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NSAIDs increase survival in the Sandhoff disease mouse: Synergy with N ‐butyldeoxynojirimycin
Author(s) -
Jeyakumar Mylvaganam,
Smith David A.,
Williams Ian M.,
Borja Mario Cortina,
Neville David C. A.,
Butters Terry D.,
Dwek Raymond A.,
Platt Frances M.
Publication year - 2004
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.20242
Subject(s) - sandhoff disease , disease , medicine , neuroscience , biology
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 α‐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. Ann Neurol 2004;56:642–649