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Exp Neurol. 2016 May;279:13-26. doi: 10.1016/j.expneurol.2016.02.009. Epub 2016 Feb 15.

Protective effects of butyrate-based compounds on a mouse model for spinal muscular atrophy.

Author information

1
Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, 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; Department of Biological Sciences, University of Delaware, Newark, DE, USA. Electronic address: butchbach@nemoursresearch.org.
2
Center for Applied Clinical Genomics, Nemours Biomedical Research, Nemours Alfred I. duPont Hospital for Children, Wilmington, DE, USA; Department of Biological Sciences, University of Delaware, Newark, DE, USA.
3
Center for Applied Clinical Genomics, Nemours Biomedical Research, Nemours Alfred I. duPont Hospital for Children, Wilmington, DE, USA.
4
Center for Motor Neuron Biology and Disease, Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
5
Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
6
Department of Biochemistry and Medical Genetics, University of Manitoba Faculty of Health Sciences, Winnipeg, Manitoba, Canada.
7
Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA. Electronic address: burghes.1@osu.edu.

Abstract

Proximal spinal muscular atrophy (SMA) is a childhood-onset degenerative disease resulting from the selective loss of motor neurons in the spinal cord. SMA is caused by the loss of SMN1 (survival motor neuron 1) but retention of SMN2. The number of copies of SMN2 modifies disease severity in SMA patients as well as in mouse models, making SMN2 a target for therapeutics development. Sodium butyrate (BA) and its analog (4PBA) have been shown to increase SMN2 expression in SMA cultured cells. In this study, we examined the effects of BA, 4PBA as well as two BA prodrugs-glyceryl tributyrate (BA3G) and VX563-on the phenotype of SMNΔ7 SMA mice. Treatment with 4PBA, BA3G and VX563 but not BA beginning at PND04 significantly improved the lifespan and delayed disease end stage, with administration of VX563 also improving the growth rate of these mice. 4PBA and VX563 improved the motor phenotype of SMNΔ7 SMA mice and prevented spinal motor neuron loss. Interestingly, neither 4PBA nor VX563 had an effect on SMN expression in the spinal cords of treated SMNΔ7 SMA mice; however, they inhibited histone deacetylase (HDAC) activity and restored the normal phosphorylation states of Akt and glycogen synthase kinase 3β, both of which are altered by SMN deficiency in vivo. These observations show that BA-based compounds with favorable pharmacokinetics ameliorate SMA pathology possibly by modulating HDAC and Akt signaling.

KEYWORDS:

4-phenylbutyrate; Akt; Butyrate prodrug; Neuroprotection; Preclinical drug trial; Spinal muscular atrophy

PMID:
26892876
PMCID:
PMC4834225
DOI:
10.1016/j.expneurol.2016.02.009
[Indexed for MEDLINE]
Free PMC Article

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