Benefit of valproic acid in suppressing disease progression of ALS model mice

Abstract

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.

Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model

“…On the other hand, pre or post-symptomatic VPA treatment was reported to prolong disease duration (i.e. life span), but had no effect on the onset of motor symptoms in G93A mice containing low copies of the mutant gene (Sugai et al, 2004). A more recent study using SOD-1 G86R ALS mice reported that VPA treatment robustly restores the loss of levels of acetylated histone-H3 and cyclic AMP response element binding protein (CREB) binding protein (CBP), and rescues motor neurons from death (Rouaux et al, 2007).…”

“…A clinical study showed that lithium and riluzole cotreatment markedly reduces the mortality of ALS patients during 15 months of follow-up, compared with matched control patients treated only with riluzole (Fornai et al, 2008). VPA treatment was also reported to exhibit variable effects on disease symptom onset and duration in G93A and G86R ALS mice (Sugai et al, 2004;Rouaux et al, 2007). It was recently reported that cotreatment with lithium and VPA elicits robust synergistic neuroprotective effects against glutamate-induced excitotoxicity in cultured rat brain neurons (Leng et al, 2008).…”

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…Mouse models bearing a SOD1 mutation have been used to test therapeutic strategies with HDACi. Some studies have described an amelioration of motor performance and/or an increased survival of motor neurons in the G93A transgenic ALS mouse model, with phenylbutyrate [122] or valproate [123]. Sodium phenylbutyrate combined with an antioxidant [124] or riluzole [125] showed a beneficial effect.…”

Epigenetic Mechanisms of Neurodegeneration in Huntington's Disease

“…HDAC inhibitors have been preclinically tested in many neurodegenerative conditions, including animal models of HD, amyotrophic lateral sclerosis, and multiple sclerosis [55,56,65,66,89,90]. Suberoylanilide hydroxamic acid and sodium butyrate are the first compounds that provide the efficacy of HDAC inhibition and histone modification in HD transgenic mice [91,92].…”