PMID- 15287886
OWN - NLM
STAT- MEDLINE
DCOM- 20041028
LR  - 20131121
IS  - 0022-3042 (Print)
IS  - 0022-3042 (Linking)
VI  - 90
IP  - 4
DP  - 2004 Aug
TI  - AMPA protects cultured neurons against glutamate excitotoxicity through a 
      phosphatidylinositol 3-kinase-dependent activation in extracellular 
      signal-regulated kinase to upregulate BDNF gene expression.
PG  - 807-18
AB  - The signal transduction and molecular mechanisms underlying 
      alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-mediated 
      neuroprotection are unknown. In the present study, we determined a major AMPA 
      receptor-mediated neuroprotective pathway. Exposure of cerebellar granule cells 
      to AMPA (500 microM) + aniracetam (1 microM), a known blocker of AMPA receptor 
      desensitization, evoked an accumulation of brain-derived neurotropic factor 
      (BDNF) in the culture medium and enhanced TrkB-tyrosine phosphorylation following 
      the release of BDNF. AMPA also activated the src-family tyrosine kinase, Lyn, and 
      the downstream target of the phosphatidylinositol 3-kinase (PI3-K) pathway, Akt. 
      Extracellular signal regulated kinase (ERK), a component of the mitogen-activated 
      protein kinase (MAPK) pathway, was also activated. K252a, a selective inhibitor 
      of neurotrophin signaling, blocked the AMPA-mediated neuroprotection. The 
      involvement of BDNF release in protecting neurons by AMPA was confirmed using a 
      BDNF-blocking antibody. AMPA-mediated neuroprotection is blocked by PP1, an 
      inhibitor of src family kinases, LY294002, a PI3-K inhibitor, or U0126, a MAPK 
      kinase (MEK) inhibitor. Neuroprotective concentrations of AMPA increased BDNF 
      mRNA levels that was blocked by the AMPA receptor antagonist, 
      1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX). 
      The increase in BDNF gene expression appeared to be the downstream target of the 
      PI3-K-dependent activation of the MAPK cascade since MEK or the PI3-K inhibitor 
      blocked the AMPA receptor-mediated increase in BDNF mRNA. Thus, AMPA receptors 
      protect neurons through a mechanism involving BDNF release, TrkB receptor 
      activation, and a signaling pathway involving a PI3-K dependent activation of 
      MAPK that increases BDNF expression.
FAU - Wu, Xuan
AU  - Wu X
AD  - Department of Neurology and Neuroscience, Uniformed Services University of the 
      Health Sciences, Bethesda, MD 20814, USA.
FAU - Zhu, Daming
AU  - Zhu D
FAU - Jiang, Xueying
AU  - Jiang X
FAU - Okagaki, Peter
AU  - Okagaki P
FAU - Mearow, Karen
AU  - Mearow K
FAU - Zhu, Guanshan
AU  - Zhu G
FAU - McCall, Sherman
AU  - McCall S
FAU - Banaudha, Krishna
AU  - Banaudha K
FAU - Lipsky, Robert H
AU  - Lipsky RH
FAU - Marini, Ann M
AU  - Marini AM
LA  - eng
PT  - Journal Article
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Antibodies)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Neurotoxins)
RN  - 0 (Protein Synthesis Inhibitors)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, AMPA)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - 77521-29-0 (alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - EC 2.7.10.2 (lyn protein-tyrosine kinase)
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Antibodies/pharmacology
MH  - Brain-Derived Neurotrophic Factor/antagonists & inhibitors/*genetics
MH  - Cells, Cultured
MH  - Enzyme Inhibitors/pharmacology
MH  - Excitatory Amino Acid Antagonists/pharmacology
MH  - Gene Expression Regulation/drug effects
MH  - Glutamic Acid/*toxicity
MH  - Mitogen-Activated Protein Kinases/drug effects/*metabolism
MH  - Neurons/cytology/*drug effects/metabolism
MH  - Neuroprotective Agents/pharmacology
MH  - Neurotoxins/toxicity
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Protein Synthesis Inhibitors/pharmacology
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptor, trkB/drug effects/metabolism
MH  - Receptors, AMPA/antagonists & inhibitors/metabolism
MH  - Signal Transduction/drug effects
MH  - Up-Regulation/drug effects
MH  - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/*pharmacology
MH  - src-Family Kinases/drug effects/metabolism
EDAT- 2004/08/04 05:00
MHDA- 2004/10/29 09:00
CRDT- 2004/08/04 05:00
PHST- 2004/08/04 05:00 [pubmed]
PHST- 2004/10/29 09:00 [medline]
PHST- 2004/08/04 05:00 [entrez]
AID - JNC2526 [pii]
AID - 10.1111/j.1471-4159.2004.02526.x [doi]
PST - ppublish
SO  - J Neurochem. 2004 Aug;90(4):807-18. doi: 10.1111/j.1471-4159.2004.02526.x.