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).

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

“…The effect of reducing soluble Aβ levels has been confirmed by several studies, although the reduction of Aβ plaques by Targretin remains controversial. Targretin also acts to prevent loss of dopaminergic neurons and restore behavioral function in rodent models of Parkinson's disease [54] , and it relieved positive symptoms of schizophrenia in a randomized, double-blind, placebo-controlled multicenter trial [55] . Thus, RXRα-selective modulators are a class of very promising drug candidates for cancer, metabolic syndromes, and neurodegenerative disorders.…”

Toward neuroprotective treatments of Parkinson’s disease

“…Another study by Volakakis et al recently showed that bexarotene could induce expression of a subset of Nurr1 target genes, including the GDNF receptor kinase Ret (19). However, unlike the McFarland et al study (18), bexarotene failed to protect 6-OHDA-lesioned rats (19), highlighting the importance of developing more potent Nurr1:RXR heterodimer ligands. Thus, Spathis et al (6) attempted to develop novel and specific Nurr1:RXRα activators by synthesizing a series of compounds optimized using in silico docking simulations, and testing their effectiveness using a variety of assays.…”

“…Based on these findings, a potential approach to enhance Nurr1's function in PD is to activate Nurr1:RXRα heterodimers using RXR ligands. Indeed, a recent study by McFarland et al (18) demonstrated that a synthetic RXR ligand, bexarotene (a cancer drug under the name Targretin), successfully activated Nurr1's function by inducing expression of DA-specific genes, rescued mDA neurons, and reversed behavioral deficits in 6-hydroxydopamine (6-OHDA)-lesioned rats. It is important to note that in that study, bexarotene's effective concentration was 100-fold lower than that used in rodent cancer models (18).…”

“…Indeed, a recent study by McFarland et al (18) demonstrated that a synthetic RXR ligand, bexarotene (a cancer drug under the name Targretin), successfully activated Nurr1's function by inducing expression of DA-specific genes, rescued mDA neurons, and reversed behavioral deficits in 6-hydroxydopamine (6-OHDA)-lesioned rats. It is important to note that in that study, bexarotene's effective concentration was 100-fold lower than that used in rodent cancer models (18). Another study by Volakakis et al recently showed that bexarotene could induce expression of a subset of Nurr1 target genes, including the GDNF receptor kinase Ret (19).…”

Nurr1:RXRα heterodimer activation as monotherapy for Parkinson’s disease

“…Two such ligands, XCT0135908 and bexarotene (14,16), have been shown to activate Nurr1:RXRα as well as other RXRα heterodimers. Bexarotene, an approved antineoplastic agent activates RXRα heterodimers with liver X receptor (LXR), peroxisome proliferator-activated receptor gamma (PPARγ), and Nurr1, has shown promising results in animal models of Alzheimer's disease and PD (16,17), but these results have not been replicated (18,19). In vitro, XCT0135908 (14) activates Nurr1:RXRα heterodimers and RXRα:RXRα homodimers (17), but its bioavailability is unknown.…”