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

Research output: Contribution to journalArticle

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.

Details

Authors
Organisations
External organisations
  • Teva Pharmaceutical Industries Ltd.
  • Prilenia Therapeutics Development Ltd
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Pharmaceutical Sciences
  • Neurosciences

Keywords

  • disease modification, endoplasmic reticulum, MAM, neuroinflammation, neuroprotection, plasticity
Original languageEnglish
Pages (from-to)465-479
JournalNeurotherapeutics
Volume16
Issue number2
Early online date2019 Feb 12
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes