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Restricted ketogenic diet enhances the therapeutic action of N ‐butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice
Author(s) -
Denny Christine A.,
Heinecke Karie A.,
Kim Youngho P.,
Baek Rena C.,
Loh Katrina S.,
Butters Terry D.,
Bronson Roderick T.,
Platt Frances M.,
Seyfried Thomas N.
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2010.06733.x
Subject(s) - sandhoff disease , ketogenic diet , ganglioside , medicine , endocrinology , sphingolipid , gangliosidosis , glycosphingolipid , pharmacology , biology , disease , biochemistry , epilepsy , neuroscience
J. Neurochem. (2010) 113 , 1525–1535. Abstract Sandhoff disease is an autosomal recessive, neurodegenerative disease involving the storage of brain ganglioside GM2 and asialo‐GM2. Previous studies showed that caloric restriction, which augments longevity, and N ‐butyldeoxynojirimycin ( N B‐DNJ, Miglustat), an imino sugar that hinders the glucosyltransferase catalyzing the first step in glycosphingolipid biosynthesis, both increase longevity and improve motor behavior in the β‐hexosaminidase ( Hexb ) knockout (−/−) murine model of Sandhoff disease. In this study, we used a restricted ketogenic diet (KD‐R) and N B‐DNJ to combat ganglioside accumulation. Adult Hexb −/− mice were placed into one of the following groups: (i) a standard diet (SD), (ii) a SD with N B‐DNJ (SD + N B‐DNJ), (iii) a KD‐R, and (iv) a KD‐R with N B‐DNJ (KD‐R + N B‐DNJ). Forebrain GM2 content (μg sialic acid/100 mg dry wt) in the four groups was 375 ± 15, 312 ± 8, 340 ± 28, and 279 ± 26, respectively, indicating an additive interaction between N B‐DNJ and the KD‐R. Most interestingly, brain N B‐DNJ content was 3.5‐fold greater in the KD‐R + N B‐DNJ mice than in the SD + N B‐DNJ mice. These data suggest that the KD‐R and N B‐DNJ may be a potential combinatorial therapy for Sandhoff disease by enhancing N B‐DNJ delivery to the brain and may allow lower dosing to achieve the same degree of efficacy as high dose monotherapy.