Restricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice.
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 glucosyltr...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2010
|
| _version_ | 1797078883710795776 |
|---|---|
| author | Denny, C Heinecke, K Kim, Y Baek, R Loh, K Butters, T Bronson, RT Platt, F Seyfried, T |
| author_facet | Denny, C Heinecke, K Kim, Y Baek, R Loh, K Butters, T Bronson, RT Platt, F Seyfried, T |
| author_sort | Denny, C |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T00:37:55Z |
| format | Journal article |
| id | oxford-uuid:820b3465-a6d8-4997-8c3e-93cc96b7ac62 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:37:55Z |
| publishDate | 2010 |
| record_format | dspace |
| spelling | oxford-uuid:820b3465-a6d8-4997-8c3e-93cc96b7ac622022-03-26T21:34:37ZRestricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:820b3465-a6d8-4997-8c3e-93cc96b7ac62EnglishSymplectic Elements at Oxford2010Denny, CHeinecke, KKim, YBaek, RLoh, KButters, TBronson, RTPlatt, FSeyfried, TSandhoff 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. |
| spellingShingle | Denny, C Heinecke, K Kim, Y Baek, R Loh, K Butters, T Bronson, RT Platt, F Seyfried, T Restricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice. |
| title | Restricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice. |
| title_full | Restricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice. |
| title_fullStr | Restricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice. |
| title_full_unstemmed | Restricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice. |
| title_short | Restricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice. |
| title_sort | restricted ketogenic diet enhances the therapeutic action of n butyldeoxynojirimycin towards brain gm2 accumulation in adult sandhoff disease mice |
| work_keys_str_mv | AT dennyc restrictedketogenicdietenhancesthetherapeuticactionofnbutyldeoxynojirimycintowardsbraingm2accumulationinadultsandhoffdiseasemice AT heineckek restrictedketogenicdietenhancesthetherapeuticactionofnbutyldeoxynojirimycintowardsbraingm2accumulationinadultsandhoffdiseasemice AT kimy restrictedketogenicdietenhancesthetherapeuticactionofnbutyldeoxynojirimycintowardsbraingm2accumulationinadultsandhoffdiseasemice AT baekr restrictedketogenicdietenhancesthetherapeuticactionofnbutyldeoxynojirimycintowardsbraingm2accumulationinadultsandhoffdiseasemice AT lohk restrictedketogenicdietenhancesthetherapeuticactionofnbutyldeoxynojirimycintowardsbraingm2accumulationinadultsandhoffdiseasemice AT butterst restrictedketogenicdietenhancesthetherapeuticactionofnbutyldeoxynojirimycintowardsbraingm2accumulationinadultsandhoffdiseasemice AT bronsonrt restrictedketogenicdietenhancesthetherapeuticactionofnbutyldeoxynojirimycintowardsbraingm2accumulationinadultsandhoffdiseasemice AT plattf restrictedketogenicdietenhancesthetherapeuticactionofnbutyldeoxynojirimycintowardsbraingm2accumulationinadultsandhoffdiseasemice AT seyfriedt restrictedketogenicdietenhancesthetherapeuticactionofnbutyldeoxynojirimycintowardsbraingm2accumulationinadultsandhoffdiseasemice |