来源:Scientific Reports 发布时间:2019/1/29 14:34:27
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新型钙蛋白酶抑制剂对转基因动物模型的帕金森氏病和路易体痴呆的影响

论文标题:Effects of Novel Calpain Inhibitors in Transgenic Animal Model of Parkinson’s disease/dementia with Lewy bodies

期刊:Scientific Reports

作者:Getaw Worku Hassen, Leo Kesner, Alfred Stracher, Abraham Shulman, Edward Rockenstein, Michael Mante, Anthony Adame, Cassia Overk, Robert A. Rissman, Eliezer Masliah

发表时间:2018/12/27

数字识别码: 10.1038/s41598-018-35729-1

原文链接:http://t.cn/E5dA9o4

帕金森氏病(PD)和路易体痴呆(DLB)是衰老人群的神经退行性疾病,其特征在于α-突触核蛋白(α-syn)的堆积。目前触发α-syn毒性的机制尚不完全清楚,但可能与α-syn的c-末端被蛋白酶(如钙蛋白酶)截短有关。

因此,钙蛋白酶抑制剂对于这些疾病的治疗有着潜在的应用价值。美国加州大学圣地亚哥分校的Eliezer Masliah团队在转基因小鼠模型上评估了全身性注射新型低分子量钙蛋白酶抑制剂对α-syn病变的抑制作用。为此,非转基因和和α-syn转基因小鼠每天两次,持续30天接受钙蛋白酶抑制剂 (Gabadur,Neurodur或载体)的注射。

免疫细胞化学分析显示Gabadur处理组减少了60%的α-syn沉积, 而Neurodur处理组减少了40%。这些药物同时也减少了α-syn的c-末端的截短,改善了神经退行性变。蛋白质印迹分析显示,Gabadur处理组减少了77%的α-血影蛋白的分解,Neurodur处理组减少63%。Gabadur处理组减少了65%有活性的钙蛋白酶的数量,Neurodur处理组减少45%。钙蛋白酶抑制剂处理还改善了α-syn 转基因小鼠的活跃性。总之,该研究表明在治疗突触核蛋白病时可考虑使用钙蛋白酶抑制。

图1:Gabadur 和 Neurodur对α-syn转基因小鼠大脑皮层和海马体中神经退行性变的影响

摘要:Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders of the aging population characterized by the accumulation of α-synuclein (α-syn). The mechanisms triggering α-syn toxicity are not completely understood, however, c-terminus truncation of α-syn by proteases such as calpain may have a role. Therefore, inhibition of calpain may be of value. The main objective of this study was to evaluate the effects of systemically administered novel low molecular weight calpain inhibitors on α-syn pathology in a transgenic mouse model. For this purpose, non-tg and α-syn tg mice received the calpain inhibitors - Gabadur, Neurodur or a vehicle, twice a day for 30 days. Immunocytochemical analysis showed a 60% reduction in α-syn deposition using Gabadur and a 40% reduction using Neurodur with a concomitant reduction in c-terminus α-syn and improvements in neurodegeneration. Western blot analysis showed a 77% decrease in α-spectrin breakdown products (SBDPs) SBDPs with Gabadur and 63% reduction using Neurodur. There was a 65% reduction in the active calpain form with Gabadur and a 45% reduction with Neurodur. Moreover, treatment with calpain inhibitors improved activity performance of the α-syn tg mice. Taken together, this study suggests that calpain inhibition might be considered in the treatment of synucleinopathies.

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期刊介绍:Scientific Reports (https://www.nature.com/srep/) is an online, open access journal from the publishers of Nature. We publish scientifically valid primary research from all areas of the natural and clinical sciences.

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(来源:科学网)

 
 
 
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