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

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 14; no. 3; p. 257
• Main Authors: Singer, Elisabeth, Hunanyan, Lilit, Melkonyan, Magda M, Weber, Jonasz J, Danielyan, Lusine, Nguyen, Huu Phuc
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 12.03.2021; MDPI AG
• Subjects: alpha-2 adrenoceptor; autophagy; beditin; huntingtin; Huntington’s disease; neurodegeneration; autophagy; huntingtin; neurodegeneration; neuronal cell survival; Huntington’s disease; alpha-2 adrenoceptor; beditin
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph14030257

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 (ST 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.