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Pridopidine activates neuroprotective pathways impaired in Huntington Disease

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...

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Autores principales: Geva, Michal, Kusko, Rebecca, Soares, Holly, Fowler, Kevin D., Birnberg, Tal, Barash, Steve, -Wagner, Avia Merenlender, Fine, Tania, Lysaght, Andrew, Weiner, Brian, Cha, Yoonjeong, Kolitz, Sarah, Towfic, Fadi, Orbach, Aric, Laufer, Ralph, Zeskind, Ben, Grossman, Iris, Hayden, Michael R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291233/
https://www.ncbi.nlm.nih.gov/pubmed/27466197
http://dx.doi.org/10.1093/hmg/ddw238
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author Geva, Michal
Kusko, Rebecca
Soares, Holly
Fowler, Kevin D.
Birnberg, Tal
Barash, Steve
-Wagner, Avia Merenlender
Fine, Tania
Lysaght, Andrew
Weiner, Brian
Cha, Yoonjeong
Kolitz, Sarah
Towfic, Fadi
Orbach, Aric
Laufer, Ralph
Zeskind, Ben
Grossman, Iris
Hayden, Michael R.
author_facet Geva, Michal
Kusko, Rebecca
Soares, Holly
Fowler, Kevin D.
Birnberg, Tal
Barash, Steve
-Wagner, Avia Merenlender
Fine, Tania
Lysaght, Andrew
Weiner, Brian
Cha, Yoonjeong
Kolitz, Sarah
Towfic, Fadi
Orbach, Aric
Laufer, Ralph
Zeskind, Ben
Grossman, Iris
Hayden, Michael R.
author_sort Geva, Michal
collection PubMed
description 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.
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spelling pubmed-52912332017-02-10 Pridopidine activates neuroprotective pathways impaired in Huntington Disease Geva, Michal Kusko, Rebecca Soares, Holly Fowler, Kevin D. Birnberg, Tal Barash, Steve -Wagner, Avia Merenlender Fine, Tania Lysaght, Andrew Weiner, Brian Cha, Yoonjeong Kolitz, Sarah Towfic, Fadi Orbach, Aric Laufer, Ralph Zeskind, Ben Grossman, Iris Hayden, Michael R. Hum Mol Genet Articles 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. Oxford University Press 2016-09-15 2016-07-27 /pmc/articles/PMC5291233/ /pubmed/27466197 http://dx.doi.org/10.1093/hmg/ddw238 Text en © The Author 2016. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Articles
Geva, Michal
Kusko, Rebecca
Soares, Holly
Fowler, Kevin D.
Birnberg, Tal
Barash, Steve
-Wagner, Avia Merenlender
Fine, Tania
Lysaght, Andrew
Weiner, Brian
Cha, Yoonjeong
Kolitz, Sarah
Towfic, Fadi
Orbach, Aric
Laufer, Ralph
Zeskind, Ben
Grossman, Iris
Hayden, Michael R.
Pridopidine activates neuroprotective pathways impaired in Huntington Disease
title Pridopidine activates neuroprotective pathways impaired in Huntington Disease
title_full Pridopidine activates neuroprotective pathways impaired in Huntington Disease
title_fullStr Pridopidine activates neuroprotective pathways impaired in Huntington Disease
title_full_unstemmed Pridopidine activates neuroprotective pathways impaired in Huntington Disease
title_short Pridopidine activates neuroprotective pathways impaired in Huntington Disease
title_sort pridopidine activates neuroprotective pathways impaired in huntington disease
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291233/
https://www.ncbi.nlm.nih.gov/pubmed/27466197
http://dx.doi.org/10.1093/hmg/ddw238
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