The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington's Disease

Elisabeth Singer; Lilit Hunanyan; Magda M Melkonyan; Jonasz J Weber; Lusine Danielyan; Huu Phuc Nguyen

doi:10.3390/ph14030257

The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington's Disease

Pharmaceuticals (Basel). 2021 Mar 12;14(3):257. doi: 10.3390/ph14030257.

Authors

Elisabeth Singer^{1

2

3}, Lilit Hunanyan⁴, Magda M Melkonyan⁴, Jonasz J Weber^{1

2

3}, Lusine Danielyan^{5

6}, Huu Phuc Nguyen³

Affiliations

¹ Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
² Centre for Rare Diseases (ZSE), University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
³ Department of Human Genetics, Ruhr University Bochum, Universitaetsstrasse 150, 44801 Bochum, Germany.
⁴ Department of Medical Chemistry, Yerevan State Medical University, Yerevan 0025, Armenia.
⁵ Department of Clinical Pharmacology, University Hospital of Tuebingen, 72076 Tuebingen, Germany.
⁶ Department of Biochemistry and Neuroscience Laboratory, Yerevan State Medical University, Yerevan 0025, Armenia.

Abstract

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.

Keywords: Huntington’s disease; alpha-2 adrenoceptor; autophagy; beditin; huntingtin; neurodegeneration; neuronal cell survival.

Grants and funding

not applicable/Deutscher Akademischer Austauschdienst