Abstract
Objective: Investigate the role of S1R in the mechanism of action of pridopidine.
Background: Sigma-1 receptor (S1R) is an ER chaperone protein involved in neuromodulation and neuroplasticity. Pridopidine is a selective S1R agonist small molecule currently in clinical development for Huntington disease by Teva Pharmaceuticals Ltd.
Design/Methods: Transcriptomic analysis of WT and S1R-deficient mice treated with increasing concentrations of pridopidine (0, 0.3, 3, 30, or 60 mg/kg) for 10 days. Prefrontal cortex, striatum and hippocampus tissues were collected and profiled via RNAseq.
Results: In experiments comparing vehicle-treated WT and S1R KO mice, differential expression analysis revealed significant changes across all brain regions. We identified 26 differential expression genes (DEGs) in prefrontal cortex, 18 in striatum, and 6 in hippocampus (p.adj<0.05). Several genes play a role in proteasomal and transcriptional regulation. In pridopidine-treated experiments, lowest (0.3, 3, and 30 mg/kg) doses of pridopidine induced almost no change in gene expression across the three brain regions. In contrast, we observed a significant effect of 60 mg/kg pridopidine on gene expression in WT mice: 794 cortical DEGs, 27 striatal DEGs, and 19 hippocampus DEGs (p.adj<0.05), whereas differential gene expression was nearly absent in the S1R KO mice treated with the same dose. Pathway analysis of these DEGs revealed enrichment for circadian rhythm across all three tissues along with calcium, phosphatidylinositol, and insulin signaling in the prefrontal cortex (p.adj<0.05). We also confirmed that pridopidine induces brain-derived neurotrophic factor (BDNF) and glucocorticoid receptor (GR) pathways in the striatum, as previously reported. Analyses of gene expression in S1R-deficient models showed reduced effect of 60 mg/kg pridopidine on gene expression in the striatum (3 DEGs), prefrontal cortex (1 DEG), and hippocampus (0 DEGs) (p.adj<0.05).
Conclusions: S1R is necessary for pridopidine-induced gene expression in the CNS. Consistent with previously published data, pridopidine promotes modification of the BDNF and GR pathways in the striatum.
Disclosure: Dr. Dreymann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Geva has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Ross has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceuticals Ltd. Dr. Ross has received research support from Teva Pharmaceuticals Ltd. Dr. Cha has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceuticals Ltd. Dr. Cha has received research support from Teva Pharmaceuticals Ltd. Dr. Kusko has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceuticals Ltd. Dr. Kusko has received research support from Teva Pharmaceuticals Ltd. Dr. Escalante-Chong has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceuticals Ltd. Dr. Escalante-Chong has received research support from Teva Pharmaceuticals Ltd. Dr. Zeskind has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Immuneering. Dr. Laifenfeld has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Grossman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Hayden has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries.
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