Treatment with trichostatin A initiated after disease onset delays disease progression and increases survival in a mouse model of amyotrophic lateral sclerosis
- PMID: 21712032
- DOI: 10.1016/j.expneurol.2011.06.003
Treatment with trichostatin A initiated after disease onset delays disease progression and increases survival in a mouse model of amyotrophic lateral sclerosis
Abstract
Recent studies suggest that progressive motoneuron death in amyotrophic lateral sclerosis (ALS) is non-cell autonomous and may involve the participation of non-neuronal cells such as glial cells and skeletal muscle. Therefore, a drug that targets motoneurons as well as neighboring non-neuronal cells might be a potential therapeutic strategy to delay disease progression in ALS. Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, has shown protective effects in multiple cell types implicated in ALS by resetting gene transcription profiles through increased histone acetylation. To test whether TSA could serve as a potential therapeutic agent, we intraperitoneally injected TSA from postnatal day 90 (P90), after disease symptoms appear, until P120 or the end-stage in SOD1-G93A mice. We found that TSA ameliorated motoneuron death and axonal degeneration in SOD1-G93A mice. Reduced gliosis and upregulation of the glutamate transporter (GLT-1) were also observed in the spinal cord of TSA-treated SOD1-G93A mice. In addition, TSA ameliorated muscle atrophy and neuromuscular junction (NMJ) denervation, which are the pathological characteristics of ALS found in skeletal muscle. Improved morphology in TSA-treated SOD1-G93A mice was accompanied by enhanced motor functions as assessed by rota-rod and grip strength analyses. Furthermore, TSA treatment significantly increased the mean survival duration after the treatment by 18% and prolonged lifespan by 7%. Our findings suggest that TSA may provide a potential therapy to slow disease progression as well as to enhance motor performance to improve the quality of life for ALS patients.
Copyright © 2011 Elsevier Inc. All rights reserved.
Comment in
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New drugs for ALS: how do we get there?Exp Neurol. 2012 Jan;233(1):112-7. doi: 10.1016/j.expneurol.2011.10.007. Epub 2011 Oct 18. Exp Neurol. 2012. PMID: 22033032 No abstract available.
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