HDAC inhibitor protects chronic cerebral hypoperfusion and oxygen-glucose deprivation injuries via H3K14 and H4K5 acetylation-mediated BDNF expression

Vascular dementia (VaD) is the second most common cause of dementia, but the
treatment is still lacking. Although many studies have reported that histone dea-
cetylase inhibitors (HDACis) confer protective effects against ischemic and hypoxic
injuries, their role in VaD is still uncertain. Previous studies shown, one HDACi
protected against cognitive decline in animals with chronic cerebral hypoperfusion
(CCH). However, the underlying mechanisms remain elusive. In this study, we tested
several 10,11-dihydro-5H-dibenzo[b,f]azepine hydroxamates, which act as HDACis
in the CCH model (in vivo), and SH-SY5Y (neuroblastoma cells) with oxygen-glucose
deprivation (OGD, in vitro). We identified a compound 13, which exhibited the best
cell viability under OGD. The compound 13 could increase, in part, the protein levels
of brain-derived neurotrophic factor (BDNF). It increased acetylation status on lysine
14 residue of histone 3 (H3K14) and lysine 5 of histone 4 (H4K5). We further clarified
which promoters (I, II, III, IV or IX) could be affected by histone acetylation altered
by compound 13. The results of chromatin immunoprecipitation and Q-PCR analysis
indicate that an increase in H3K14 acetylation leads to an increase in the expression
of BDNF promoter II, while an increase in H4K5 acetylation results in an increase in
the activity of BDNF promoter II and III. Afterwards, these cause an increase in the
expression of BDNF exon II, III and coding exon IX. In summary, the HDACi com-
pound 13 may increase BDNF specific isoforms expression to rescue the ischemic
and hypoxic injuries through changes of acetylation on histones.