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.
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Authors | Christine 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 |
Journal | Journal of neurochemistry
(J Neurochem)
Vol. 113
Issue 6
Pg. 1525-35
(Jun 2010)
ISSN: 1471-4159 [Electronic] England |
PMID | 20374428
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Blood Glucose
- 1-Deoxynojirimycin
- G(M2) Ganglioside
- migalastat
- beta-N-Acetylhexosaminidases
- 3-Hydroxybutyric Acid
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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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