The HDAC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain

Abstract

In the healthy adult brain, neurogenesis normally occurs in the subventricular zone (SVZ) and hippocampal dentate gyrus (DG). Cerebral ischemia enhances neurogenesis in neurogenic and non‐neurogenic regions of the ischemic brain of adult rodents. This study demonstrated that post‐insult treatment with a histone deacetylase inhibitor, sodium butyrate (SB), stimulated the incorporation of bromo‐2′‐deoxyuridine (BrdU) in the SVZ, DG, striatum, and frontal cortex in the ischemic brain of rats subjected to permanent cerebral ischemia. SB treatment also increased the number of cells expressing polysialic acid–neural cell adhesion molecule, nestin, glial fibrillary acidic protein, phospho‐cAMP response element‐binding protein (CREB), and brain‐derived neurotrophic factor (BDNF) in various brain regions after cerebral ischemia. Furthermore, extensive co‐localization of BrdU and polysialic acid–neural cell adhesion molecule was observed in multiple regions after ischemia, and SB treatment up‐regulated protein levels of BDNF, phospho‐CREB, and glial fibrillary acidic protein. Intraventricular injection of K252a, a tyrosine kinase B receptor antagonist, markedly reduced SB‐induced cell proliferation detected by BrdU and Ki67 in the ipsilateral SVZ, DG, and other brain regions, blocked SB‐induced nestin expression and CREB activation, and attenuated the long‐lasting behavioral benefits of SB. Together, these results suggest that histone deacetylase inhibitor‐induced cell proliferation, migration and differentiation require BDNF–tyrosine kinase B signaling and may contribute to long‐term beneficial effects of SB after ischemic injury.

Epigenetic Mechanisms in Cerebral Ischemia

“…[121][122][123] Histone deacetylase inhibition induces BDNF-receptor tyrosine kinase (TrkB)-dependent cell proliferation, migration, and differentiation in experimental stroke. 91 Moreover, postischemic application of HDACi triggers cell division outside the subventricular zone and dentate gyrus , for example in the striatum and frontal cortex. However, simultaneous inhibition of the BDNF TrkB abolishes the effects of HDACi sodium butyrate.…”

Interplay between histone acetylation/deacetylation and poly(ADP-ribosyl)ation in the development of ischemic tolerance in vitro

“…A mild increase in the acetylation of histone H3, as observed in our study following the application of preconditioning doses of NMDA, is expected to result in an increase in expression of neuroprotective proteins or downregulation of pro-inflammatory genes. According to this hypothesis, HDAC inhibitors, that are able to prevent the reduction of acetylation in models of cerebral ischemia, up-regulate protein levels of Bcl-2, Hsp70, pCREB, BDNF, GFAP, pAKT and reduce the ischemia-induced increase in expression of p53, NOS, COX-2, TNF-a and IL-b; (Faraco et al, 2006;Kim et al, 2007Kim et al, , 2009. In this study, we show that the mild increase in acetylation induced by NMDA preconditioning is associated with a downstream increase in ERK 1/2 phosphorylation, a crucial prosurvival signaling pathway in models of ischemic tolerance (Shamloo et al, 1999;Choi et al, 2006;Gao et al, 2010;Gerace et al, 2012).…”

“…These effects appear to be due to the maintenance of histone acetylation levels, the expression of cell survival (Bcl-2, Bcl-XL, Hsp70) and regenerative (BDNF) pathways, and the downregulation of pro-inflammatory genes (COX-2, iNOS, TNF-a, IL-b) (Faraco et al, 2006;Kim et al, 2007Kim et al, , 2009. In a more recent study, the combined pretreatment with a class I HDAC inhibitor and an activator of SIRT1 (a class III HDAC belonging to the sirtuin family) restored acetylation of RelA and histones and limited postischemic injury in in vivo an in vitro models of stroke (Lanzillotta et al, 2013).…”

“…A number of studies (reviewed in: Langley et al, 2009;Gibson and Murphy, 2010;Schweizer et al, 2013) have shown that histone acetylation is reduced following cerebral ischemia and that class I, II and IV HDAC inhibitors are able to ameliorate neuronal death and cognitive deficits following transient (Endres et al, 2000;Ren et al, 2004;Qi et al, 2004;Faraco et al, 2006;Yildrim et al, 2008;Wang et al, 2012) and permanent Langley et al, 2008;Kim et al, 2009) focal ischemia and in a model of transient global ischemia (Xuan et al, 2012). These effects appear to be due to the maintenance of histone acetylation levels, the expression of cell survival (Bcl-2, Bcl-XL, Hsp70) and regenerative (BDNF) pathways, and the downregulation of pro-inflammatory genes (COX-2, iNOS, TNF-a, IL-b) (Faraco et al, 2006;Kim et al, 2007Kim et al, , 2009.…”

Effect of Organic Acid Salts as an Alternative to Antibiotic Growth Promoters on the Production Performance of Commercial Broiler Chicken

“…Moreover, organic acid (acetic acid) supplementation increased the water consumption even in heat stressed birds that resulted in enhanced performance and immune response than control birds (Hassan et al, 2009). Besides, butyrate induced the cell proliferation; migration and differentiation require BDNF-tyrosine kinase B signaling and may contribute to long-term beneficial effects of butyrate after ischemic injury this may resulted in reduced mortality in organic acid supplemented groups (Kim et al, 2009). …”