McFarland K, Spalding TA, Hubbard D, Ma JN, Olsson R, Burstein ES.
Low Dose Bexarotene Treatment Rescues Dopamine Neurons and Restores Behavioral Function in Models of Parkinson's Disease.
ACS Chem Neurosci. 2013 Oct 11;
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The positive effects of bexarotene treatment observed by McFarland and coworkers in the 6-hydroxydopamine Parkinson’s mouse model add to a growing body of literature that suggest pharmacological targeting of nuclear hormone receptors (NHRs), including RXRs, LXRs, and PPARs, may be beneficial in neurodegenerative diseases. Of particular interest was the fact that chronic bexarotene administration inhibited the loss of tyrosine hydroxylase-positive neurons in response to 6-OHDA challenge. This is the first report of bexarotene exerting neuroprotective effects rather than altering the clearance of proteins associated with neurodegenerative disease, such as Aβ. While the mechanism by which NHR agonists exert beneficial effects is undoubtedly complex, an intriguing component may be modulation of microglial activation in the brain. In the MPTP model of Parkinson’s disease, Dai and coworkers implicated microglial LXRβ activation as being neuroprotective of dopaminergic neurons (Dai et al., 2012). In regard to Alzheimer’s disease, Michael Heneka’s group reported that agonists of PPAR-γ increased microglial phagocytosis and degradation of soluble Aβ in vitro and in vivo (Yamanaka et al., 2012. Gary Landreth’s group reported similar effects of pioglitazone treatment and also noted that pioglitazone shifted the activation state from pro-inflammatory M1 to a more phagocytic M2 state Mandrekar-Colucci et al., 2012. It will be interesting to know whether the effects observed by McFarland and coworkers are also dependent upon microglia function. It is important to underscore that transgenic or pharmacological mouse models of neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, while useful tools, do not recapitulate the human disease. Therefore, it is critical to develop biomarkers that can validate whether NHR-regulated pathways are also relevant in the setting of the human disease.
Dai YB, Tan XJ, Wu WF, Warner M, Gustafsson JÅ.
Liver X receptor β protects dopaminergic neurons in a mouse model of Parkinson disease.
Proc Natl Acad Sci U S A. 2012 Aug 7;109(32):13112-7.
Yamanaka M, Ishikawa T, Griep A, Axt D, Kummer MP, Heneka MT.
PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice.
J Neurosci. 2012 Nov 28;32(48):17321-31.
Mandrekar-Colucci S, Karlo JC, Landreth GE.
Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease.
J Neurosci. 2012 Jul 25;32(30):10117-28.
This is a very exciting paper discussing the role of Rexinoid X Receptor (RXR) agonists in the treatment of Parkinson’s disease. Overall, at least from a conceptual point of view, McFarland et al. provide confirmatory evidence for the mechanistic role of RXR agonists in protecting the dopaminergic system.
Interestingly, in this study the investigators show that the compound may have equivalent efficacious doses lower than those that are currently used in the treatment of T-cell lymphoma. The paper would have greatly benefited from presenting more evidence of binding affinity of bexarotene for activation of Nurr1, as well as evidence that bexarotene does or does not transactivate other RXRs, including RAR, fXR, lXR, PPRγ. Bexarotene affinity for these receptors may play an important role in its efficacy and side effects. This should have been reported in this manuscript, since this issue is a major hurdle in the clinical development of RXR agonists.
We also note that Dr. Bjorklund (personal communication) found that bexarotene increases expression of the Liver X Receptor-dependent genes ApoE and ABCA1 in the model presented by McFarland. This is interesting since Dr. Gary Landreth’s group showed that bexarotene, delivered at 100mg/kg, cleared Aβ through upregulation of ApoE. Despite the present authors concluding that neuroprotective mechanisms are likely to be complex, several studies reported within the last few months were unable to reproduce the beneficial role of bexarotene in mouse models of Alzheimer’s disease.
More research on novel RXR agonists is underway, with the goal of identifying a third generation of RXR agonists with higher potency and increased affinity for selective RXR/Nurr1 transactivation.
The studies reported with low-dose bexarotene are promising and consistent with findings in preclinical Parkinson's studies we have reported at various meetings using IRX4204, a more potent and selective RXR agonist than bexarotene. IRX4204 is a clinical-stage experimental compound. It has been well tolerated as a chronic treatment in Phase 2 clinical trials by patients with various cancers. We hope IRX4204 will be safe and effective for the treatment of PD. The use of RXR agonists to treat PD has a compelling biologic rationale. RXR agonists have the potential to alter the disease course of PD through their trophic effects on dopaminergic neurons, and may play an important role in the future therapy of PD.