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α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid‐mediated neuroprotection requires TRKB receptor activation
Author(s) -
Marini A. M.,
Banaudha K.,
McCall S.,
Zhu D.,
Lipsky R.
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.81.s1.11_6.x
Subject(s) - ampa receptor , neuroprotection , tropomyosin receptor kinase b , glutamate receptor , excitotoxicity , neurotrophic factors , nbqx , nmda receptor , chemistry , microbiology and biotechnology , biology , brain derived neurotrophic factor , kainic acid , neuroscience , receptor , biochemistry
α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) plus aniracetam, an AMPA potentiator, prevents glutamate‐mediated neurotoxicity and apoptosis in cultured rat cerebellar granule cells. However, the mechanism of AMPA‐mediated neuroprotection is unknown. N‐methyl‐ d ‐aspartate (NMDA) protects neurons against glutamate‐mediated excitotoxicity via a brain‐derived neurotrophic factor (BDNF) autocrine loop. Thus, we tested whether AMPA mediates neuronal survival in a manner similar to NMDA. We show that AMPA (500 μ m ) plus aniracetam (1 μ m ) increases BDNF mRNA in a time‐dependent manner as measured by a 5′nuclease assay. AMPA elicited two peaks of BDNF mRNA, one at 15 min (2‐fold) and a second peak at 4 h (1.8‐fold). AMPA and aniracetam alone actually reduced baseline levels of BDNF mRNA. Preincubation with the tyrosine phosphorylation antagonist K252a (10 n m ) or the mitogen‐activated protein kinase pathway inhibitor, U0126 (10 μ m ) inhibited AMPA receptor‐mediated neuroprotection suggesting that neuronal survival evoked by AMPA requires activation of TrkB receptors and the MAPK signal transduction pathway. In summary, AMPA increases BDNF mRNA with two peaks of expression. The early rapid increase in BDNF expression may be ‘preformed’ messenger RNA while the latter peak may be new synthesis. TrkB receptor activation and the MAPK pathway are also required. These results suggest that ionotropic glutamate receptors may use similar mechanisms to activate intrinsic neuronal survival pathways.