title: Pridopidine activates neuroprotective pathways impaired in Huntington Disease.
abstract: Pridopidine has demonstrated improvement in Huntington Disease (HD) motor symptoms as measured by secondary endpoints in clinical trials. Originally described as a dopamine stabilizer, this mechanism is insufficient to explain the clinical and preclinical effects of pridopidine. This study therefore explored pridopidine's potential mechanisms of action. The effect of pridopidine versus sham treatment on genome-wide expression profiling in the rat striatum was analysed and compared to the pathological expression profile in Q175 knock-in (Q175 KI) vs Q25 WT mouse models. A broad, unbiased pathway analysis was conducted, followed by testing the enrichment of relevant pathways. Pridopidine upregulated the BDNF pathway (P = 1.73E-10), and its effect on BDNF secretion was sigma 1 receptor (S1R) dependent. Many of the same genes were independently found to be downregulated in Q175 KI mice compared to WT (5.2e-7 < P < 0.04). In addition, pridopidine treatment upregulated the glucocorticoid receptor (GR) response, D1R-associated genes and the AKT/PI3K pathway (P = 1E-10, P = 0.001, P = 0.004, respectively). Pridopidine upregulates expression of BDNF, D1R, GR and AKT/PI3K pathways, known to promote neuronal plasticity and survival, as well as reported to demonstrate therapeutic benefit in HD animal models. Activation of S1R, necessary for its effect on the BDNF pathway, represents a core component of the mode of action of pridopidine. Since the newly identified pathways are downregulated in neurodegenerative diseases, including HD, these findings suggest that pridopidine may exert neuroprotective effects beyond its role in alleviating some symptoms of HD.
authors.affiliation: Teva Pharmaceutical Industries Ltd, Petach Tikva, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Geva
authors.affiliation: Immuneering Corporation, Cambridge, MA, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kusko
authors.affiliation: Teva Pharmaceutical Industries Ltd, Petach Tikva, Israel.
authors.forename: Holly
authors.initials: H
authors.lastname: Soares
authors.affiliation: Immuneering Corporation, Cambridge, MA, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Fowler
authors.affiliation: Teva Pharmaceutical Industries Ltd, Petach Tikva, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Birnberg
authors.affiliation: Teva Pharmaceutical Industries Ltd, Petach Tikva, Israel.
authors.forename: Steve
authors.initials: S
authors.lastname: Barash
authors.affiliation: Teva Pharmaceutical Industries Ltd, Petach Tikva, Israel.
authors.forename: Avia Merenlender
authors.initials: AM
authors.lastname: -Wagner
authors.affiliation: Teva Pharmaceutical Industries Ltd, Petach Tikva, Israel.
authors.forename: Tania
authors.initials: T
authors.lastname: Fine
authors.affiliation: Immuneering Corporation, Cambridge, MA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lysaght
authors.affiliation: Immuneering Corporation, Cambridge, MA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Weiner
authors.affiliation: Immuneering Corporation, Cambridge, MA, USA.
authors.forename: Yoonjeong
authors.initials: Y
authors.lastname: Cha
authors.affiliation: Immuneering Corporation, Cambridge, MA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kolitz
authors.affiliation: Immuneering Corporation, Cambridge, MA, USA.
authors.forename: Fadi
authors.initials: F
authors.lastname: Towfic
authors.affiliation: Teva Pharmaceutical Industries Ltd, Petach Tikva, Israel.
authors.forename: Aric
authors.initials: A
authors.lastname: Orbach
authors.affiliation: Teva Pharmaceutical Industries Ltd, Petach Tikva, Israel.
authors.forename: Ralph
authors.initials: R
authors.lastname: Laufer
authors.affiliation: Immuneering Corporation, Cambridge, MA, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Zeskind
authors.affiliation: Teva Pharmaceutical Industries Ltd, Petach Tikva, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Grossman
authors.affiliation: Teva Pharmaceutical Industries Ltd, Petach Tikva, Israel Michael.Hayden@teva.co.il.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D016678:Genome; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage*; D051381:Rats; D050641:Receptors, Dopamine D5 / Q000096:biosynthesis / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D010880:Piperidines; D011965:Receptors, Glucocorticoid; D050641:Receptors, Dopamine D5; C483720:pridopidine