The potential neuroprotective role of a histone deacetylase inhibitor, sodium butyrate, after neonatal hypoxia-ischemia

Abstract

BackgroundHistone deacetylase inhibitor (HDACi), sodium butyrate (SB), has been shown to be neuroprotective in adult brain injury models. Potential explanation for the inhibitor action involves among others reduced inflammation. We therefore anticipated that SB will provide a suitable option for brain injury in immature animals. The aim of our study was to test the hypothesis that one of the mechanisms of protection afforded by SB after neonatal hypoxia-ischemia is associated with anti-inflammatory action. We examined the effect of SB on the production of inflammatory factors including analysis of the microglial and astrocytic cell response. We also examined the effect of SB on molecular mediators that are crucial for inducing cerebral damage after ischemia (transcription factors, HSP70, as well as pro- and anti-apoptotic proteins).MethodsSeven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 60 min of hypoxia (7.6% O2). SB (300 mg/kg) was administered in a 5-day regime with the first injection given immediately after hypoxic exposure. The damage of the ipsilateral hemisphere was evaluated by hematoxylin-eosin staining (HE) 6 days after the insult. Samples were collected at 24 and 48 h and 6 days. Effects of SB on hypoxia-ischemia (HI)-induced inflammation (cytokines and chemokine) were assessed by Luminex assay and immunohistochemistry. Expression of molecular mediators (NFκB, p53, HSP70, COX-2, pro- and anti-apoptotic factors Bax, Bcl-2, caspase-3) were assayed by Western blot analysis.ResultsSB treatment-reduced brain damage, as assessed by HE staining, suppressed the production of inflammatory markers—IL-1β, chemokine CXCL10, and blocked ischemia-elicited upregulation of COX-2 in the damaged ipsilateral hemisphere. Furthermore, administration of SB promoted the conversion of microglia phenotype from inflammatory M1 to anti-inflammatory M2. None of the investigated molecular mediators that are known to be affected by HDACis in adults were modified after SB administration.ConclusionsAdministration of SB is neuroprotective in neonatal hypoxia-ischemia injury. This neuroprotective activity prevented the delayed rise in chemokine CXCL10, IL-1β, and COX-2 in the ipsilateral hemisphere. SB appears to exert a beneficial effect via suppression of HI-induced cerebral inflammation.

Long Noncoding RNA H19 Promotes Neuroinflammation in Ischemic Stroke by Driving Histone Deacetylase 1–Dependent M1 Microglial Polarization

“…10 Interestingly, H19 regulates the expression of several HDACs. 11,12 In addition, the HDAC inhibitor sodium butyrate shifts microglia to a neuroprotective phenotype in an experimental model of ischemic stroke, 13 which could serve as a point of therapeutic intervention. We considered whether H19 participates in the phenotypic changes of microglia through regulation of HDACs during ischemic stroke and if H19 could serve as a biomarker for stroke in humans.…”

Sodium Butyrate Protects N2a Cells against Aβ Toxicity In Vitro

“…Butyrate reportedly exerts numerous beneficial effects on the gut, immune system, central nervous system, and cardiovascular system [21]. Previous studies have shown that butyrate has a positive effect on both astrocytes [22] and microglia [23][24][25][26] of the central nervous system. Moreover, previous research in our laboratory shows that β-hydroxybutyric acid as a short-chain fatty acid, the same with butyrate, protected dopaminergic neurons through inhibiting microglia-mediated neuroinflammation both in vitro and in vivo [27] and limited the excessive activation of microglia and inhibited the production of inflammatory cytokines Figure 3: NaB attenuates Aβ toxicity and maintains mitochondrial respiratory function in N2a cells.…”

“…Cells. Aβ [25][26][27][28][29][30][31][32][33][34][35] (synthesized by Shanghai Sangon Biological Engineering Technology & Services Co.) was diluted in distilled water at a concentration of 16 mmol/L and was maintained at 37°C for 7 days to preage the peptide. N2a cells were divided into four groups: the control (NT) group, the NaB (2 mM) group, the Aβ 25-35 (40 μmol/L) treatment group, and the Aβ 25-35 (40 μmol/L) with NaB (2 mM) pretreatment group.…”

“…N2a cells were divided into four groups: the control (NT) group, the NaB (2 mM) group, the Aβ 25-35 (40 μmol/L) treatment group, and the Aβ 25-35 (40 μmol/L) with NaB (2 mM) pretreatment group. Cells were starved for 4 h and then pretreated with 2 mM NaB for 2 h before Aβ [25][26][27][28][29][30][31][32][33][34][35] was added. RNA or protein from N2a cells was extracted after 24 h. Each experiment was repeated three times.…”

“…After 24 hours, the complete medium was removed, and 200 μL prewarmed DMEM basal medium was added for cell starvation. Subsequently, NaB was added after 4 h to pretreat the cells, and after 2 h, Aβ [25][26][27][28][29][30][31][32][33][34][35] was added for stimulation. There were 5 replicates for each test group.…”