Journal
NEUROTHERAPEUTICS
Volume 16, Issue 2, Pages 465-479Publisher
SPRINGER
DOI: 10.1007/s13311-018-00699-9
Keywords
MAM; endoplasmic reticulum; disease modification; neuroprotection; neuroinflammation; plasticity
Funding
- Swedish Governmental Funding for clinical research (ALF grant) [43301]
- Swedish Parkinson Foundation
- Swedish Research Council
- TEVA Pharmaceutical Industries
Ask authors/readers for more resources
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 5weeks of daily administration, a low dose of pridopidine (0.3mg/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 (1mg/kg) significantly improved only the rotational bias, with a trend towards improvement in forelimb use. The behavioral recovery induced by pridopidine 0.3mg/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 0.3mg/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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available