Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Bâtiment 3 de la Faculté de Médecine, 11 rue Humann, 67 000 Strasbourg, France; Neurobiology Laboratory for Brain Aging and Mental Health, Transfaculty Research Platform, Molecular and Cognitive Neuroscience, University of Basel, Wilhelm Klein-Str. 27, 4012 Basel, Switzerland; Psychiatric University Clinics, University of Basel, Wilhelm Klein-Str. 27, 4012 Basel, Switzerland.
Neurobiology Laboratory for Brain Aging and Mental Health, Transfaculty Research Platform, Molecular and Cognitive Neuroscience, University of Basel, Wilhelm Klein-Str. 27, 4012 Basel, Switzerland; Psychiatric University Clinics, University of Basel, Wilhelm Klein-Str. 27, 4012 Basel, Switzerland.
Biochim Biophys Acta Mol Basis Dis. 2017 Mar;1863(3):631-642. doi: 10.1016/j.bbadis.2016.12.007. Epub 2016 Dec 13.
Allopregnanolone (AP) is supposed to exert beneficial actions including anxiolysis, analgesia, neurogenesis and neuroprotection. However, although mitochondrial dysfunctions are evidenced in neurodegenerative diseases, AP actions against neurodegeneration-induced mitochondrial deficits have never been investigated. Also, the therapeutic exploitation of AP is limited by its difficulty to pass the liver and its rapid clearance after sulfation or glucuronidation of its 3-hydroxyl group. Therefore, the characterization of novel potent neuroprotective analogs of AP may be of great interest. Thus, we synthesized a set of AP analogs (ANS) and investigated their ability to counteract APP-overexpression-evoked bioenergetic deficits and to protect against oxidative stress-induced death of control and APP-transfected SH-SY5Y cells known as a reliable cellular model of Alzheimer's disease (AD). Especially, we examined whether ANS were more efficient than AP to reduce mitochondrial dysfunctions or bioenergetic decrease leading to neuronal cell death. Our results showed that the ANS BR 297 exhibits notable advantages over AP with regards to both protection of mitochondrial functions and reduction of oxidative stress. Indeed, under physiological conditions, BR 297 does not promote cell proliferation but efficiently ameliorates the bioenergetics by increasing cellular ATP level and mitochondrial respiration. Under oxidative stress situations, BR 297 treatment, which decreases ROS levels, improves mitochondrial respiration and cell survival, appears more potent than AP to protect control and APP-transfected cells against HO-induced death. Our findings lend further support to the neuroprotective effects of BR 297 emphasizing this analog as a promising therapeutic tool to counteract age- and AD-related bioenergetic deficits.
别孕烯醇酮（AP）被认为具有多种有益作用，包括抗焦虑、镇痛、神经发生和神经保护。然而，尽管神经退行性疾病中存在线粒体功能障碍，但 AP 对抗神经退行性病变引起的线粒体缺陷的作用尚未得到研究。此外，AP 的治疗应用受到其难以通过肝脏以及其 3-羟基的硫酸化或葡萄糖醛酸化后迅速清除的限制。因此，鉴定新型强效 AP 神经保护类似物可能具有重要意义。因此，我们合成了一组 AP 类似物（ANS），并研究了它们对抗 APP 过表达引起的生物能量缺陷的能力，以及对氧化应激诱导的对照和 APP 转染的 SH-SY5Y 细胞死亡的保护作用，该细胞系是阿尔茨海默病（AD）的可靠细胞模型。特别是，我们研究了 ANS 是否比 AP 更有效地减少线粒体功能障碍或生物能量下降导致的神经元细胞死亡。我们的结果表明，与 AP 相比，ANS BR 297 在保护线粒体功能和减少氧化应激方面具有显著优势。事实上，在生理条件下，BR 297 不会促进细胞增殖，但通过增加细胞内 ATP 水平和线粒体呼吸有效地改善生物能量。在氧化应激情况下，BR 297 处理可降低 ROS 水平，改善线粒体呼吸和细胞存活，与 AP 相比，它更能保护对照和 APP 转染的细胞免受 HO 诱导的死亡。我们的研究结果进一步支持了 BR 297 的神经保护作用，强调了这种类似物作为一种有前途的治疗工具，可用于对抗与年龄和 AD 相关的生物能量缺陷。
