title: 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.
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Denny
authors.forename: Karie A
authors.initials: KA
authors.lastname: Heinecke
authors.forename: Youngho P
authors.initials: YP
authors.lastname: Kim
authors.forename: Rena C
authors.initials: RC
authors.lastname: Baek
authors.forename: Katrina S
authors.initials: KS
authors.lastname: Loh
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Seyfried
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020155:3-Hydroxybutyric Acid / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002855:Chromatography, Thin Layer / Q000379:methods; D055423:Diet, Ketogenic / Q000379:methods*; D004435:Eating / Q000187:drug effects; D005678:G(M2) Ganglioside / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D012497:Sandhoff Disease / Q000178:diet therapy / Q000188:drug therapy / Q000473:pathology; D001619:beta-N-Acetylhexosaminidases / Q000172:deficiency / Q000235:genetics
chemical_list: D001786:Blood Glucose; D017485:1-Deoxynojirimycin; D005678:G(M2) Ganglioside; C090092:migalastat; D001619:beta-N-Acetylhexosaminidases; D020155:3-Hydroxybutyric Acid