NSAIDs increase survival in the Sandhoff disease mouse:: Synergy with N-butyldeoxynojirimycin
NSAIDs increase survival in the Sandhoff disease mouse:: Synergy with N-butyldeoxynojirimycin
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DOI：
10.1002/ana.20242
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发表时间：
2004-11-01
影响因子：
11.2
通讯作者：
Platt, FM
中科院分区：
文献类型：
--
作者：
Jeyakumar, M;Smith, DA;Platt, FM
GM2神经节苷脂沉积症是由溶酶体中GM2神经节苷脂不完全分解代谢引起的，导致进行性蓄积以及神经退行性临床病程。已发现炎症反应（小胶质细胞激活、巨噬细胞浸润、氧化损伤）是GM2在大脑中蓄积的结果，尽管尚不清楚这是否对发病机制或疾病进展有促进作用。在本研究中，我们用非甾体抗炎药（吲哚美辛、阿司匹林和布洛芬）以及抗氧化剂（L - 抗坏血酸和醋酸α - 生育酚）对桑德霍夫病小鼠进行治疗。接受治疗的小鼠比未接受治疗的同窝小鼠存活时间显著更长（12 - 23%，P < 0.0001），并且疾病进展速度更慢（p < 0.001）。当阿司匹林治疗与底物减少疗法联合使用时，产生了协同作用（11%，p < 0.05），存活率最大提高了73%（p < 0.00001）。这项研究表明炎症促进了疾病进展，并确定抗炎和抗氧化疗法是减缓这种及相关疾病临床病程的一种潜在辅助方法。
The GM2 gangliosidoses are caused by incomplete catabolism of GM2 ganglioside in the lysosome, leading to progressive storage and a neurodegenerative clinical course. An inflammatory response (microglial activation, macrophage infiltration, oxidative damage) has been found to be a consequence of GM2 storage in the brain, although it remains unclear whether this contributes to pathogenesis or disease progression. In this study, we treated Sandhoff disease mice with nonsteroidal antiinflammatory drugs (indomethacin, aspirin, and ibuprofen) and antioxidants (L-ascorbic acid and alpha-tochopherol acetate). The treated mice lived significantly longer than untreated littermates (12-23%, P < 0.0001) and showed a slower rate of disease progression (p < 0.001). When aspirin treatment was combined with substrate reduction therapy, synergy resulted (11%, p < 0.05) with a maximum improvement of 73% in survival (p < 0.00001). This study demonstrates that inflammation contributes to disease progression and identifies antiinflammatory and antioxidant therapies as a potential adjunctive approach to slow the clinical course of this and related disorders.