Pridopidine Reverses Phencyclidine-Induced Memory Impairment.

Kristoffer Sahlholm,Francisco Ciruela,Víctor Fernández-Dueñas,Marta Valle-León

doi:10.3389/fphar.2018.00338

Abstract

Pridopidine is in clinical trials for Huntington's disease treatment. Originally developed as a dopamine D2 receptor (D2R) ligand, pridopidine displays about 100-fold higher affinity for the sigma-1 receptor (sigma-1R). Interestingly, pridopidine slows disease progression and improves motor function in Huntington's disease model mice and, in preliminarily reports, Huntington's disease patients. The present study examined the anti-amnesic potential of pridopidine. Thus, memory impairment was produced in mice by administration of phencyclidine (PCP, 10 mg/kg/day) for 10 days, followed by 14 days' treatment with pridopidine (6 mg/kg/day), or saline. Finally, novel object recognition performance was assessed in the animals. Mice receiving PCP and saline exhibited deficits in novel object recognition, as expected, while pridopidine treatment counteracted PCP-induced memory impairment. The effect of pridopidine was attenuated by co-administration of the sigma receptor antagonist, NE-100 (10 mg/kg). Our results suggest that pridopidine exerts anti-amnesic and potentially neuroprotective actions. These data provide new insights into the therapeutic potential of pridopidine as a pro-cognitive drug.

Highlights

IntroductionPridopidine (formerly ACR16), was originally developed as a fast-dissociating, micromolar affinity dopamine D2 receptor (D2R) antagonist (Pettersson et al, 2010), showing antipsychotic-like activity in rodents with low liability to induce catalepsy (Nilsson et al, 2004; Natesan et al, 2006; Ponten et al, 2010) and pro-social effects in MK-801-treated rats (Rung et al, 2005)
Pridopidine, was originally developed as a fast-dissociating, micromolar affinity dopamine D2 receptor (D2R) antagonist (Pettersson et al, 2010), showing antipsychotic-like activity in rodents with low liability to induce catalepsy (Nilsson et al, 2004; Natesan et al, 2006; Ponten et al, 2010) and pro-social effects in MK-801-treated rats (Rung et al, 2005)
The present study aimed to investigate the ability of pridopidine to counteract novel object recognition deficits induced by subchronic PCP treatment in mice

Summary

Introduction

Pridopidine (formerly ACR16), was originally developed as a fast-dissociating, micromolar affinity dopamine D2 receptor (D2R) antagonist (Pettersson et al, 2010), showing antipsychotic-like activity in rodents with low liability to induce catalepsy (Nilsson et al, 2004; Natesan et al, 2006; Ponten et al, 2010) and pro-social effects in MK-801-treated rats (Rung et al, 2005). While showing promising effects on negative symptoms of schizophrenia in limited clinical studies (Carlsson and Carlsson, 2006), pridopidine subsequently underwent phase IIb and phase III trials in Huntington’s disease patients, where improvements in motor function were observed (de Yebenes et al, 2011; Huntington Study Group HART Investigators, 2013). Preliminary results showed a slower decline in total functional capacity in Huntington’s disease patients receiving pridopidine, suggesting a possible neuroprotective effect (Reilmann et al, 2017). Pridopidine has been found to increase brainderived neurotrophic factor (BDNF) signaling, improve motor function and extend the lifespan of Huntington’s disease model mice, and may exert Sigma-1R-dependent neuroprotective effects in neurons from such mice (Squitieri et al, 2015; Geva et al, 2016; Ryskamp et al, 2017). Neurodegenerative pathologies, including Huntington’s disease, often feature cognitive deficits and memory impairment (Tyebji and Hannan, 2017), the putative effects of pridopidine on memory function have not yet been studied

Objectives

Methods

Results

Conclusion