http://www.pnas.org/content/early/2013/06/05/1308950110.short
Abstract
Acute traumatic brain injury
(TBI) is associated with long-term cognitive and behavioral dysfunction.
In vivo studies have
shown histone deacetylase inhibitors
(HDACis) to be neuroprotective following TBI in rodent models. HDACis
are intriguing
candidates because they are capable of
provoking widespread genetic changes and modulation of protein function.
By using known
HDACis and a unique small-molecule
pan-HDACi (LB-205), we investigated the effects and mechanisms
associated with HDACi-induced
neuroprotection following CNS injury in an
astrocyte scratch assay in vitro and a rat TBI model in vivo. We
demonstrate the
preservation of sufficient expression of
nerve growth factor (NGF) and activation of the neurotrophic tyrosine
kinase receptor
type 1 (TrkA) pathway following HDACi
treatment to be crucial in stimulating the survival of CNS cells after
TBI. HDACi treatment
up-regulated the expression of NGF,
phospho-TrkA, phospho-protein kinase B (p-AKT), NF-κB, and B-cell
lymphoma 2 (Bcl-2) cell
survival factors while down-regulating the
expression of p75 neurotrophin receptor (NTR), phospho-JNK, and
Bcl-2–associated
X protein apoptosis factors. HDACi
treatment also increased the expression of the stem cell biomarker
nestin, and decreased
the expression of reactive astrocyte
biomarker GFAP within damaged tissue following TBI. These findings
provide further insight
into the mechanisms by which HDACi
treatment after TBI is neuroprotective and support the continued study
of HDACis following
acute TBI.
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