Multiple therapeutic effects of valproic acid in spinal muscular atrophy model mice
Journal
Journal of Molecular Medicine
Journal Volume
86
Journal Issue
11
Pages
1243-1254
Date Issued
2008
Author(s)
Abstract
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. ? 2008 Springer-Verlag.
SDGs
Other Subjects
messenger RNA; protein bcl 2; protein bcl x; survival motor neuron protein; valproic acid; animal experiment; animal model; animal tissue; article; astrocyte; cell differentiation; comparative study; controlled study; evoked muscle response; motoneuron; motor performance; mouse; muscle atrophy; nervous system development; neuromuscular synapse; neuroprotection; nonhuman; spinal cord nerve cell; spinal muscular atrophy; Animals; Astrocytes; Cell Proliferation; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Motor Neurons; Muscle Fibers, Skeletal; Muscular Atrophy, Spinal; Neurogenesis; Neuromuscular Junction; Promoter Regions, Genetic; Proto-Oncogene Proteins c-bcl-2; SMN Complex Proteins; Spinal Cord; Survival of Motor Neuron 1 Protein; Valproic Acid
Type
journal article