RESUMO
Treatment with bexarotene, a selective retinoid X receptor (RXR) agonist, significantly improves behavioral dysfunctions in various neurodegenerative animal models. Additionally, it activates neurodevelopmental and plasticity pathways in the brains of adult mice. Our objective was to investigate the impact of RXR activation by bexarotene on adult neural stem cells (aNSC) and their cell lineages. To achieve this, we treated NSCs isolated from the subventricular zone (SVZ) of adult rat brains from the proliferative stage to the differentiated status. The results showed that bexarotene-treated aNSC exhibited increased BrdU incorporation, SOX2+ dividing cell pairs, and cell migration from neurospheres, revealing that the treatment promotes self-renewing proliferation and cell motility in SVZ-aNCS. Furthermore, bexarotene induced a cell fate shift characterized by a significant increase in GFAP+/S100B+ differentiated astrocytes, which uncovers the participation of activated-RXR in astrogenesis. In the neuronal lineage, the fate shift was counteracted by bexarotene-induced enhancement of NeuN+ nuclei together with neurite network outgrowth, indicating that the RXR agonist stimulates SVZ-aNCS neuronal differentiation at later stages. These findings establish new connections between RXR activation, astro- and neurogenesis in the adult brain, and contribute to the development of therapeutic strategies targeting nuclear receptors for neural repair.
RESUMO
The receptor for advanced glycation end products (RAGE) is a transmembrane receptor that belongs to the immunoglobulin superfamily and is extensively associated with chronic inflammation in non-transmissible diseases. As chronic inflammation is consistently present in neurodegenerative diseases, it was largely assumed that RAGE could act as a critical modulator of neuroinflammation in Parkinson's disease (PD), similar to what was reported for Alzheimer's disease (AD), where RAGE is postulated to mediate pro-inflammatory signaling in microglia by binding to amyloid-ß peptide. However, accumulating evidence from studies of RAGE in PD models suggests a less obvious scenario. Here, we review physiological aspects of RAGE and address the current questions about the potential involvement of this receptor in the cellular events that may be critical for the development and progression of PD, exploring possible mechanisms beyond the classical view of the microglial activation/neuroinflammation/neurodegeneration axis that is widely assumed to be the general mechanism of RAGE action in the adult brain.