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I: Experimental therapeutics – preclinical
I12 The novel alpha-2 adrenoceptor inhibitor beditin reduces cytotoxicity and huntingtin aggregates in cell models of Huntington’s disease
  1. Elisabeth Singer-Mikosch1,2,3,
  2. Lilit Hunanyan4,
  3. Magda M Melkonyan4,
  4. Jonasz J Weber1,2,3,
  5. Lusine Danielyan5,6,
  6. Huu Phuc Nguyen3
  1. 1Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany
  2. 2Centre for Rare Diseases (ZSE), University of Tuebingen, Tuebingen, Germany
  3. 3Department of Human Genetics, Ruhr University Bochum, Bochum, Germany
  4. 4Department of Medical Chemistry, Yerevan State Medical University, Yerevan, Armenia
  5. 5Department of Clinical Pharmacology, University Hospital of Tuebingen, Tuebingen, Germany
  6. 6Department of Biochemistry and Neuroscience Laboratory, Yerevan State Medical University, Yerevan, Armenia

Abstract

Background Cellular hallmarks of Huntington Disease include aggregate formation in neurons and neuronal loss. Encouraging findings on neuroprotection in AD and PD have led us to explore the effects of a novel α2-adrenoceptor (α2A-AR) antagonist, Beditin, in HD cell models. α2-ARs have been implicated in the reduction of oxidative stress, neuroprotection and reduction of excitotoxicity.

Aim We sought to assess the neuroprotective properties of α2-AR inhibition with beditin in cell models of HD.

Methods α2A-AR levels were assessed in cell models of HD and brain homogenates of R6/2 mice. In STHdhQ111/Q111 cells, effects of beditin were assessed by LDH and TUNEL cytotoxicity assays. Levels of mHTT and autophagy markers were analyzed by western blot and HTT levels by TR-FRET. Aggregation was analyzed by fluorescence microscopy and filter trap in an HEK293T eGFP-exon1-fragment overexpression model.

Results/Outcome α2A-AR levels were found to be increased in STHdh Q111/Q111 cells. Beditin did not only decrease cytotoxicity in this cell line, but it also showed effects on the levels of HTT fragments. It further reduced aggregation in an overexpression cell model. mTOR independent induction of autophagy was observed, possibly contributing to the mHTT reducing effects.

Conclusion In line with findings in AD and PD, we could confirm the neuroprotective effects of α2-AR inhibition and showed a reduction of aggregates in an in vitro model. The study suggests α2-ARs as a therapeutic target in HD and pharmacological manipulation of the receptor by beditin can be used to further characterize the molecular mechanisms underlying the observed effects.

  • α2- adrenoceptor (AR) antagonist
  • huntingtin
  • aggregation
  • beditin

https://doi.org/10.1136/jnnp-2022-ehdn.238

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