title: Low dose bexarotene treatment rescues dopamine neurons and restores behavioral function in models of Parkinson's disease.
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).
authors.affiliation: ACADIA Pharmaceuticals Inc. , 11085 Torreyana Road, Suite 100, San Diego, California 92121, United States.
authors.forename: Krista
authors.initials: K
authors.lastname: McFarland
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Spalding
authors.forename: David
authors.initials: D
authors.lastname: Hubbard
authors.forename: Jian-Nong
authors.initials: JN
authors.lastname: Ma
authors.forename: Roger
authors.initials: R
authors.lastname: Olsson
authors.forename: Ethan S
authors.initials: ES
authors.lastname: Burstein
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D000077610:Bexarotene; D060807:Bioluminescence Resonance Energy Transfer Techniques / Q000379:methods*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D055104:Infusions, Subcutaneous; D007276:Injections, Intraventricular; D008297:Male; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000737:chemistry / Q000502:physiology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D061251:Primary Cell Culture; D055503:Protein Multimerization; D051381:Rats; D017207:Rats, Sprague-Dawley; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: C539884:Nr4a2 protein, rat; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene