Pridopidine activates neuroprotective pathways impaired in Huntington Disease

摘要: Pridopidine has demonstrated improvement in Huntington Disease (HD) motor symptoms as measured by secondary endpoints clinical trials. Originally described a dopamine stabilizer, this mechanism is insufficient to explain the and preclinical effects of pridopidine. This study therefore explored pridopidine's potential mechanisms action. The effect pridopidine versus sham treatment on genome-wide expression profiling rat striatum was analysed compared pathological profile Q175 knock-in (Q175 KI) vs Q25 WT mouse models. A broad, unbiased pathway analysis conducted, followed testing enrichment relevant pathways. upregulated BDNF (P = 1.73E-10), its secretion sigma 1 receptor (S1R) dependent. Many same genes were independently found be downregulated KI mice WT (5.2e-7 < P < 0.04). In addition, glucocorticoid (GR) response, D1R-associated AKT/PI3K (P = 1E-10, P = 0.001, P = 0.004, respectively). upregulates BDNF, D1R, GR pathways, known promote neuronal plasticity survival, well reported demonstrate therapeutic benefit HD animal Activation S1R, necessary for pathway, represents core component mode action Since newly identified pathways are neurodegenerative diseases, including HD, these findings suggest that may exert neuroprotective beyond role alleviating some HD.