Da Pozzo Eleonora, Giacomelli Chiara, Costa Barbara, Cavallini Chiara, Taliani Sabrina, Barresi Elisabetta, Da Settimo Federico, Martini Claudia
Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy.
Int J Mol Sci. 2016 Jun 29;17(7):1028. doi: 10.3390/ijms17071028.
The steroidogenic 18 kDa translocator protein (TSPO) is an emerging, attractive therapeutic tool for several pathological conditions of the nervous system. Here, 13 high affinity TSPO ligands belonging to our previously described N,N-dialkyl-2-phenylindol-3-ylglyoxylamide (PIGA) class were evaluated for their potential ability to affect the cellular Oxidative Metabolism Activity/Proliferation index, which is used as a measure of astrocyte well-being. The most active PIGA ligands were also assessed for steroidogenic activity in terms of pregnenolone production, and the values were related to the metabolic index in rat and human models. The results showed a positive correlation between the increase in the Oxidative Metabolism Activity/Proliferation index and the pharmacologically induced stimulation of steroidogenesis. The specific involvement of steroid molecules in mediating the metabolic effects of the PIGA ligands was demonstrated using aminoglutethimide, a specific inhibitor of the first step of steroid biosynthesis. The most promising steroidogenic PIGA ligands were the 2-naphthyl derivatives that showed a long residence time to the target, in agreement with our previous data. In conclusion, TSPO ligand-induced neurosteroidogenesis was involved in astrocyte well-being.
类固醇生成性18 kDa转位蛋白（TSPO）是一种新兴的、有吸引力的治疗工具，可用于治疗多种神经系统病理状况。在此，对属于我们先前描述的N，N-二烷基-2-苯基吲哚-3-基乙二醛酰胺（PIGA）类的13种高亲和力TSPO配体进行了评估，以确定它们影响细胞氧化代谢活性/增殖指数的潜在能力，该指数用作衡量星形胶质细胞健康状况的指标。还根据孕烯醇酮的产生评估了活性最高的PIGA配体的类固醇生成活性，并将这些值与大鼠和人类模型中的代谢指数相关联。结果表明，氧化代谢活性/增殖指数的增加与药理学诱导的类固醇生成刺激之间存在正相关。使用氨基导眠能（一种类固醇生物合成第一步的特异性抑制剂）证明了类固醇分子在介导PIGA配体的代谢作用中的特定参与。与我们之前的数据一致，最有前景的具有类固醇生成活性的PIGA配体是对靶点具有较长停留时间的2-萘基衍生物。总之，TSPO配体诱导的神经类固醇生成与星形胶质细胞的健康状况有关。
