摘要
二苯环(或latrepirdine)最初被用作抗组胺药,但后来又重新发现了新的治疗特性,增加了一个“老”药物的生长体,具有显著的神经保护作用。在目前的手稿中,我们将重点关注我们最新的研究,关于使用体内蛋白病变模型的大脑病理过程的二聚体。在这项研究中,神经退行性病理学被归因于一组聚集倾向的蛋白质:高磷酸化tau,融合在肉瘤和γ-突触核蛋白中,它们参与了许多神经疾病。我们还提出了基于在培养的SH-SY5Y神经母细胞瘤细胞中一种异常突变形式的转录应答DNA结合43kDa蛋白的体外模型。二聚体处理后激活自噬标记物导致含有包涵体的细胞数量减少。二聚苯环的最显著作用似乎是通过增加非选择性线粒体孔开口的阈值来改善细胞能量平衡、线粒体稳定性,以及在降低脂质过氧化的同时增加钙保留能力。二聚苯环和新设计的类似物的治疗潜力显示出疾病修饰特性,可用于治疗神经退行性疾病。此外,新的数据提示了一种可能的抗衰老作用和潜在的应用二苯甲酮治疗焦虑,缺血和抑郁症。总的来说,我们的研究结果表明,当在疾病发病的早期开始治疗时,观察到二聚苯环最显著的作用,在计划未来的临床试验时需要考虑这个因素。
关键词: Dimebon,Latrepirdine,蛋白质病,神经保护,线粒体通透性转换,神经退行性疾病。
Current Medicinal Chemistry
Title:New Therapeutic Property of Dimebon as a Neuroprotective Agent
Volume: 25 Issue: 39
关键词: Dimebon,Latrepirdine,蛋白质病,神经保护,线粒体通透性转换,神经退行性疾病。
摘要: Dimebon (or Latrepirdine) was initially used as an anti-histamergic drug but later new therapeutic properties were rediscovered, adding to a growing body of “old” agents with prominent neuroprotective effects. In the present manuscript, we are focusing on our latest study on Dimebon with regard to brain’s pathological processes using in vivo proteinopathy models. In the study, neurodegenerative pathology has been attributed to a group of aggregate-prone proteins: hyperphosphorylated tau, fused in sarcoma and γ-synuclein , which are involved in a number of neurological disorders. We have also presented our in vitro model based on overexpression of an aberrant mutant form of transactive response DNA binding 43 kDa protein in cultured SH-SY5Y neuroblastoma cells. Dimebon treatment followed by the activation of autophagy markers resulted in reduced number of inclusion containing cells. The most significant effects of Dimebon appeared to be on the improving cellular energy balance, mitochondria stability by increasing the threshold for nonselective mitochondrial pore opening as well as on increased calcium retention capacity while reducing lipid peroxidation. The therapeutic potential of Dimebon and newly designed analogs show disease modifying properties and could be used to treat neurodegenerative disorders. In addition, new data hint on a possible anti-aging effect and potential application of Dimebon for treatment of anxiety, ischemia and depression. Overall, our findings suggest that the most pronounced effect of Dimebon was observed when treatment was started at the early stages of disease onset and this factor needs to be taken into account while planning future clinical trials.
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Cite this article as:
New Therapeutic Property of Dimebon as a Neuroprotective Agent, Current Medicinal Chemistry 2018; 25 (39) . https://dx.doi.org/10.2174/0929867323666160804122746
DOI https://dx.doi.org/10.2174/0929867323666160804122746 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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