Papadopoulos V, Lecanu L, Brown R C, Han Z, Yao Z-X
Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Northwest, Washington, DC 20057, USA.
Neuroscience. 2006;138(3):749-56. doi: 10.1016/j.neuroscience.2005.05.063. Epub 2005 Dec 7.
The peripheral-type benzodiazepine receptor is a mitochondrial protein expressed at high levels in steroid synthesizing tissues, including the glial cells of the brain. Peripheral-type benzodiazepine receptor binds cholesterol with high affinity and is a key element of the cholesterol mitochondrial import machinery responsible for supplying the substrate cholesterol to the first steroidogenic enzyme, thus initiating and maintaining neurosteroid biosynthesis. Neurosteroid formation and metabolism of steroid intermediates are critical components of normal brain function. Peripheral-type benzodiazepine receptor also binds with high affinity various classes of compounds. Upon ligand activation peripheral-type benzodiazepine receptor-dependent cholesterol transport into mitochondria is accelerated leading in increased formation of neuroactive steroids. These steroids, such as allopregnanolone, have been shown to be involved in various neurological disorders, such as anxiety and mood disorders. Thus, peripheral-type benzodiazepine receptor drug ligand-induced neuroactive steroid formation offers a means to regulate brain dysfunction. Peripheral-type benzodiazepine receptor basal expression is upregulated in a number of neuropathologies, including gliomas and neurodegenerative disorders, as well as in various forms of brain injury and inflammation. In Alzheimer's disease pathology neurosteroid biosynthesis is altered and a decrease in the intermediate 22R-hydroxycholesterol levels is observed. This steroid was found to exert neuroprotective properties against beta-amyloid neurotoxicity. Based on this observation, a stable spirostenol derivative showing to display neuroprotective properties was identified, suggesting that compounds developed based on critical intermediates of neurosteroid biosynthesis could offer novel means for neuroprotection. In conclusion, changes in peripheral-type benzodiazepine receptor and neurosteroid levels are part of the phenotype seen in neuropathology and neurological disorders and offer potential targets for new therapies.
外周型苯二氮䓬受体是一种线粒体蛋白，在包括脑胶质细胞在内的类固醇合成组织中高水平表达。外周型苯二氮䓬受体以高亲和力结合胆固醇，是胆固醇线粒体导入机制的关键元件，负责将底物胆固醇供应给首个类固醇生成酶，从而启动和维持神经甾体生物合成。神经甾体的形成以及类固醇中间体的代谢是正常脑功能的关键组成部分。外周型苯二氮䓬受体还以高亲和力结合各类化合物。配体激活后，依赖外周型苯二氮䓬受体的胆固醇向线粒体的转运加速，导致神经活性类固醇的生成增加。这些类固醇，如别孕烯醇酮，已被证明与各种神经疾病有关，如焦虑症和情绪障碍。因此，外周型苯二氮䓬受体药物配体诱导的神经活性类固醇形成提供了一种调节脑功能障碍的手段。外周型苯二氮䓬受体的基础表达在多种神经病理学中上调，包括胶质瘤和神经退行性疾病，以及各种形式的脑损伤和炎症。在阿尔茨海默病病理学中，神经甾体生物合成发生改变，观察到中间体22R-羟基胆固醇水平降低。发现这种类固醇对β-淀粉样蛋白神经毒性具有神经保护特性。基于这一观察结果，鉴定出一种显示出神经保护特性的稳定螺甾醇衍生物，这表明基于神经甾体生物合成关键中间体开发的化合物可能为神经保护提供新的手段。总之，外周型苯二氮䓬受体和神经甾体水平的变化是神经病理学和神经疾病中所见表型的一部分，并为新疗法提供了潜在靶点。
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