Institute of Physiologically Active Compounds RAS, Chernogolovka, Russian Federation, Cambridge, UK.
Neurodegener Dis. 2011;8(6):430-7. doi: 10.1159/000324989. Epub 2011 May 12.
Recent clinical studies have demonstrated that dimebon, a drug originally designed and used as a non-selective antihistamine, ameliorates symptoms and delays progress of mild to moderate forms of Alzheimer's and Huntington's diseases. Although the mechanism of dimebon action on pathological processes in degenerating brain is elusive, results of studies carried out in cell cultures and animal models suggested that this drug might affect the process of pathological accumulation and aggregation of various proteins involved in the pathogenesis of proteinopathies. However, the effect of this drug on the pathology caused by overexpression and aggregation of alpha-synuclein, including Parkinson's disease (PD), has not been assessed.
To test if dimebon affected alpha-synuclein-induced pathology using a transgenic animal model.
We studied the effects of chronic dimebon treatment on transgenic mice expressing the C-terminally truncated (1-120) form of human alpha-synuclein in dopaminergic neurons, a mouse model that recapitulates several biochemical, histopathological and behavioral characteristics of the early stage of PD.
Dimebon did not improve balance and coordination of aging transgenic animals or increase the level of striatal dopamine, nor did it prevent accumulation of alpha-synuclein in cell bodies of dopaminergic neurons.
Our observations suggest that in the studied model of alpha-synucleinopathy dimebon has very limited effect on certain pathological alterations typical of PD and related diseases.
最近的临床研究表明，最初设计并用作非选择性抗组胺药的 dimebon 可改善轻度至中度阿尔茨海默病和亨廷顿病的症状并延缓其进展。虽然 dimebon 对变性大脑中病理过程的作用机制尚不清楚，但在细胞培养和动物模型中进行的研究结果表明，该药物可能影响涉及蛋白病发病机制的各种蛋白质的病理性积累和聚集过程。然而，尚未评估该药物对包括帕金森病（PD）在内的过量表达和聚集的α-突触核蛋白引起的病理学的影响。
使用转基因动物模型测试 dimebon 是否影响α-突触核蛋白诱导的病理学。
我们研究了慢性 dimebon 治疗对表达在多巴胺能神经元中 C 端截断（1-120）形式的人α-突触核蛋白的转基因小鼠的影响，该小鼠模型重现了 PD 早期的多种生化、组织病理学和行为特征。
dimebon 既不能改善老化转基因动物的平衡和协调能力，也不能增加纹状体多巴胺的水平，也不能阻止多巴胺能神经元细胞体中α-突触核蛋白的积累。
我们的观察结果表明，在研究的α-突触核蛋白病模型中，dimebon 对 PD 及相关疾病的某些典型病理性改变的影响非常有限。
