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

• Published in: Journal of neurochemistry 2010-06, Vol.113 (6), p.1525-1535
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: 1-Deoxynojirimycin - analogs & derivatives; 1-Deoxynojirimycin - therapeutic use; 3-Hydroxybutyric Acid - blood; Analysis of Variance; Animals; beta-N-Acetylhexosaminidases - deficiency; beta-N-Acetylhexosaminidases - genetics; Biochemistry; Biological and medical sciences; Blood Glucose - drug effects; Body Weight - drug effects; Brain - cytology; Brain - drug effects; Brain - metabolism; Chromatography, High Pressure Liquid - methods; Chromatography, Thin Layer - methods; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Diet; Diet, Ketogenic - methods; Eating - drug effects; Errors of metabolism; G(M2) Ganglioside - metabolism; GA2; ganglioside; Genetic disorders; GM2; ketogenic diet; Lipid Metabolism - drug effects; Lipids (lysosomal enzyme disorders, storage diseases); lysosomal storage disease; Medical sciences; Metabolic diseases; Mice; Mice, Knockout; Myelin Sheath - metabolism; Neurological disorders; Neurology; Purkinje Cells - metabolism; Purkinje Cells - pathology; Rodents; Sandhoff disease; Sandhoff Disease - diet therapy; Sandhoff Disease - drug therapy; Sandhoff Disease - pathology
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2010.06733.x

J. Neurochem. (2010) 113, 1525–1535. 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 β‐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 (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 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.