The novel function of bexarotene for neurological diseases.

Bexarotene, a retinoid X receptor (RXR) agonist, is approved by FDA to treat cutaneous T-cell lymphoma. However, it has also demonstrated promising therapeutic potential for neurological diseases such as stroke, traumatic brain injury, Parkinson's disease, and particularly Alzheimer's disease(AD). In AD, bexarotene inhibits the production and aggregation of amyloid ß (Aß), activates Liver X Receptor/RXR heterodimers to increase lipidated apolipoprotein E to remove Aß, mitigates the negative impact of Aß, regulates neuroinflammation, and ultimately improves cognitive function. For other neurological diseases, its mechanisms of action include inhibiting inflammatory responses, up-regulating microglial phagocytosis, and reducing misfolded protein aggregation, all of which aid in alleviating neurological damage. Here, we briefly discuss the characteristics, applications, and adverse effects of bexarotene, summarize its pharmacological mechanisms and therapeutic results in various neurological diseases, and elaborate on the problems encountered in preclinical research, with the aim of providing help for the further application of bexarotene in central nervous system diseases.

Neuroprotective effect of naturally occurring RXR agonists isolated from Sophora tonkinensis Gagnep. on amyloid-ß-induced cytotoxicity in PC12 cells.

Neuronal cell death induced by amyloid-ß (Aß) oligomers is implicated in neuronal degeneration and is a leading cause of Alzheimer's disease (AD). Therefore, to identify effective therapeutic agents for AD, we investigated the neuroprotective effects of two naturally occurring retinoid X receptor (RXR) agonists (SPF1 and SPF2), isolated from the root of Sophora tonkinensis Gagnep., on the Aß25-35-induced cytotoxicity against nerve growth factor-differentiated rat pheochromocytoma (PC12) cells. Pretreatment with SPFs significantly prevented Aß25-35-induced apoptosis in PC12 cells, similarly to the synthetic RXR agonist bexarotene. These effects were blocked by the RXR antagonist PA452. When the effects of SPFs were studied in the presence of the liver X receptor (LXR) agonist T0901317, the protective effects of SPFs were enhanced, suggesting that RXR/LXR heterodimers may play a key role in the neuroprotective effects of SPFs. SPFs and T0901317 induced ATP-binding cassette transporter 1 (ABCA1) protein expression in PC12 cells when administered alone or in combination. Intriguingly, a functional inhibitor of ABCA1 cyclosporine A negated the neuroprotective effects of SPFs or T0901317. Taken together, these results demonstrate that the RXR agonists SPF1 and SPF2 protect PC12 cells from Aß25-35-induced neurotoxicity in an RXR-dependent manner and that their effects are markedly enhanced by the LXR agonist T0901317, in part related to ABCA1 function. These results suggest a novel approach to the treatment or prevention of AD.

Therapeutic advances in cutaneous T-cell lymphoma (CTCL): from retinoids to rexinoids.

Retinoids comprise a family of polyisoprenoid lipids that include vitamin A (retinol) and its various natural and synthetic analogues. Retinoids are compounds with multiple actions. They are involved in the control of cell proliferation, cell differentiation, and embryonic development. Each retinoid has its own profile of pharmacologic properties that determines its usefulness in clinical dermatology or oncology. Although numerous synthetic retinoids have been synthesized, their biological activities are usually associated with clinical disadvantages such as toxicity and teratogenicity. Retinoids that bind to both the retinoic acid receptor and retinoid X receptor subtypes have shown clinical activity in hematologic malignancies and can mediate genes associated with both growth and differentiation. Retinoid X receptor-specific rexinoids have also shown efficacy in the treatment of cutaneous T-cell lymphomas, but their exact mechanism of action is unclear. This article summarizes the clinical relevance of both groups of compounds in this important patient population.