Benefit of valproic acid in suppressing disease progression of ALS model mice.
Valproic acid (VPA) has long been used as an antiepileptic drug and recently as a mood stabilizer, and evidence is increasing that VPA exerts neuroprotective effects through changes in a variety of intracellular signalling pathways including upregulation of Bcl-2 protein with an antiapoptotic property and inhibiting glycogen synthase kinase 3-beta, which is considered to promote cell survival. Although the neuroprotective effects of VPA have been demonstrated in a murine model of human immunodeficiency virus-1 encephalitis, there have been no reports on the effect of VPA in chronic progressing neurodegenerative disease models including amyotrophic lateral sclerosis (ALS). ALS is a devastating disease selectively affecting motoneurons, and its disease model mice bear a close resemblance to ALS symptomatically and pathologically. First, we used an organotypic slice culture using mouse spinal cord, and showed that VPA protected spinal motoneurons against death from glutamate toxicity in vitro. Then, we treated ALS model mice with VPA at the dose effective level for epileptic model mice after 45 days of age (pre-onset treatment) or the day of the disease onset (post-onset treatment). We found a significant prolongation of the disease duration in ALS model mice in both methods of treatment. Considering the long usage of VPA for epileptic patients with good tolerance and safety, these data strongly support the clinical application of VPA for ALS treatment.
Sugai
Fuminobu
F
Department of Neurology (D-4), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Yamamoto
Yoichi
Y
Miyaguchi
Katsuyuki
K
Zhou
Zhiwei
Z
Sumi
Hisae
H
Hamasaki
Toshimitsu
T
Goto
Masashi
M
Sakoda
Saburo
S
D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000818:Animals; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D003998:Dicarboxylic Acids / Q000633:toxicity; D004195:Disease Models, Animal; D018450:Disease Progression; D004347:Drug Interactions; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000517:prevention & control; D009924:Organ Culture Techniques; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects; D013482:Superoxide Dismutase / Q000235:genetics; D013997:Time Factors; D014635:Valproic Acid / Q000627:therapeutic use*
D003998:Dicarboxylic Acids; D018696:Neuroprotective Agents; D014635:Valproic Acid; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase