The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington’s Disease
| Autor: | Huu Phuc Nguyen, Magda M Melkonyan, Elisabeth Singer, Lilit Hunanyan, Lusine Danielyan, Jonasz J. Weber |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
autophagy Huntingtin huntingtin Pharmaceutical Science lcsh:Medicine lcsh:RS1-441 Article lcsh:Pharmacy and materia medica 03 medical and health sciences 0302 clinical medicine Huntington's disease Drug Discovery medicine Progenitor cell Cytotoxicity TUNEL assay Chemistry HEK 293 cells Neurodegeneration lcsh:R neurodegeneration beditin alpha-2 adrenoceptor neuronal cell survival medicine.disease Cell biology 030104 developmental biology Terminal deoxynucleotidyl transferase Molecular Medicine 030217 neurology & neurosurgery Huntington’s disease |
| Zdroj: | Pharmaceuticals Volume 14 Issue 3 Pharmaceuticals, Vol 14, Iss 257, p 257 (2021) |
| ISSN: | 1424-8247 |
| DOI: | 10.3390/ph14030257 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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