Relaunching an old drug: the potential role of bexarotene in neurodegenerative diseases

Vitamin A (retinol) and its derivatives (retinoids) play an important role in embryonic development, cellular differentiation, programmed cell death, and in other vital cellular functions. These substances exert their effects throughout the activation of their nuclear receptors. There are two main families of retinoid receptors, the retinoid acid receptors (RAR) and the retinoid X receptors (RXR) [1]. Retinoid agonists bound to RXR regulate gene transcription resulting in chromatin remodelling and transcriptional regulation of their target genes, some of them involved in protein metabolism, intracellular signalling, synaptic homeostasis, inflammation, programmed cell death, and other vital cellular functions [2]. Since protein metabolism disruption, synaptic alterations, or astroglial response are important events in the pathogenesis of neurodegeneration, several authors have hypothesized that retinoids could be useful in neurodegenerative disorders. Bexarotene (Bxt) is the only FDA approved RXR agonist. This drug is currently being used in the clinic for treating cutaneous lymphoma with a favourable safety profile [3]. For the last 3 years, this drug has been tested in different neurodegenerative diseases, comprising Alzheimeŕs disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) with promising results (Table 1). First, Cramer et al. [4] tested this drug in a murine model of AD demonstrating a marked reduction in both soluble amyloid beta (Ab) and Ab plaques that correlated with a rapid reversal of cognitive, social, and other functional capabilities. The authors showed that Bxt facilitated Ab clearance by increasing apoE expression and also stimulating Ab phagocytosis by microglial cells [4]. Subsequently, other groups were not able to reproduce completely these promising results [5–9]. Supporting a potential neuroprotective effect, Bomben et al. demonstrated that Bxt reduced cortical network excitability in a murine model of the disease [10]. In addition, Lefterov et al. reported that Bxt influenced diverse regulatory pathways that are considered critical for cognitive performance, inflammatory response, and Ab clearance, providing an explanation of the therapeutic effect of the Bxt at the molecular level [11]. However, the role of Bxt in AD remains unclear since other groups continue reporting no benefits with its use [12, 13]. To date, two clinical trials in healthy volunteers and in patients with mild to moderate AD have been initiated (registered in the clinical trials as NCT01782742 and NCT02061878). Although with limited evidence, Bxt has also been tested in other neurodegenerative diseases such as PD and ALS. In the field of PD, McFarland et al. described the ability of RXR to form heterodimers with other nuclear hormone receptors, such as nuclear receptor related 1 protein (Nurr1), which is strongly implicated in the growth, maintenance and survival of dopaminergic neurons. Remarkably, these authors demonstrated that treatment with low-dose Bxt rescued dopamine neurons and reversed the behavioural deficits in the 6-OHDA rat model of PD [14]. Regarding ALS, we have been working with Bxt as an attractive candidate for this disease because it helps to modulate some of the most important pathways related to & Javier Riancho javier.riancho86@gmail.com