Low Dose Bexarotene Treatment Rescues Dopamine Neurons and Restores Behavioral Function in Models of Parkinson's Disease
Författare
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).
Avdelning/ar
Publiceringsår
2013
Språk
Engelska
Sidor
1430-1438
Publikation/Tidskrift/Serie
ACS Chemical Neuroscience
Volym
4
Issue
11
Dokumenttyp
Artikel i tidskrift
Förlag
The American Chemical Society (ACS)
Ämne
- Neurosciences
Nyckelord
- Bexarotene
- Nurr1
- retinoid X receptor
- dopamine neuron
- behavior
- Parkinson's disease
Status
Published
Forskningsgrupp
- Chemical Biology and Therapeutics
ISBN/ISSN/Övrigt
- ISSN: 1948-7193