The excitoprotective effect of N‐methyl‐d‐aspartate receptors is mediated by a brain‐derived neurotrophic factor autocrine loop in cultured hippocampal neurons

• DOI: 10.1111/j.1471-4159.2005.03200.x
• Publication Date: 2005-07-15T16:54:18Z
• Authors: Xueying Jiang; Feng Tian; Karen Mearow; Peter Okagaki; Robert H. Lipsky; Ann M. Marini
• Keywords: Excitotoxicity; Ifenprodil

Abstract The neuroprotective effect and molecular mechanisms underlying preconditioning with N ‐methyl‐D‐aspartate (NMDA) in cultured hippocampal neurons have not been described. Pre‐incubation subtoxic concentrations of the endogenous neurotransmitter glutamate protects vulnerable against NMDA receptor‐mediated excitotoxicity. As a result physiological preconditioning, significantly antagonizes neurotoxicity resulting from subsequent exposure to an excitotoxic concentration glutamate. protective or is time‐ concentration‐dependent, suggesting that sufficient agonist time are required establish intracellular state. In these cells, TrkB ligand, brain‐derived neurotrophic factor (BDNF) attenuates toxicity. Therefore, we tested hypothesis via BDNF‐dependent mechanism. Exposure cultures (50 μ m ) evoked release BDNF within 2 min without attendant changes protein gene expression. accumulated increase medium followed by phosphorylation (activation) receptors later exon 4‐specific mRNA. was attenuated pre‐incubation BDNF‐blocking antibody TrkB‐IgG, fusion known inhibit activity extracellular BDNF, plays major role NMDA‐mediated survival. These results demonstrate low level stimulation protect excitotoxicity autocrine loop suggest activation neurotrophin signaling pathways key neuroprotection NMDA.