Frontiers in Molecular Neuroscience ( IF 4.8 ) Pub Date : 2020-10-06 , DOI: 10.3389/fnmol.2020.568641 Michael Popiolek 1 , Yukitoshi Izumi 2 , Allen T Hopper 1 , Jing Dai 1 , Silke Miller 1 , Hong-Jin Shu 2 , Charles F Zorumski 2 , Steven Mennerick 2
The manipulation of cholesterol and its metabolites has been hypothesized to be therapeutically beneficial for mood disorders, neurodegenerative disorders, and epilepsies. A major regulator of cholesterol clearance and turnover in the central nervous system is CYP46A1, a brain enriched enzyme responsible for metabolism of cholesterol into 24S-hydroxycholesterol. Inhibition of this enzyme may negatively modulate NMDARs as 24S-hydroxycholesterol was shown to enhance NMDAR function. In addition, alterations of local cholesterol or other changes mediated by CYP46A1 activity could have important influences on central nervous system function. Here we demonstrate that humans and mice display brain region specific and similar CYP46A1 and 24S-hydroxycholesterol distribution. Treatment with distinct classes of CYP46A1 inhibitors led to central 24S-hydroxycholesterol reduction
中文翻译:
CYP46A1 抑制对离体海马切片长期抑郁和体内 24S-羟基胆固醇水平的影响
据推测,控制胆固醇及其代谢物对情绪障碍、神经退行性疾病和癫痫有治疗作用。中枢神经系统中胆固醇清除和周转的主要调节剂是 CYP46A1,这是一种大脑富集酶,负责将胆固醇代谢为 24S-羟基胆固醇。抑制该酶可能会对 NMDAR 产生负向调节,因为 24S-羟基胆固醇已被证明可以增强 NMDAR 功能。此外,局部胆固醇的改变或由 CYP46A1 活性介导的其他变化可能对中枢神经系统功能产生重要影响。在这里,我们证明人类和小鼠表现出大脑区域特异性和相似的 CYP46A1 和 24S-羟基胆固醇分布。使用不同类别的 CYP46A1 抑制剂治疗导致中枢 24S-羟基胆固醇减少