Combined riluzole and sodium phenylbutyrate therapy in transgenic amyotrophic lateral sclerosis mice

Amyotroph Lateral Scler. 2009 Apr;10(2):85-94. doi: 10.1080/17482960802226148.


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylation / drug effects
  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / mortality
  • Animals
  • Anterior Horn Cells / drug effects
  • Body Weight / drug effects
  • Drug Synergism
  • Drug Therapy, Combination
  • Female
  • Histones / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Muscle Strength / drug effects
  • NF-kappa B p50 Subunit / metabolism
  • Neuroprotective Agents / pharmacology*
  • Phenotype
  • Phenylbutyrates / pharmacology*
  • Riluzole / pharmacology*
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase-1


  • Histones
  • NF-kappa B p50 Subunit
  • Neuroprotective Agents
  • Phenylbutyrates
  • SOD1 protein, human
  • Riluzole
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1