title: The potential neuroprotective role of a histone deacetylase inhibitor, sodium butyrate, after neonatal hypoxia-ischemia.
abstract: Histone 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).
  
  
  
  Seven-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.
  
  
  
  SB 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.
  
  
  
  Administration 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.
authors.affiliation: NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 A. Pawinskiego Street, 02-106, Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Jaworska
authors.affiliation: NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 A. Pawinskiego Street, 02-106, Warsaw, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Ziemka-Nalecz
authors.affiliation: NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 A. Pawinskiego Street, 02-106, Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Sypecka
authors.affiliation: NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 A. Pawinskiego Street, 02-106, Warsaw, Poland. terezal@imdik.pan.pl.
authors.forename: Teresa
authors.identifier: 0000-0002-4301-9495
authors.initials: T
authors.lastname: Zalewska
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001238:Asphyxia Neonatorum / Q000378:metabolism / Q000517:prevention & control; D020148:Butyric Acid / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D056572:Histone Deacetylase Inhibitors; D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D020148:Butyric Acid
keywords: Astrocytes; Cytokines; Histone deacetylase inhibitors; Inflammation; Microglia; Neonatal hypoxia-ischemia; Neuroprotection; Sodium butyrate