Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice
Abstract
Multiple molecular defects trigger cell death in amyotrophic lateral sclerosis (ALS). Among these, altered transcriptional activity may perturb many cellular functions, leading to a cascade of secondary pathological effects. We showed that pharmacological treatment, using the histone deacetylase inhibitor sodium phenylbutyrate, significantly extended survival and improved both the clinical and neuropathological phenotypes in G93A transgenic ALS mice. Phenylbutyrate administration ameliorated histone hypoacetylation observed in G93A mice and induced expression of nuclear factor‐κB (NF‐κB) p50, the phosphorylated inhibitory subunit of NF‐κB (pIκB) and beta cell lymphoma 2 (bcl‐2), but reduced cytochrome c and caspase expression. Curcumin, an NF‐κB inhibitor, and mutation of the NF‐κB responsive element in the bcl‐2 promoter, blocked butyrate‐induced bcl‐2 promoter activity . We provide evidence that the pharmacological induction of NF‐κB‐dependent transcription and bcl‐2 gene expression is neuroprotective in ALS mice by inhibiting programmed cell death. Phenylbutyrate acts to phosphorylate IκB, translocating NF‐κB p50 to the nucleus, or to directly acetylate NF‐κB p50. NF‐κB p50 transactivates bcl‐2 gene expression. Up‐regulated bcl‐2 blocks cytochrome c release and subsequent caspase activation, slowing motor neuron death. These transcriptional and post‐translational pathways ultimately promote motor neuron survival and ameliorate disease progression in ALS mice. Phenylbutyrate may therefore provide a novel therapeutic approach for the treatment of patients with ALS.
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Benzamide compound 1 has a significantly different binding mode, in which the thiophene group is inserted into the foot pocket.
“The benzamide compound 1 has a significantly different binding mode, in which the thiophene group is inserted into the 'foot pocket' (Fig. 3 B ) (20-23, 32, 33).”
From Histone Deacetylase (HDAC) Inhibitor Kinetic Rate Constants Correlate with Cellular Histone Acetylation but Not Transcription and Cell Viability (2013) · cites this paper as [20]
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- Authors
- Ryu, H., Smith, K., Camelo, S. I., Carreras, I., Lee, J., Iglesias, A. H., Dangond, F., Cormier, K. A., Cudkowicz, M. E., H. Brown, R., & Ferrante, R. J.
- Affiliations
- Edith Nourse Rogers Memorial Veterans Hospital (US)
- Boston University (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Corresponding author
- Ferrante, Robert J.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2005-04-26
- Volume
- 93
- Issue
- 5
- Pages
- 1087-1098
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1987105053
- Cited by
- 353
- References
- 2
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 24 · 2023: 18 · 2022: 22 · 2021: 12 · 2020: 19 · 2019: 9 · 2018: 14 · 2017: 9 · 2016: 19 · 2015: 13 · 2014: 16 · 2013: 22 · 2012: 14
- FWCI
- 11.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- ALS Association
- National Institutes of Health
- National Institute on Aging (AG 12992, AG 13846, P30AG013846, P01AG012992)
- National Institute of Neurological Disorders and Stroke (R01NS037912, NS 31248, NS37912)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Keywords
- amyotrophic lateral sclerosis, 4-phenylbutyric acid, histone deacetylase inhibitors, NF-κB p50, Bcl-2, histone hypoacetylation, IκB phosphorylation, cytochrome c release, caspase activation, motor neuron degeneration, neuroprotection, curcumin, anti-apoptotic gene expression
- MeSH terms
- Acetylation, Amyotrophic Lateral Sclerosis, Animals, Cell Survival, Curcumin, Histones, Male, Mice, Transgenic, Motor Neurons, Phenylbutyrates, Promoter Regions, Genetic, Protein Precursors, Spinal Cord, Gene Expression, NF-kappa B, Apoptosis, Disease Progression, Proto-Oncogene Proteins c-bcl-2, Cytochromes c, Mice, NF-kappa B p50 Subunit, Caspase Inhibitors
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