test) and abolished the ipsilateral rotational bias typical of hemiparkinsonian animals. A higher dose of pridopidine (1 mg/kg) significantly improved only the rotational bias, with a trend towards improvement in forelimb use. The behavioral recovery induced by pridopidine 0.3 mg/kg was accompanied by a significant protection of nigral dopamine cell bodies, an increased dopaminergic fiber density in the striatum, and striatal upregulation of GDNF, BDNF, and phosphorylated ERK1/2. The beneficial effects of pridopidine 0.3 mg/kg were absent in 6-OHDA-lesioned mice lacking the sigma-1 receptor. Pharmacokinetic data confirmed that the effective dose of pridopidine reached brain concentrations sufficient to bind S1R. Our results are the first to show that pridopidine promotes functional neurorestoration in the damaged nigrostriatal system acting via the sigma-1 receptor.
(Less)
- author
- Francardo, Veronica
LU
; Geva, Michal
; Bez, Francesco
LU
; Denis, Quentin
LU
; Steiner, Lilach
; Hayden, Michael R.
and Cenci, M. Angela
LU
- organization
- publishing date
- 2019-02-12
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- disease modification, endoplasmic reticulum, MAM, neuroinflammation, neuroprotection, plasticity
- in
- Neurotherapeutics
- volume
- 16
- issue
- 2
- pages
- 465 - 479
- publisher
- Springer
- external identifiers
-
- pmid:30756361
- scopus:85061478183
- ISSN
- 1933-7213
- DOI
- 10.1007/s13311-018-00699-9
- language
- English
- LU publication?
- yes
- id
- eef0b0e0-594c-417b-9983-0bcc44f61039
- date added to LUP
- 2019-02-22 09:25:25
- date last changed
- 2024-05-28 04:33:53
@article{eef0b0e0-594c-417b-9983-0bcc44f61039,
abstract = {{<p>Pridopidine is a small molecule in clinical development for the treatment of Huntington’s disease. It was recently found to have high binding affinity to the sigma-1 receptor, a chaperone protein involved in cellular defense mechanisms and neuroplasticity. Here, we have evaluated the neuroprotective and neurorestorative effects of pridopidine in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of parkinsonism in mice. By 5 weeks of daily administration, a low dose of pridopidine (0.3 mg/kg) had significantly improved deficits in forelimb use (cylinder test, stepping test) and abolished the ipsilateral rotational bias typical of hemiparkinsonian animals. A higher dose of pridopidine (1 mg/kg) significantly improved only the rotational bias, with a trend towards improvement in forelimb use. The behavioral recovery induced by pridopidine 0.3 mg/kg was accompanied by a significant protection of nigral dopamine cell bodies, an increased dopaminergic fiber density in the striatum, and striatal upregulation of GDNF, BDNF, and phosphorylated ERK1/2. The beneficial effects of pridopidine 0.3 mg/kg were absent in 6-OHDA-lesioned mice lacking the sigma-1 receptor. Pharmacokinetic data confirmed that the effective dose of pridopidine reached brain concentrations sufficient to bind S1R. Our results are the first to show that pridopidine promotes functional neurorestoration in the damaged nigrostriatal system acting via the sigma-1 receptor.</p>}},
author = {{Francardo, Veronica and Geva, Michal and Bez, Francesco and Denis, Quentin and Steiner, Lilach and Hayden, Michael R. and Cenci, M. Angela}},
issn = {{1933-7213}},
keywords = {{disease modification; endoplasmic reticulum; MAM; neuroinflammation; neuroprotection; plasticity}},
language = {{eng}},
month = {{02}},
number = {{2}},
pages = {{465--479}},
publisher = {{Springer}},
series = {{Neurotherapeutics}},
title = {{Pridopidine Induces Functional Neurorestoration Via the Sigma-1 Receptor in a Mouse Model of Parkinson’s Disease}},
url = {{http://dx.doi.org/10.1007/s13311-018-00699-9}},
doi = {{10.1007/s13311-018-00699-9}},
volume = {{16}},
year = {{2019}},
}