Department of Chemistry, Vanderbilt Institute of Chemical Biology and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee 37235, United States.
Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska 68105, United States.
ACS Chem Neurosci. 2021 Feb 17;12(4):735-745. doi: 10.1021/acschemneuro.0c00765. Epub 2021 Feb 2.
Mouse brain contains over 100 million neuronal, glial, and other support cells. Developing neurons and astrocytes synthesize their own cholesterol, and disruption of this process can occur by both genetic and chemical mechanisms. In this study we have exposed cultured murine neurons and astrocytes to six different prescription medications that cross the placenta and blood-brain barriers and analyzed the effects of these drugs on cholesterol biosynthesis by an LC-MS/MS protocol that assays 14 sterols and 7 oxysterols in a single run. Three antipsychotics (haloperidol, cariprazine, aripiprazole), two antidepressants (trazodone and sertraline), and an antiarhythmic (amiodarone) inhibited one or more sterol synthesis enzymes. The result of the exposures was a dose-dependent increase in levels of various sterol intermediates and a decreased level of cholesterol in the cultured cells. Four prescription medications (haloperidol, aripiprazole, cariprazine, and trazodone) acted primarily on the DHCR7 enzyme. The result of this exposure was an increase in 7-dehydrocholesterol in neurons and astrocytes to levels that were comparable to those found in cultured neurons and astrocytes from transgenic mice that carried a pathogenic mutation modeling the neurodevelopmental disorder Smith-Lemli-Opitz syndrome.
鼠脑中含有超过 1 亿个神经元、神经胶质细胞和其他支持细胞。发育中的神经元和星形胶质细胞合成自身的胆固醇，这个过程可以被遗传和化学机制所破坏。在这项研究中，我们将培养的鼠神经元和星形胶质细胞暴露于六种不同的处方药物中，这些药物可以穿过胎盘和血脑屏障，并通过 LC-MS/MS 方案分析这些药物对胆固醇生物合成的影响，该方案在单次运行中检测 14 种甾醇和 7 种氧化甾醇。三种抗精神病药物（氟哌啶醇、卡利培嗪、阿立哌唑）、两种抗抑郁药（曲唑酮和舍曲林）和一种抗心律失常药（胺碘酮）抑制了一种或多种甾醇合成酶。暴露的结果是各种甾醇中间产物的水平呈剂量依赖性增加，培养细胞中的胆固醇水平降低。四种处方药物（氟哌啶醇、阿立哌唑、卡利培嗪和曲唑酮）主要作用于 DHCR7 酶。这种暴露的结果是 7-脱氢胆固醇在神经元和星形胶质细胞中的增加，达到与携带模拟神经发育障碍史密斯-莱姆利-奥皮茨综合征的致病突变的转基因小鼠中培养的神经元和星形胶质细胞中相当的水平。
