Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, Frankfurt, 60438, Germany.
Department of Pharmacy, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, Munich, 81377, Germany.
Adv Sci (Weinh). 2022 Jun;9(18):e2104640. doi: 10.1002/advs.202104640. Epub 2022 Apr 30.
The ligand-sensing transcription factor Nurr1 emerges as a promising therapeutic target for neurodegenerative pathologies but Nurr1 ligands for functional studies and therapeutic validation are lacking. Here pronounced Nurr1 modulation by statins for which clinically relevant neuroprotective effects are demonstrated, is reported. Several statins directly affect Nurr1 activity in cellular and cell-free settings with low micromolar to sub-micromolar potencies. Simvastatin as example exhibits anti-inflammatory effects in astrocytes, which are abrogated by Nurr1 knockdown. Differential gene expression analysis in native and Nurr1-silenced cells reveals strong proinflammatory effects of Nurr1 knockdown while simvastatin treatment induces several neuroprotective mechanisms via Nurr1 involving changes in inflammatory, metabolic and cell cycle gene expression. Further in vitro evaluation confirms reduced inflammatory response, improved glucose metabolism, and cell cycle inhibition of simvastatin-treated neuronal cells. These findings suggest Nurr1 involvement in the well-documented but mechanistically elusive neuroprotection by statins.
配体感应转录因子 Nurr1 作为神经退行性病变的有前途的治疗靶点出现，但缺乏用于功能研究和治疗验证的 Nurr1 配体。本文报道了他汀类药物可显著调节 Nurr1，而他汀类药物具有临床相关的神经保护作用。几种他汀类药物在细胞和无细胞环境中直接影响 Nurr1 活性，其效力为低微摩尔至亚微摩尔。以辛伐他汀为例，它在星形胶质细胞中表现出抗炎作用，而 Nurr1 敲低可消除这种作用。在天然和 Nurr1 沉默细胞中的差异基因表达分析显示，Nurr1 敲低具有强烈的促炎作用，而辛伐他汀通过 Nurr1 治疗诱导几种神经保护机制，导致炎症、代谢和细胞周期基因表达的变化。进一步的体外评估证实了辛伐他汀处理的神经元细胞的炎症反应降低、葡萄糖代谢改善和细胞周期抑制。这些发现表明 Nurr1 参与了他汀类药物具有良好记载但机制尚不清楚的神经保护作用。
