PMID- 23404502
OWN - NLM
STAT- MEDLINE
DCOM- 20130515
LR  - 20211021
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 288
IP  - 12
DP  - 2013 Mar 22
TI  - 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.
PG  - 8299-8312
LID - S0021-9258(19)33479-9 [pii]
LID - 10.1074/jbc.M112.426536 [doi]
AB  - 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.
FAU - Corbett, Grant T
AU  - Corbett GT
AD  - Graduate Program in Neuroscience, Department of Neurological Sciences, Rush 
      University Medical Center, Chicago, Illinois 60612; Department of Neurological 
      Sciences, Rush University Medical Center, Chicago, Illinois 60612.
FAU - Roy, Avik
AU  - Roy A
AD  - Department of Neurological Sciences, Rush University Medical Center, Chicago, 
      Illinois 60612.
FAU - Pahan, Kalipada
AU  - Pahan K
AD  - Department of Neurological Sciences, Rush University Medical Center, Chicago, 
      Illinois 60612. Electronic address: Kalipada_Pahan@rush.edu.
LA  - eng
GR  - R21 NS071479/NS/NINDS NIH HHS/United States
GR  - T32 AG000269/AG/NIA NIH HHS/United States
GR  - R01 AG043375/AG/NIA NIH HHS/United States
GR  - NS71479/NS/NINDS NIH HHS/United States
GR  - P01 AG014449/AG/NIA NIH HHS/United States
GR  - NS64564/NS/NINDS NIH HHS/United States
GR  - R01 AT006681/AT/NCCIH NIH HHS/United States
GR  - R21 NS064564/NS/NINDS NIH HHS/United States
GR  - T32 AG00269/AG/NIA NIH HHS/United States
GR  - AT6681/AT/NCCIH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130212
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Creb1 protein, mouse)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (Formates)
RN  - 0 (Glial Fibrillary Acidic Protein)
RN  - 0 (Neurotrophin 3)
RN  - 0 (Phenylbutyrates)
RN  - 0 (Receptors, Nerve Growth Factor)
RN  - 0YIW783RG1 (formic acid)
RN  - EC 2.7.11.13 (Protein Kinase C)
SB  - IM
MH  - Administration, Oral
MH  - Alzheimer Disease/*drug therapy/metabolism/psychology
MH  - Animals
MH  - Astrocytes/drug effects/*metabolism/physiology
MH  - Brain-Derived Neurotrophic Factor/genetics/metabolism
MH  - Cell Shape
MH  - Cells, Cultured
MH  - Cyclic AMP Response Element-Binding Protein/*metabolism
MH  - Formates/pharmacology
MH  - Glial Fibrillary Acidic Protein/metabolism
MH  - Hippocampus/pathology
MH  - Humans
MH  - Male
MH  - Memory/drug effects
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Neurons/drug effects/metabolism
MH  - Neurotrophin 3/genetics/*metabolism
MH  - Phenylbutyrates/administration & dosage/*pharmacology
MH  - Phosphorylation
MH  - Primary Cell Culture
MH  - Protein Kinase C
MH  - Protein Processing, Post-Translational
MH  - Receptors, Nerve Growth Factor/genetics/metabolism
MH  - Up-Regulation/drug effects
PMC - PMC3605648
EDAT- 2013/02/14 06:00
MHDA- 2013/05/17 06:00
PMCR- 2014/03/22
CRDT- 2013/02/14 06:00
PHST- 2013/02/14 06:00 [entrez]
PHST- 2013/02/14 06:00 [pubmed]
PHST- 2013/05/17 06:00 [medline]
PHST- 2014/03/22 00:00 [pmc-release]
AID - S0021-9258(19)33479-9 [pii]
AID - M112.426536 [pii]
AID - 10.1074/jbc.M112.426536 [doi]
PST - ppublish
SO  - J Biol Chem. 2013 Mar 22;288(12):8299-8312. doi: 10.1074/jbc.M112.426536. Epub 
      2013 Feb 12.