<p class="first" id="d2239864e95">Ischemic stroke is an acute cerebrovascular disease
due to poor blood flow to the
brain. Nevertheless, there is still no effective therapy for it and the pathology
contributing to ischemic stroke is not fully understood. Histone Deacetylase 9 (HDAC9)
is a class IIa chromatin-modifying enzyme. HDAC9 gene region is a leading risk locus
for large artery atherosclerotic stroke. However, the mechanisms linking HDAC9 to
ischemic remain elusive. In the study, we attempted to explore HDAC9-associated inflammatory
response using the wild type (WT) and HDAC9-knockout (KO) mice with brain ischemic
injury. The results indicated that WT mice with ischemia brain exhibited higher expression
levels of HDAC9. HDAC9 depletion resulted in a decreased infarct volume and an improved
neurological function in mice after ischemic reperfusion (I/R) injury. I/R injury
markedly enhanced GFAP and Iba-1 expressions in cortex and HDAC9 knockout significantly
reversed this up-regulation. Loss of HDAC9 inhibited the release of inducible NO-synthase
(iNOS), cyclooxygenase-2 (COX-2), interleukin 1β (IL-1β), IL-6, tumor necrosis factor-α
(TNF-α), and IL-18 in cortex, hippocampus and hypothalamus of mice with I/R injury,
which occurred at the transcription levels. Furthermore, the inhibitory actions of
HDAC9 deficiency were associated with the down-regulation of phosphorylated-IκBα,
phosphorylated-nuclear factor-kappa B (NF-κB), and p-mitogen-activated protein kinases
(MAPKs), including phosphorylated-p38, phosphorylated-extracellular signal-regulated
kinase 1/2 (ERK1/2), and phosphorylated-c-Jun N-terminal kinase (JNK). Importantly,
the in vitro study indicated that HDAC9 inhibition-reduced inflammation and activation
of IκBα/NF-κB were restored by promoting MAPKs activity in LPS-stimulated cells. Our
findings suggest that HDAC9 inhibition showed neuroprotective effects on ischemic
stroke by restraining inflammation, which might help develop new and effective strategies
for the therapeutic interventions in ischemic stroke.
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