AMPA protects cultured neurons against glutamate excitotoxicity through a phosphatidylinositol 3‐kinase‐dependent activation in extracellular signal‐regulated kinase to upregulate BDNF gene expression

Abstract

The signal transduction and molecular mechanisms underlying a-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 lM) + aniracetam (1 lM), 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. Keywords: Akt, AMPA, aniracetam, BDNF, ERK1/ 2, neuroprotection. J. Neurochem. (2004) 90, 807-818. Glutamate is the major excitatory neurotransmitter in the mammalian CNS and acts through two types of receptors, ionotropic and metabotropic (Hollman et al. 1989;Schoepp et al. 1999). Glutamate has also been implicated in the pathophysiology of hypoxic/ischemic neuronal damage (Olney et al. 1971;Choi 1995). The ionotropic glutamate receptor subtypes, N-methyl-D-aspartate (NMDA) (Choi 1995) and a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors are thought to play a major role in the pathophysiology of hypoxic-ischemic neuronal damage

Rapid Enhancement of Glutamatergic Neurotransmission in Bipolar Depression Following Treatment with Riluzole

“…Increased AMPA receptor 'throughput' may ultimately cause downstream neuroproliferative effects through the induction of brain-derived neurotrophic factor and multiple intracellular signaling cascades (Lauterborn et al, 2000;Lauterborn et al, 2009;Mackowiak et al, 2002;Voss et al, 2007;Wu et al, 2004;Zhang et al, 2009). These speculations accord with previous evidence .…”

Presynaptic AMPA and kainate receptors increase the size of GABAergic terminals and enhance GABA release

“…It was previously found that AMPA at a high concentration (500 μM) increased granule cells survival (Wu et al, 2004). Our data support these findings but also show that much lower concentrations of either AMPA or kainate are required for this action and that AMPA or NMDA receptors can independently mediate the increased survival of cerebellar granule neurons.…”

Neuroprotective Effect of Taurine against Oxidative Stress-Induced Damages in Neuronal Cells

“…Recently, it has been suggested that ERK I/II plays an essential role in the neuroprotective processes (Wu et al, 2004;Shen et al, 2009;Jiang et al, 2009). Our study present evidence for the first time that ERK I/II activation by taurine may be an important step for the neuroprotection exerted by taurine.…”