title: Protective effects of butyrate-based compounds on a mouse model for spinal muscular atrophy.
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.
authors.affiliation: 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.
authors.forename: Matthew E R
authors.initials: MER
authors.lastname: Butchbach
authors.affiliation: 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.
authors.forename: Casey J
authors.initials: CJ
authors.lastname: Lumpkin
authors.affiliation: Center for Applied Clinical Genomics, Nemours Biomedical Research, Nemours Alfred I. duPont Hospital for Children, Wilmington, DE, USA.
authors.forename: Ashlee W
authors.initials: AW
authors.lastname: Harris
authors.affiliation: Center for Motor Neuron Biology and Disease, Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
authors.forename: Luciano
authors.initials: L
authors.lastname: Saieva
authors.affiliation: Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Edwards
authors.affiliation: Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Workman
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba Faculty of Health Sciences, Winnipeg, Manitoba, Canada.
authors.forename: Louise R
authors.initials: LR
authors.lastname: Simard
authors.affiliation: Center for Motor Neuron Biology and Disease, Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
authors.forename: Livio
authors.initials: L
authors.lastname: Pellizzoni
authors.affiliation: 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.
authors.forename: Arthur H M
authors.initials: AHM
authors.lastname: Burghes
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002087:Butyrates / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000473:pathology / Q000517:prevention & control* / Q000523:psychology; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D011355:Prodrugs / Q000627:therapeutic use; D013116:Spinal Cord / Q000254:growth & development / Q000473:pathology
chemical_list: D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D018696:Neuroprotective Agents; D011355:Prodrugs; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3
keywords: 4-phenylbutyrate; Akt; Butyrate prodrug; Neuroprotection; Preclinical drug trial; Spinal muscular atrophy