Pridopidine

Pridopidine (ACR16, FR-310826, ASP-2314, Huntexil) is a specific dopamine stabilizer without no partial agonism; shows robust dose-dependent striatal D2 occupancy with ED50 of 18.99 mg/kg s.c. in vivo, shows high in vivo D2 receptor occupancy, antipsychotic-like efficacy, and low potential for motor side effects in rats.Parkinson Disease Discontinued (In Vitro) :Pridopidine, a dopamine (DA) stabilizer, Pridopidine may be a neuromodulatory agent with neuroprotective properties in Huntington disease (HD) . To clarify the neuroprotective efficacy of Pridopidine and to explore the potential underling molecular mechanism, the ability of Pridopidine is evaluated to protect cells from apoptosis and to eventually activate pro-survival targets. Administration of Pridopidine (150 μM), the most effective dose, significantly reduces apoptosis in immortalized striatal knock-in cells expressing endogenous levels of mutant Htt (STHdh111/111) and markedly enhances phosphorylation state of prosurvival kinase ERK. (In Vivo) :Pridopidine is known to act as a low affinity D2R antagonist. Pridopidine’s activity may be attributed to binding the sigma 1 receptor (S1R), an endoplasmic reticulum (ER) . To strengthen the hypothesis that the BDNF pathway is upregulated due to activation of the S1R, SD rats are treated with lower doses of Pridopidine (range 0.3-60 mg/kg), and analysed the expression of seven selected genes in the BDNF pathway by qPCR. Pridopidine doses of 3 and 15 mg/kg in rats occupy 57±2% and 85±2% of S1R, respectively, and both do not show occupancy of the D2R, as determined by in vivo PET imaging. The significant occupancy proportion of the D2R (44-66%) is observed only at a dose of 60 mg/kg. This PET study supports the conclusion that the upregulation of genes in rats treated with 15 mg/kg Pridopidine are a result of specific activation of the S1R. At 30 mg/kg, partial/low occupancy of the D2R is at levels of 22-33% (assuming linearity), and S1R is saturated. Indeed, qPCR analysis reveals that the upregulation of EGR1 (already up at 3 mg/kg), EGR2, HOMER1A, KLF5, and ARC expression are upregulated at the low 15 mg/kg dose and expression of CDNK1A and CEBPB are significantly upregulated from a low dose of 30 mg/kg (CEBPB is significantly increased at 3 mg/kg but not at 15 mg/kg) . To further confirm the beneficial effect of Pridopidine on HD motor phenotype and to elucidate whether Pridopidine may act also as neuroprotective agent, preclinical studies in R6/2 mice have been undertaken. Daily administration of Pridopidine at a dose of 5 mg/kg, the most effective dose with no adverse effects, starting at the pre-symptomatic stage at 5 weeks for 6 weeks, significantly preserves motor function and prevents the progressive and dramatic motor worsening commonly observed in R6/2 mice. The beneficial effects of Pridopidine are maintained for about 4 weeks, after which mice show a slight worsening in performing both the horizontal ladder task and the open field. In addition, according to a Kaplan-Meier survival curve analysis, Pridopidine efficiently extends lifespan in the same mice.