Low dose bexarotene treatment rescues dopamine neurons and restores behavioral function in models of Parkinson's disease

ACS Chem Neurosci. 2013 Nov 20;4(11):1430-8. doi: 10.1021/cn400100f. Epub 2013 Oct 11.


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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Behavior, Animal / drug effects*
  • Behavior, Animal / physiology
  • Bexarotene
  • Bioluminescence Resonance Energy Transfer Techniques / methods*
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Disease Models, Animal
  • Dopaminergic Neurons / drug effects*
  • Dopaminergic Neurons / pathology
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Infusions, Subcutaneous
  • Injections, Intraventricular
  • Male
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / chemistry
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / physiology
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / pathology*
  • Parkinson Disease / physiopathology
  • Primary Cell Culture
  • Protein Multimerization
  • Rats
  • Rats, Sprague-Dawley
  • Tetrahydronaphthalenes / administration & dosage*
  • Tetrahydronaphthalenes / therapeutic use


  • Nr4a2 protein, rat
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Tetrahydronaphthalenes
  • Bexarotene