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

McFarland, Krista ; Spalding, Tracy A. ; Hubbard, David ; Ma, Jian-Nong ; Olsson, Roger LU and Burstein, Ethan S. (2013) In ACS Chemical Neuroscience 4(11). p.1430-1438
Abstract
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... (More)
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). (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Bexarotene, Nurr1, retinoid X receptor, dopamine neuron, behavior, Parkinson's disease
in
ACS Chemical Neuroscience
volume
4
issue
11
pages
1430 - 1438
publisher
The American Chemical Society (ACS)
external identifiers
  • wos:000327412900003
  • scopus:84888380533
  • pmid:24117438
ISSN
1948-7193
DOI
10.1021/cn400100f
language
English
LU publication?
yes
id
402be0f4-39ac-44ca-900c-e665737c02eb (old id 4274232)
date added to LUP
2016-04-01 13:54:58
date last changed
2020-01-15 04:20:15
@article{402be0f4-39ac-44ca-900c-e665737c02eb,
  abstract     = {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).},
  author       = {McFarland, Krista and Spalding, Tracy A. and Hubbard, David and Ma, Jian-Nong and Olsson, Roger and Burstein, Ethan S.},
  issn         = {1948-7193},
  language     = {eng},
  number       = {11},
  pages        = {1430--1438},
  publisher    = {The American Chemical Society (ACS)},
  series       = {ACS Chemical Neuroscience},
  title        = {Low Dose Bexarotene Treatment Rescues Dopamine Neurons and Restores Behavioral Function in Models of Parkinson's Disease},
  url          = {http://dx.doi.org/10.1021/cn400100f},
  doi          = {10.1021/cn400100f},
  volume       = {4},
  year         = {2013},
}