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

Abstract

Vascular dementia (VaD) is the second most common cause of dementia, but the treatment is still lacking. Although many studies have reported that histone deacetylase 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 compound 13 may increase BDNF specific isoforms expression to rescue the ischemic and hypoxic injuries through changes of acetylation on histones.

HDACi protects against vascular cognitive impairment from CCH injury via induction of BDNF‐related AMPA receptor activation

“…Previous studies have shown the protective effects of HDACi on vascular cognitive impairment induced by CCH via histone acetylation 1 and in OGD conditions via differential BDNF isoform expression 5 . We subsequently investigated which spatial regions of the protein levels of BDNF would be affected by HDACi under CCH injury.…”

“…One HDACi in particular, compound 13, increases the acetylation status in histones 3 and 4, which further react with specific promotors of BDNF 5 . BDNF acted as a modulator to induce changes in gene expression or protein synthesis.…”

“…Previous studies have shown the protective effects of HDACi on vascular cognitive impairment induced by CCH via histone acetylation 1 and in OGD conditions via differential BDNF isoform expression. 5 We subsequently investigated which spatial regions of the protein levels of BDNF would be affected by HDACi under CCH injury. Although Western blotting analysis has shown that SAHA increases the protein levels of BDNF under ischemic conditions, 18 to our knowledge, the levels of it were never examined under CCH condition with immunohistochemistry analysis.…”

“…One HDACi in particular, compound 13, increases the acetylation status in histones 3 and 4, which further react with specific promotors of BDNF. 5 BDNF acted as a modulator to induce changes in gene expression or protein synthesis. The vesicle-released BDNF binds to the TrkB receptors and alters protein levels of AMPA receptors, but not dopamine receptors.…”

“…CCH is associated with cognitive impairment linked to vascular disease 2 and is mainly due to inflammation and subsequent neuronal apoptosis 3,4 . The protective effect of these HDAC inhibitors was through H3K14 or H4K5 acetylation–mediated differential brain‐derived neurotrophic factor (BDNF) isoform activation has been shown in vitro, 5 leading to increase BDNF concentration and improve cognitive function. However, the HDACi‐induced BDNF activation and the downstream molecular mechanism affecting cognitive function remains to be clarified.…”