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Restricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice.

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 (NB-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 beta-hexosaminidase (Hexb) knockout (-/-) murine model of Sandhoff disease. In this study, we used a restricted ketogenic diet (KD-R) and NB-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 NB-DNJ (SD + NB-DNJ), (iii) a KD-R, and (iv) a KD-R with NB-DNJ (KD-R + NB-DNJ). Forebrain GM2 content (mug 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 NB-DNJ and the KD-R. Most interestingly, brain NB-DNJ content was 3.5-fold greater in the KD-R + NB-DNJ mice than in the SD + NB-DNJ mice. These data suggest that the KD-R and NB-DNJ may be a potential combinatorial therapy for Sandhoff disease by enhancing NB-DNJ delivery to the brain and may allow lower dosing to achieve the same degree of efficacy as high dose monotherapy.
AuthorsChristine A Denny, Karie A Heinecke, Youngho P Kim, Rena C Baek, Katrina S Loh, Terry D Butters, Roderick T Bronson, Frances M Platt, Thomas N Seyfried
JournalJournal of neurochemistry (J Neurochem) Vol. 113 Issue 6 Pg. 1525-35 (Jun 2010) ISSN: 1471-4159 [Electronic] England
PMID20374428 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Blood Glucose
  • 1-Deoxynojirimycin
  • G(M2) Ganglioside
  • migalastat
  • beta-N-Acetylhexosaminidases
  • 3-Hydroxybutyric Acid
Topics
  • 1-Deoxynojirimycin (analogs & derivatives, therapeutic use)
  • 3-Hydroxybutyric Acid (blood)
  • Analysis of Variance
  • Animals
  • Blood Glucose (drug effects)
  • Body Weight (drug effects)
  • Brain (cytology, drug effects, metabolism)
  • Chromatography, High Pressure Liquid (methods)
  • Chromatography, Thin Layer (methods)
  • Diet, Ketogenic (methods)
  • Eating (drug effects)
  • G(M2) Ganglioside (metabolism)
  • Lipid Metabolism (drug effects)
  • Mice
  • Mice, Knockout
  • Myelin Sheath (metabolism)
  • Purkinje Cells (metabolism, pathology)
  • Sandhoff Disease (diet therapy, drug therapy, pathology)
  • beta-N-Acetylhexosaminidases (deficiency, genetics)

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