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

J Neurochem. 2009 Aug;110(4):1226-40. doi: 10.1111/j.1471-4159.2009.06212.x. Epub 2009 Jun 15.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Biomarkers / analysis
  • Biomarkers / metabolism
  • Brain / cytology
  • Brain / drug effects
  • Brain / enzymology
  • Brain Infarction / drug therapy*
  • Brain Infarction / enzymology
  • Brain Infarction / physiopathology
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / enzymology
  • Brain Ischemia / physiopathology
  • Brain-Derived Neurotrophic Factor / metabolism
  • Bromodeoxyuridine / metabolism
  • Butyrates / pharmacology*
  • Butyrates / therapeutic use
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cell Proliferation / drug effects
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Histone Deacetylase 1
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / metabolism
  • Intermediate Filament Proteins / metabolism
  • Male
  • Nerve Regeneration / drug effects*
  • Nerve Regeneration / physiology
  • Nerve Tissue Proteins / analysis
  • Nerve Tissue Proteins / metabolism
  • Nestin
  • Neural Cell Adhesion Molecule L1 / metabolism
  • Neurogenesis / drug effects*
  • Neurogenesis / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, trkB / antagonists & inhibitors
  • Receptor, trkB / metabolism
  • Sialic Acids / metabolism


  • Biomarkers
  • Brain-Derived Neurotrophic Factor
  • Butyrates
  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Intermediate Filament Proteins
  • Nerve Tissue Proteins
  • Nes protein, rat
  • Nestin
  • Neural Cell Adhesion Molecule L1
  • Sialic Acids
  • polysialyl neural cell adhesion molecule
  • Receptor, trkB
  • Hdac1 protein, rat
  • Histone Deacetylase 1
  • Histone Deacetylases
  • Bromodeoxyuridine