Q08 Potential neuroprotective effects of pridopidine in Huntington's disease

Abstract

BackgroundHuntington's disease (HD) is a neurodegenerative disorder characterised by hyperkinetic movements (chorea), cognitive and psychiatric dysfunction. The disease is caused by an expanded polyglutamine stretch in huntingtin (Htt). mHtt interferes with different cellular functions increasing susceptibility of neurons to apoptosis, which ultimately results in neurodegeneration of the striatum and cortex. Recent evidence indicates that dopamine signalling is also impaired in HD, suggesting dopaminergic circuitry may be a potential therapeutic target for this disease. The dopaminergic stabiliser pridopidine belongs to a new family of compounds known as dopidines, and is in development for treatment of motor symptoms associated with HD. In Phase IIb and III clinical trials, pridopidine has been shown to improve overall motor function in patients with HD. However, it is not known whether the molecule may exert a neuroprotective effect in brain cells.AimsTo evaluate the potential neuroprotective effect of pridopidine in HD, by investigating whether pridopidine plays a role in the regulation of molecular mechanisms essential for neuronal cell survival.MethodsWe performed in vitro experiments in mouse striatal-derived cells expressing mutant Htt (SThdh111/111) and evaluated cell survival in the presence and absence of pridopidine. SThdh111/111 cells were cultured in apoptotic conditions (serum starvation and/or quinolinic acid), in the presence or absence of pridopidine. Cell survival was detected by Annexin V staining.ResultsPreliminary results indicate that pridopidine protects cells from apoptosis and induces an increase in phosphorylation of the protein kinase ERK1/2, whose activation has been shown to be protective in several HD models.ConclusionsThese findings support the hypothesis that pridopidine exerts a neuroprotective effect in HD models and prompt us to further investigate its potential therapeutic use in HD.

Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses

“…Dopamine stabilizers show some characteristics which are not usually associated with D 2 R ligands, such as pro-cognitive actions in natural forgetting and scopolamine-induced amnesia (Nilsson and Carlsson 2013 ), neuroprotective effects in in vitro and in vivo models of Huntington’s disease (Ruiz et al 2012 ; DiPardo et al 2013 ), and increased social interaction in the MK-801 rat model of social withdrawal in schizophrenia (Rung et al 2005 ). In this context, the substantial occupancy of sigma-1R by pridopidine at 3 and 15 mg/kg, as demonstrated in the present study, is of particular interest since sigma-1R ligands have been shown to possess anti-amnesic and neuroprotective actions, efficacy against negative symptoms in schizophrenia, and positive modulatory effects on NMDA receptor activity (Maurice and Su 2009 ; Hayashi et al 2011 ; van Waarde et al 2011 ).…”

“…Based on the induction of the immediate-early gene Arc (a marker of synaptic activity) by pridopidine in prefrontal cortex, which again is not observed with other D 2 R antagonists or agonists, nondopaminergic effects of pridopidine have been postulated, which would involve an increase in cortical N -methyl-D-aspartate (NMDA) receptor activity (Ponten et al 2010 ; Waters et al 2014 ). Finally, neuroprotective effects of pridopidine and (−)-OSU6162 have recently been described in in vitro and in vivo models of Huntington’s disease (Ruiz et al 2012 ; DiPardo et al 2013 ). Taken together, the present literature findings suggest additional sites of action for pridopidine besides D 2 R, and as detailed below, we have considered the sigma-1 receptor (sigma-1R) as such an additional target.…”