利鲁唑
肌萎缩侧索硬化
医学
药理学
胶质细胞源性神经生长因子
组蛋白脱乙酰酶抑制剂
神经保护
麻醉
神经营养因子
内科学
组蛋白脱乙酰基酶
化学
疾病
受体
基因
组蛋白
生物化学
作者
Steven J. Del Signore,Daniel J. Amante,Jin-Ho Kim,Edward C. Stack,Sarah Goodrich,Kerry Cormier,Karen Smith,Merit Cudkowicz,Robert J. Ferrante
标识
DOI:10.1080/17482960802226148
摘要
Recent evidence suggests that transcriptional dysregulation may play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS). The histone deacetylase inhibitor, sodium phenylbutyrate (NaPB), is neuroprotective and corrects aberrant gene transcription in ALS mice and has recently been shown to be safe and tolerable in ALS patients while improving hypoacetylation. Since many patients are already on riluzole, it is important to ensure that any proposed therapy does not result in negative synergy with riluzole. The combined treatment of riluzole and NaPB significantly extended survival and improved both the clinical and neuropathological phenotypes in G93A transgenic ALS mice beyond either agent alone. Combination therapy increased survival by 21.5%, compared to the separate administration of riluzole (7.5%) and NaPB (12.8%), while improving both body weight loss and grip strength. The data show that the combined treatment was synergistic. In addition, riluzole/NaPB treatment ameliorated gross lumbar and ventral horn atrophy, attenuated lumbar ventral horn neuronal cell death, and decreased reactive astrogliosis. Riluzole/NaPB administration increased acetylation at H4 and increased NF-kappaB p50 translocation to the nucleus in G93A mice, consistent with a therapeutic effect. These data suggest that NaPB may not interfere with the pharmacologic action of riluzole in ALS patients.
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