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Targeting GABA(C) Receptors Improves Post-Stroke Motor Recovery

Ischemic stroke remains a leading cause of disability worldwide, with limited treatment options available. This study investigates GABA(C) receptors as novel pharmacological targets for stroke recovery. The expression of ρ1 and ρ2 mRNA in mice were determined in peri-infarct tissue following phototh...

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Autores principales: van Nieuwenhuijzen, Petra S., Parker, Kim, Liao, Vivian, Houlton, Josh, Kim, Hye-Lim, Johnston, Graham A. R., Hanrahan, Jane R., Chebib, Mary, Clarkson, Andrew N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000079/
https://www.ncbi.nlm.nih.gov/pubmed/33801560
http://dx.doi.org/10.3390/brainsci11030315
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author van Nieuwenhuijzen, Petra S.
Parker, Kim
Liao, Vivian
Houlton, Josh
Kim, Hye-Lim
Johnston, Graham A. R.
Hanrahan, Jane R.
Chebib, Mary
Clarkson, Andrew N.
author_facet van Nieuwenhuijzen, Petra S.
Parker, Kim
Liao, Vivian
Houlton, Josh
Kim, Hye-Lim
Johnston, Graham A. R.
Hanrahan, Jane R.
Chebib, Mary
Clarkson, Andrew N.
author_sort van Nieuwenhuijzen, Petra S.
collection PubMed
description Ischemic stroke remains a leading cause of disability worldwide, with limited treatment options available. This study investigates GABA(C) receptors as novel pharmacological targets for stroke recovery. The expression of ρ1 and ρ2 mRNA in mice were determined in peri-infarct tissue following photothrombotic motor cortex stroke. (R)-4-amino-cyclopent-1-enyl butylphosphinic acid (R)-4-ACPBPA and (S)-4-ACPBPA were assessed using 2-elecotrode voltage electrophysiology in Xenopus laevis oocytes. Stroke mice were treated for 4 weeks with either vehicle, the α5-selective negative allosteric modulator, L655,708, or the ρ1/2 antagonists, (R)-4-ACPBPA and (S)-4-ACPBPA respectively from 3 days post-stroke. Infarct size and expression levels of GAT3 and reactive astrogliosis were determined using histochemistry and immunohistochemistry respectively, and motor function was assessed using both the grid-walking and cylinder tasks. After stroke, significant increases in ρ1 and ρ2 mRNAs were observed on day 3, with ρ2 showing a further increase on day 7. (R)- and (S)-4-ACPBPA are both potent antagonists at ρ2 and only weak inhibitors of α5β2γ2 receptors. Treatment with either L655,708, (S)-4-ACPBPA (ρ1/2 antagonist; 5 mM only), or (R)-4-ACPBPA (ρ2 antagonist; 2.5 and 5 mM) from 3 days after stroke resulted in a significant improvement in motor recovery on the grid-walking task, with L655,708 and (R)-4-ACPBPA also showing an improvement in the cylinder task. Infarct size was unaffected, and only (R)-4-ACPBPA significantly increased peri-infarct GAT3 expression and decreased the level of reactive astrogliosis. Importantly, inhibiting GABA(C) receptors affords significant improvement in motor function after stroke. Targeting the ρ-subunit could provide a novel delayed treatment option for stroke recovery.
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spelling pubmed-80000792021-03-28 Targeting GABA(C) Receptors Improves Post-Stroke Motor Recovery van Nieuwenhuijzen, Petra S. Parker, Kim Liao, Vivian Houlton, Josh Kim, Hye-Lim Johnston, Graham A. R. Hanrahan, Jane R. Chebib, Mary Clarkson, Andrew N. Brain Sci Article Ischemic stroke remains a leading cause of disability worldwide, with limited treatment options available. This study investigates GABA(C) receptors as novel pharmacological targets for stroke recovery. The expression of ρ1 and ρ2 mRNA in mice were determined in peri-infarct tissue following photothrombotic motor cortex stroke. (R)-4-amino-cyclopent-1-enyl butylphosphinic acid (R)-4-ACPBPA and (S)-4-ACPBPA were assessed using 2-elecotrode voltage electrophysiology in Xenopus laevis oocytes. Stroke mice were treated for 4 weeks with either vehicle, the α5-selective negative allosteric modulator, L655,708, or the ρ1/2 antagonists, (R)-4-ACPBPA and (S)-4-ACPBPA respectively from 3 days post-stroke. Infarct size and expression levels of GAT3 and reactive astrogliosis were determined using histochemistry and immunohistochemistry respectively, and motor function was assessed using both the grid-walking and cylinder tasks. After stroke, significant increases in ρ1 and ρ2 mRNAs were observed on day 3, with ρ2 showing a further increase on day 7. (R)- and (S)-4-ACPBPA are both potent antagonists at ρ2 and only weak inhibitors of α5β2γ2 receptors. Treatment with either L655,708, (S)-4-ACPBPA (ρ1/2 antagonist; 5 mM only), or (R)-4-ACPBPA (ρ2 antagonist; 2.5 and 5 mM) from 3 days after stroke resulted in a significant improvement in motor recovery on the grid-walking task, with L655,708 and (R)-4-ACPBPA also showing an improvement in the cylinder task. Infarct size was unaffected, and only (R)-4-ACPBPA significantly increased peri-infarct GAT3 expression and decreased the level of reactive astrogliosis. Importantly, inhibiting GABA(C) receptors affords significant improvement in motor function after stroke. Targeting the ρ-subunit could provide a novel delayed treatment option for stroke recovery. MDPI 2021-03-02 /pmc/articles/PMC8000079/ /pubmed/33801560 http://dx.doi.org/10.3390/brainsci11030315 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
van Nieuwenhuijzen, Petra S.
Parker, Kim
Liao, Vivian
Houlton, Josh
Kim, Hye-Lim
Johnston, Graham A. R.
Hanrahan, Jane R.
Chebib, Mary
Clarkson, Andrew N.
Targeting GABA(C) Receptors Improves Post-Stroke Motor Recovery
title Targeting GABA(C) Receptors Improves Post-Stroke Motor Recovery
title_full Targeting GABA(C) Receptors Improves Post-Stroke Motor Recovery
title_fullStr Targeting GABA(C) Receptors Improves Post-Stroke Motor Recovery
title_full_unstemmed Targeting GABA(C) Receptors Improves Post-Stroke Motor Recovery
title_short Targeting GABA(C) Receptors Improves Post-Stroke Motor Recovery
title_sort targeting gaba(c) receptors improves post-stroke motor recovery
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000079/
https://www.ncbi.nlm.nih.gov/pubmed/33801560
http://dx.doi.org/10.3390/brainsci11030315
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