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
degeneratio n in SOD1-G93A mice. Reduced gliosis and upregulation of the glutama te 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 progres sion as well as to enhance motor performance to improve the quality of life for ALS patients.
One of the major critiques was that the paper did not consider the side effects of the drug as it has broad spectrum effects that could have serious consequences - for example it is likely to be carcinogenic.