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Low Dose Bexarotene Treatment Rescues Dopamine Neurons and Restores Behavioral Function in Models of Parkinson's Disease

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Author

  • Krista McFarland
  • Tracy A. Spalding
  • David Hubbard
  • Jian-Nong Ma
  • Roger Olsson
  • Ethan S. Burstein

Summary, in English

Nurr1 is a nuclear hormone receptor (NucHR) strongly implicated in the growth, maintenance, and survival of dopaminergic neurons. Nurr1 may be unable to bind ligands directly, but it forms heterodimers with other NucHRs that do. Using bioluminescence resonance energy transfer (BRET) assays to directly monitor interactions of Nurr1 with other NucHRs, we found the cancer drug bexarotene (Targretin, also LGD1069) displayed biased interactions with Nurr1-RXR heterodimers compared with RXR-RXR homodimers. Remarkably, at doses up to 100-fold lower than those effective in rodent cancer models, bexarotene rescued dopamine neurons and reversed behavioral deficits in 6-hydroxydopamine (6-OHDA) lesioned rats. Compared to the high doses used in cancer therapy, low doses of bexarotene have significantly milder side effects including a reduced increase in plasma triglycerides and less suppression of thyroid function. On the basis of extrapolations from rat to human doses, we hypothesize that low oral doses of bexarotene may provide an effective and tolerated therapy for Parkinson's disease (PD).

Publishing year

2013

Language

English

Pages

1430-1438

Publication/Series

ACS Chemical Neuroscience

Volume

4

Issue

11

Document type

Journal article

Publisher

The American Chemical Society (ACS)

Topic

  • Neurosciences

Keywords

  • Bexarotene
  • Nurr1
  • retinoid X receptor
  • dopamine neuron
  • behavior
  • Parkinson's disease

Status

Published

Research group

  • Chemical Biology and Therapeutics

ISBN/ISSN/Other

  • ISSN: 1948-7193