التفاصيل البيبلوغرافية
| العنوان: |
Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice. |
| المؤلفون: |
Ryu, Hoon, Smith, Karen, Camelo, Sandra I., Carreras, Isabel, Lee, Junghee, Iglesias, Antonio H., Dangond, Fernando, Cormier, Kerry A., Cudkowicz, Merit E., H. Brown, Robert, Ferrante, Robert J. |
| المصدر: |
Journal of Neurochemistry; Jun2005, Vol. 93 Issue 5, p1087-1098, 12p |
| مصطلحات موضوعية: |
AMYOTROPHIC lateral sclerosis, TRANSGENIC mice, APOPTOSIS, BRAIN, NEURONS, PANCREATIC beta cells |
| مستخلص: |
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 cytochromecand 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 andbcl-2gene 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 transactivatesbcl-2gene expression. Up-regulated bcl-2 blocks cytochromecrelease 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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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