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.
Highlights
Histone deacetylase inhibitor (HDACi), sodium butyrate (SB), has been shown to be neuroprotective in adult brain injury models
Microglia To determine the effect of SB administration on cerebral activation/influx of microglia/macrophages after hypoxiaischemia, we performed ED1 staining on the brain sections of sham-operated, HI, and HI + SB rat pups
In slices obtained from control animals, as well as from contralateral hemispheres, the activated microglial cells were not detected (p < 0.001, ipsi vs. contra)
Summary
Histone deacetylase inhibitor (HDACi), sodium butyrate (SB), has been shown to be neuroprotective in adult brain injury models. We 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). Inhibition of deacetylation promotes the acetylation of non-histone proteins, such as transcription factors, signal transduction mediators, determining their interaction, localization, and stability [1]. It is very likely that the non-specificity of deacetylase inhibitors is responsible for the opposing effect noted in distinct type of cells. As it is becoming apparent, HDAC inhibition promotes the demise of tumor cells. The same drugs display strong protective properties for neurons in in vitro and in vivo models of neurotoxicity and neurodegeneration (for rev see [2])
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