Cargando…
The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington’s Disease
Huntington’s disease (HD) is a monogenetic neurodegenerative disorder characterized by the accumulation of polyglutamine-expanded huntingtin (mHTT). There is currently no cure, and therefore disease-slowing remedies are sought to alleviate symptoms of the multifaceted disorder. Encouraging findings...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998230/ https://www.ncbi.nlm.nih.gov/pubmed/33809220 http://dx.doi.org/10.3390/ph14030257 |
_version_ | 1783670504046985216 |
---|---|
author | Singer, Elisabeth Hunanyan, Lilit Melkonyan, Magda M. Weber, Jonasz J. Danielyan, Lusine Nguyen, Huu Phuc |
author_facet | Singer, Elisabeth Hunanyan, Lilit Melkonyan, Magda M. Weber, Jonasz J. Danielyan, Lusine Nguyen, Huu Phuc |
author_sort | Singer, Elisabeth |
collection | PubMed |
description | Huntington’s disease (HD) is a monogenetic neurodegenerative disorder characterized by the accumulation of polyglutamine-expanded huntingtin (mHTT). There is currently no cure, and therefore disease-slowing remedies are sought to alleviate symptoms of the multifaceted disorder. Encouraging findings in Alzheimer’s and Parkinson’s disease on alpha-2 adrenoceptor (α2-AR) inhibition have shown neuroprotective and aggregation-reducing effects in cell and animal models. Here, we analyzed the effect of beditin, a novel α2- adrenoceptor (AR) antagonist, on cell viability and mHTT protein levels in cell models of HD using Western blot, time-resolved Foerster resonance energy transfer (TR-FRET), lactate dehydrogenase (LDH) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) cytotoxicity assays. Beditin decreases cytotoxicity, as measured by TUNEL staining and LDH release, in a neuronal progenitor cell model (STHdh cells) of HD and decreases the aggregation propensity of HTT exon 1 fragments in an overexpression model using human embryonic kidney (HEK) 293T cells. α2-AR is a promising therapeutic target for further characterization in HD models. Our data allow us to suggest beditin as a valuable candidate for the pharmaceutical manipulation of α2-AR, as it is capable of modulating neuronal cell survival and the level of mHTT. |
format | Online Article Text |
id | pubmed-7998230 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-79982302021-03-28 The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington’s Disease Singer, Elisabeth Hunanyan, Lilit Melkonyan, Magda M. Weber, Jonasz J. Danielyan, Lusine Nguyen, Huu Phuc Pharmaceuticals (Basel) Article Huntington’s disease (HD) is a monogenetic neurodegenerative disorder characterized by the accumulation of polyglutamine-expanded huntingtin (mHTT). There is currently no cure, and therefore disease-slowing remedies are sought to alleviate symptoms of the multifaceted disorder. Encouraging findings in Alzheimer’s and Parkinson’s disease on alpha-2 adrenoceptor (α2-AR) inhibition have shown neuroprotective and aggregation-reducing effects in cell and animal models. Here, we analyzed the effect of beditin, a novel α2- adrenoceptor (AR) antagonist, on cell viability and mHTT protein levels in cell models of HD using Western blot, time-resolved Foerster resonance energy transfer (TR-FRET), lactate dehydrogenase (LDH) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) cytotoxicity assays. Beditin decreases cytotoxicity, as measured by TUNEL staining and LDH release, in a neuronal progenitor cell model (STHdh cells) of HD and decreases the aggregation propensity of HTT exon 1 fragments in an overexpression model using human embryonic kidney (HEK) 293T cells. α2-AR is a promising therapeutic target for further characterization in HD models. Our data allow us to suggest beditin as a valuable candidate for the pharmaceutical manipulation of α2-AR, as it is capable of modulating neuronal cell survival and the level of mHTT. MDPI 2021-03-12 /pmc/articles/PMC7998230/ /pubmed/33809220 http://dx.doi.org/10.3390/ph14030257 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 Singer, Elisabeth Hunanyan, Lilit Melkonyan, Magda M. Weber, Jonasz J. Danielyan, Lusine Nguyen, Huu Phuc The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington’s Disease |
title | The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington’s Disease |
title_full | The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington’s Disease |
title_fullStr | The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington’s Disease |
title_full_unstemmed | The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington’s Disease |
title_short | The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington’s Disease |
title_sort | novel alpha-2 adrenoceptor inhibitor beditin reduces cytotoxicity and huntingtin aggregates in cell models of huntington’s disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998230/ https://www.ncbi.nlm.nih.gov/pubmed/33809220 http://dx.doi.org/10.3390/ph14030257 |
work_keys_str_mv | AT singerelisabeth thenovelalpha2adrenoceptorinhibitorbeditinreducescytotoxicityandhuntingtinaggregatesincellmodelsofhuntingtonsdisease AT hunanyanlilit thenovelalpha2adrenoceptorinhibitorbeditinreducescytotoxicityandhuntingtinaggregatesincellmodelsofhuntingtonsdisease AT melkonyanmagdam thenovelalpha2adrenoceptorinhibitorbeditinreducescytotoxicityandhuntingtinaggregatesincellmodelsofhuntingtonsdisease AT weberjonaszj thenovelalpha2adrenoceptorinhibitorbeditinreducescytotoxicityandhuntingtinaggregatesincellmodelsofhuntingtonsdisease AT danielyanlusine thenovelalpha2adrenoceptorinhibitorbeditinreducescytotoxicityandhuntingtinaggregatesincellmodelsofhuntingtonsdisease AT nguyenhuuphuc thenovelalpha2adrenoceptorinhibitorbeditinreducescytotoxicityandhuntingtinaggregatesincellmodelsofhuntingtonsdisease AT singerelisabeth novelalpha2adrenoceptorinhibitorbeditinreducescytotoxicityandhuntingtinaggregatesincellmodelsofhuntingtonsdisease AT hunanyanlilit novelalpha2adrenoceptorinhibitorbeditinreducescytotoxicityandhuntingtinaggregatesincellmodelsofhuntingtonsdisease AT melkonyanmagdam novelalpha2adrenoceptorinhibitorbeditinreducescytotoxicityandhuntingtinaggregatesincellmodelsofhuntingtonsdisease AT weberjonaszj novelalpha2adrenoceptorinhibitorbeditinreducescytotoxicityandhuntingtinaggregatesincellmodelsofhuntingtonsdisease AT danielyanlusine novelalpha2adrenoceptorinhibitorbeditinreducescytotoxicityandhuntingtinaggregatesincellmodelsofhuntingtonsdisease AT nguyenhuuphuc novelalpha2adrenoceptorinhibitorbeditinreducescytotoxicityandhuntingtinaggregatesincellmodelsofhuntingtonsdisease |