Institute of Physiologically Active Compounds of RAS, 1 Severniy Proezd, Chernogolovka, 142432, Moscow Region, Russian Federation.
Neurotox Res. 2012 Jul;22(1):33-42. doi: 10.1007/s12640-011-9299-y. Epub 2011 Dec 17.
Intermediates and final products of protein aggregation play crucial role in the development of degenerative changes in a number of neurological diseases. Pathological protein aggregation is currently regarded as one of the most promising therapeutic targets for treatment of these diseases. Transgenic mouse models of proteinopathies are an effective tool for screening and validation of compounds, which can selectively affect metabolism of aggregate-prone proteins. In this study, we assessed effects of dimebon, a compound with known neuroprotective properties, on a recently established transgenic mouse model recapitulating key pathological features of amyotrophic lateral sclerosis (ALS) as the consequence of neuron-specific overexpression of γ-synuclein. Cohorts of experimental transgenic mice received dimebon in drinking water with this chronic treatment starting either before or after the onset of clinical signs of pathology. We detected statistically significant improvement of motor performance in a rotarod test in both dimebon-treated animal groups, with more pronounced effect in a group that received dimebon from an earlier age. We also revealed substantially reduced number of amyloid inclusions, decreased amount of insoluble γ-synuclein species and a notable amelioration of astrogliosis in the spinal cord of dimebon-treated compared with control transgenic animals. However, dimebon did not prevent the loss of spinal motor neurons in this model. Our results demonstrated that chronic dimebon administration is able to slow down but not halt progression of γ-synucleinopathy and resulting signs of pathology in transgenic animals, suggesting potential therapeutic use of this drug for treatment of this currently incurable disease.
蛋白质聚集的中间体和最终产物在许多神经退行性疾病的发展中起着关键作用。病理性蛋白质聚集目前被认为是治疗这些疾病的最有前途的治疗靶点之一。蛋白质病的转基因小鼠模型是筛选和验证化合物的有效工具，这些化合物可以选择性地影响易聚集蛋白的代谢。在这项研究中，我们评估了 dimebon（一种具有已知神经保护特性的化合物）对最近建立的转基因小鼠模型的影响，该模型模拟了由于神经元特异性过度表达 γ-突触核蛋白而导致的肌萎缩侧索硬化症 (ALS) 的关键病理特征。实验组的实验性转基因小鼠在饮用水中接受 dimebon 治疗，这种慢性治疗在出现病理迹象之前或之后开始。我们在转棒试验中检测到 dimebon 治疗的两组动物的运动性能均有统计学意义的改善，而在更早开始接受 dimebon 治疗的组中效果更为明显。我们还发现淀粉样蛋白包涵体的数量明显减少，不溶性 γ-突触核蛋白的含量减少，与对照组转基因动物相比，脊髓中的星形胶质细胞增生得到显著改善。然而， dimebon 并不能阻止该模型中脊髓运动神经元的丧失。我们的研究结果表明，慢性 dimebon 给药能够减缓但不能阻止转基因动物中 γ-突触核蛋白病和由此产生的病理迹象的进展，这表明该药物有治疗这种目前无法治愈的疾病的潜在治疗用途。
