Sodium phenylbutyrate enhances astrocytic neurotrophin synthesis via protein kinase C (PKC)-mediated activation of cAMP-response element-binding protein (CREB): implications for Alzheimer disease therapy

J Biol Chem. 2013 Mar 22;288(12):8299-8312. doi: 10.1074/jbc.M112.426536. Epub 2013 Feb 12.


Neurotrophins, such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), are believed to be genuine molecular mediators of neuronal growth and homeostatic synapse activity. However, levels of these neurotrophic factors decrease in different brain regions of patients with Alzheimer disease (AD). Induction of astrocytic neurotrophin synthesis is a poorly understood phenomenon but represents a plausible therapeutic target because neuronal neurotrophin production is aberrant in AD and other neurodegenerative diseases. Here, we delineate that sodium phenylbutyrate (NaPB), a Food and Drug Administration-approved oral medication for hyperammonemia, induces astrocytic BDNF and NT-3 expression via the protein kinase C (PKC)-cAMP-response element-binding protein (CREB) pathway. NaPB treatment increased the direct association between PKC and CREB followed by phosphorylation of CREB (Ser(133)) and induction of DNA binding and transcriptional activation of CREB. Up-regulation of markers for synaptic function and plasticity in cultured hippocampal neurons by NaPB-treated astroglial supernatants and its abrogation by anti-TrkB blocking antibody suggest that NaPB-induced astroglial neurotrophins are functionally active. Moreover, oral administration of NaPB increased the levels of BDNF and NT-3 in the CNS and improved spatial learning and memory in a mouse model of AD. Our results highlight a novel neurotrophic property of NaPB that may be used to augment neurotrophins in the CNS and improve synaptic function in disease states such as AD.

Publication types

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

MeSH terms

  • Administration, Oral
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / psychology
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Astrocytes / physiology
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cell Shape
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Formates / pharmacology
  • Glial Fibrillary Acidic Protein / metabolism
  • Hippocampus / pathology
  • Humans
  • Male
  • Memory / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurotrophin 3 / genetics
  • Neurotrophin 3 / metabolism*
  • Phenylbutyrates / administration & dosage
  • Phenylbutyrates / pharmacology*
  • Phosphorylation
  • Primary Cell Culture
  • Protein Kinase C
  • Protein Processing, Post-Translational
  • Receptors, Nerve Growth Factor / genetics
  • Receptors, Nerve Growth Factor / metabolism
  • Up-Regulation / drug effects


  • Brain-Derived Neurotrophic Factor
  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Formates
  • Glial Fibrillary Acidic Protein
  • Neurotrophin 3
  • Phenylbutyrates
  • Receptors, Nerve Growth Factor
  • formic acid
  • Protein Kinase C