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Neurotherapeutics. 2019 Apr;16(2):465-479. doi: 10.1007/s13311-018-00699-9.

Pridopidine Induces Functional Neurorestoration Via the Sigma-1 Receptor in a Mouse Model of Parkinson's Disease.

Author information

1
Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, BMC F11, Lund, Sweden.
2
Prilenia Therapeutics, Herzliya, Israel.
3
Teva Pharmaceutical Industries Global Research and Development, Netanya, Israel.
4
Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, BMC F11, Lund, Sweden. Angela.Cenci_Nilsson@med.lu.se.

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 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.

KEYWORDS:

MAM; disease modification; endoplasmic reticulum; neuroinflammation; neuroprotection; plasticity

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