Multiple therapeutic effects of valproic acid in spinal muscular atrophy model mice

J Mol Med (Berl). 2008 Nov;86(11):1243-54. doi: 10.1007/s00109-008-0388-1. Epub 2008 Jul 23.


Spinal muscular atrophy (SMA) is a progressive disease involving the degeneration of motor neurons with no currently available treatment. While valproic acid (VPA) is a potential treatment for SMA, its therapeutic mechanisms are still controversial. In this study, we investigated the mechanisms of action of VPA in the treatment of type III-like SMA mice. SMA and wild-type mice were treated with VPA from 6 to 12 months and 10 to 12 months of age, respectively. Untreated SMA littermates and age-matched wild-type mice were used for comparison. VPA-treated SMA mice showed better motor function, larger motor-evoked potentials, less degeneration of spinal motor neurons, less muscle atrophy, and better neuromuscular junction innervation than non-treated SMA mice. VPA elevated SMN protein levels in the spinal cord through SMN2 promoter activation and probable restoration of correct splicing of SMN2 pre-messenger RNA. VPA also increased levels of anti-apoptotic factors, Bcl-2 and Bcl-x(L), in spinal neurons. VPA probably induced neurogenesis and promoted astrocyte proliferation in the spinal cord of type III-like SMA mice, which might contribute to therapeutic effects by enhancing neuroprotection. Through these effects of elevation of SMN protein level, anti-apoptosis, and probable neuroprotection, VPA-treated SMA mice had less degeneration of spinal motor neurons and better motor function than untreated type III-like SMA mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / pathology
  • Cell Proliferation
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Transgenic
  • Motor Neurons / pathology
  • Muscle Fibers, Skeletal / pathology
  • Muscular Atrophy, Spinal / drug therapy*
  • Muscular Atrophy, Spinal / pathology
  • Muscular Atrophy, Spinal / physiopathology
  • Neurogenesis
  • Neuromuscular Junction / pathology
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • SMN Complex Proteins / biosynthesis
  • SMN Complex Proteins / genetics
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Survival of Motor Neuron 1 Protein / metabolism
  • Survival of Motor Neuron 2 Protein
  • Valproic Acid / therapeutic use*


  • Proto-Oncogene Proteins c-bcl-2
  • SMN Complex Proteins
  • SMN2 protein, human
  • Survival of Motor Neuron 1 Protein
  • Survival of Motor Neuron 2 Protein
  • Valproic Acid