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Exp Neurol. 2014 Jun;256:1-6. doi: 10.1016/j.expneurol.2014.03.005. Epub 2014 Mar 25.

The effect of diet on the protective action of D156844 observed in spinal muscular atrophy mice.

Author information

1
Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, OH USA; Center for Applied Clinical Genomics, Nemours Biomedical Research, Nemours Alfred I. duPont Hospital for Children, Wilmington, DE, USA; Center for Pediatric Research, Nemours Biomedical Research, Nemours Alfred I. duPont Hospital for Children, Wilmington, DE, USA; Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA. Electronic address: butchbach@nemoursresearch.org.
2
deCODE chemistry, Inc., Woodridge, IL, USA.
3
deCODE genetics, Inc., Reykjavik, Iceland.
4
Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, OH USA; Department of Neurology, College of Medicine, The Ohio State University, Columbus, OH USA; Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, OH USA.

Abstract

Spinal muscular atrophy (SMA) is an early-onset motor neuron disease characterized by loss of spinal motor neurons which leads to skeletal muscle atrophy. Proximal SMA results from the loss or mutation of the survival motor neuron (SMN) gene. In humans, the SMN gene is duplicated to produce two nearly identical genes, SMN1 and SMN2. SMN1 is lost in SMA but SMN2 is retained; in fact, the number of SMN2 copies correlates with disease severity. The SMN2 inducer D156844 increases the survival and improves phenotype of SMN∆7 SMA mice. Maternal diet also modifies the survival and phenotype of these mice. In this study, we show the effect of maternal diet on the protective effects of D156844 in SMN∆7 SMA mice. SMA mice maintained on the PicoLab20 Mouse diet survived longer when treated with D156844; the effect of diet was additive to the effect of D156844 on these mice. Brain levels of D156844 were higher in neonatal mice maintained on the PicoLab20 diet than those on the Harlan-Teklad 22/5 diet. SMN protein levels in the spinal cord were modestly elevated in D156844-treated, PicoLab20-maintained SMA mice. These data show that maternal diet does influence the responsiveness of D156844 in neonatal SMN∆7 SMA mice.

KEYWORDS:

2,4-Diaminoquinazoline; Maternal diet; Motor neuron disease; Neonatal mouse; Preclinical drug trial; Spinal muscular atrophy

PMID:
24681157
PMCID:
PMC4029929
DOI:
10.1016/j.expneurol.2014.03.005
[Indexed for MEDLINE]
Free PMC Article

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