Multiple therapeutic effects of valproic acid in spinal muscular atrophy model mice.
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.
Tsai
Li-Kai
LK
Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 100, Taiwan.
Tsai
Ming-Shiun
MS
Ting
Chen-Hung
CH
Li
Hung
H
D000818:Animals; D001253:Astrocytes / Q000473:pathology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D055495:Neurogenesis; D009469:Neuromuscular Junction / Q000473:pathology; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D055532:SMN Complex Proteins / Q000096:biosynthesis / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D055533:Survival of Motor Neuron 1 Protein / Q000378:metabolism; D055540:Survival of Motor Neuron 2 Protein; D014635:Valproic Acid / Q000627:therapeutic use*
D019253:Proto-Oncogene Proteins c-bcl-2; D055532:SMN Complex Proteins; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D014635:Valproic Acid