A drug currently under investigation as an Alzheimer’s treatment may show promise for Parkinson’s disease as well, suggests a paper in the October 11 ACS Chemical Neuroscience. Bexarotene, an approved cancer drug, made headlines in 2012 when researchers claimed it cleared Aβ plaques and improved cognition in mice modeling AD (see ARF related news story). Subsequent attempts to independently reproduce these original findings have met with mixed success (see ARF related news story). Now a new group joins the fray, reporting that bexarotene protects dopaminergic neurons and improves movement in models of Parkinson’s. What’s more, the drug seems to work differently than AD researchers had envisaged. Scientists led by Ethan Burstein of Acadia Pharmaceuticals in San Diego, California, report that the drug activates a nuclear hormone receptor called Nurr1, known to promote growth and survival of dopamine neurons. Curiously, much lower doses are needed for these effects than are typically used for cancer treatment. The authors suggest the drug could one day be used to treat PD.
Bexarotene binds the retinoic acid receptor heterodimers RXR-PPARγ and RXR-LXR, upregulating expression of ApoE. “It seems that bexarotene can also work through Nurr1 to elicit these robust neuroprotective effects,” said Gary Landreth, Case Western Reserve University, Cleveland, Ohio, who originally put the drug on the map for AD. “We and everyone else have focused on astrocyte-driven ApoE production or the microglial inflammatory reaction,” he said.
Nurr1 shields dopaminergic neurons from neurotoxicity, regulates genes needed for their trophic support, and limits brain inflammation. Mutations in the Nurr1 gene also associate with PD (see PDGene entry). Scientists have reasoned in principle that a Nurr1 activator could help treat Parkinson’s, but Nurr1 itself has no known natural agonists. It does, however, form complexes with other nuclear hormone receptors, such as RXR, suggesting that agonists of these partner receptors may indirectly modulate Nurr1 action.
To find such compounds, first author Krista McFarland and colleagues screened a library of small molecules, looking for those that interact specifically with Nurr1 complexes. The scientists found that bexarotene activated Nurr1-RXR complexes better than it did RXR homodimers. Since bexarotene is FDA-approved for use in humans, they pursued it as a potential PD therapy.
They first tested the drug in a 6-hydroxydopamine (6-OHDA)-based rat model of PD. Within three days this chemical destroyed half the dopamine neurons in the substantia nigra pars compacta, a site of neuron loss in PD. For 28 days, the researchers then administered bexarotene into the brain, under the skin, or orally. Each of these treatments prevented the motor deficits usually seen in this model, and restored the number of dopaminergic neurons to normal (see image below). Bexarotene-treated rats performed as well as wild-type controls in a cognitive test as well, outsmarting the 6-OHDA-lesioned animals in a novel object recognition task.
Reprinted with permission from McFarland et al., 2013. 2013 American Chemical Society.
The effects were dose-dependent and the drug seemed potent. As little as 1 milligram per kilogram per day delivered orally had pronounced effects, versus the 100 mg/kg/day used in rat cancer studies. “I am completely blown away by the effect sizes and the remarkable dose dependency,” Landreth told Alzforum. The average cancer patient takes about 650 mg (about 8.0 mg/kg) of bexarotene per day, a dose typically associated with side effects such as rising cholesterol and hyperthyroidism. Based on these rat studies, however, the authors estimate that PD patients would need less than a tenth of that dose (about 10–60 milligrams per day) to see benefits. Lower doses produced fewer side effects in rats, and would likely be safer in humans as well, wrote the authors.
The cognitive boosting power of low-dose bexarotene in PD models suggests that similar amounts could rescue cognition in other neurodegenerative diseases, said Rada Koldamova, University of Pittsburgh, Pennsylvania. “This study tells me we should try lower doses in our experiments with AD mouse models,” she said. It is unknown whether such small amounts would clear Aβ, she noted.
Part of the bexarotene controversy surrounds the way the drug was prepared. According to Landreth, McFarland and colleagues used the same oral formulation of bexarotene he used in the original AD mouse study; that is, suspension in oil or water and administration by gavage. This maintains the microcrystalline structure of the drug. Landreth contends that recent attempts to replicate his data fell short because researchers chose different formulations of the drug.
Interestingly, the low doses of bexarotene used in the current study bumped up expression of ApoE and ABCA1, an effect Landreth previously reported using 100-fold higher doses. Landreth said he is steadily reducing the bexarotene dose in further experiments, but has not yet gone as low as 1 mg/kg. He recently initiated a Phase 1b study of bexarotene in 12 young, healthy volunteers to examine bexarotene’s effect on Aβ production and clearance. A separate Phase 2 trial is currently underway at the Cleveland Clinic’s Lou Ruvo Center for Brain Health in Las Vegas.—Gwyneth Dickey Zakaib
- Upping Brain ApoE, Drug Treats Alzheimer's Mice
- Bexarotene Revisited: Improves Mouse Memory But No Effect on Plaques
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- Price AR, Xu G, Siemienski ZB, Smithson LA, Borchelt DR, Golde TE, Felsenstein KM. Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science. 2013 May 24;340(6135):924-d. PubMed.
- Parkinson disease: Transcription factor Nurr1 maintains dopaminergic neurons. Folia Neuropathol. 2012;50(4):322-9. PubMed.
- 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; PubMed.