School of Mathematical and Natural Sciences, Arizona State University, Phoenix, Arizona 85306, United States.
ACS Chem Neurosci. 2021 Mar 3;12(5):857-871. doi: 10.1021/acschemneuro.0c00707. Epub 2021 Feb 11.
There is considerable interest in identifying effective and safe drugs for neurodegenerative disorders. Cell culture and animal model work have demonstrated that modulating gene expression through RXR-mediated pathways may mitigate or reverse cognitive decline. However, because RXR is a dimeric partner for several transcription factors, activating off-target transcription is a concern with RXR ligands (rexinoids). This off-target gene modulation leads to unwanted side effects that can include low thyroid function and significant hyperlipidemia. There is a need to develop rexinoids that have binding specificity for subsets of RXR heterodimers, to drive desired gene modulation, but that do not induce spurious effects. Herein, we describe experiments in which we analyze a series of novel and previously reported rexinoids for their ability to modulate specific gene pathways implicated in neurodegenerative disorders employing a U87 cell culture model. We demonstrate that, compared to the FDA-approved rexinoid bexarotene (), several of these compounds are equally or more effective at stimulating gene expression via LXREs or Nurr1/NBREs and are superior at inducing ApoE and/or tyrosine hydroxylase (TH) gene and protein expression, including analogs , , , , , , and , suggesting a possible therapeutic role for these compounds in Alzheimer's or Parkinson's disease (PD). A subset of these potent RXR agonists can synergize with a presumed Nurr1 ligand and antimalarial drug (amodiaquine) to further enhance Nurr1/NBREs-directed transcription. This novel discovery has potential clinical implications for treatment of PD since it suggests that the combination of an RXR agonist and a Nurr1 ligand can significantly enhance RXR-Nurr1 heterodimer activity and drive enhanced therapeutic expression of the TH gene to increase endogenous synthesis of dopamine. These data indicate that is it possible and prudent to develop novel rexinoids for testing of gene expression and side effect profiles for use in potential treatment of neurodegenerative disorders, as individual rexinoids can have markedly different gene expression profiles but similar structures.
人们对寻找有效且安全的神经退行性疾病治疗药物很感兴趣。细胞培养和动物模型研究表明，通过 RXR 介导的途径调节基因表达可能减轻或逆转认知能力下降。然而，由于 RXR 是几种转录因子的二聚体伴侣，激活非靶点转录是 RXR 配体（类视黄醇）的一个关注点。这种非靶点基因调节会导致不必要的副作用，包括甲状腺功能低下和明显的高脂血症。因此，需要开发具有 RXR 异二聚体亚群结合特异性的类视黄醇，以驱动所需的基因调节，但不诱导虚假效应。在此，我们描述了一系列实验，在这些实验中，我们使用 U87 细胞培养模型分析了一系列新的和以前报道的类视黄醇，以研究它们调节与神经退行性疾病相关的特定基因途径的能力。我们证明，与 FDA 批准的类视黄醇贝沙罗汀（）相比，这些化合物中的几种在通过 LXREs 或 Nurr1/NBREs 刺激基因表达方面同样有效或更有效，并且在诱导 ApoE 和/或酪氨酸羟化酶（TH）基因和蛋白表达方面更有效，包括类似物、、、、、、和，这表明这些化合物在阿尔茨海默病或帕金森病（PD）中可能具有治疗作用。这些强效 RXR 激动剂的亚组可以与假定的 Nurr1 配体和抗疟药物（阿莫地喹）协同作用，进一步增强 Nurr1/NBREs 导向的转录。这一新颖的发现对 PD 的治疗具有潜在的临床意义，因为它表明 RXR 激动剂和 Nurr1 配体的组合可以显著增强 RXR-Nurr1 异二聚体活性，并驱动 TH 基因的增强治疗表达，以增加内源性多巴胺的合成。这些数据表明，开发用于测试基因表达和副作用谱的新型类视黄醇以用于潜在的神经退行性疾病治疗是可行且谨慎的，因为单个类视黄醇可能具有明显不同的基因表达谱，但具有相似的结构。
