Positive modulation of AMPA receptors prevents downregulation of GluR2 expression and activates the Lyn-ERK1/2-CREB signaling in rat brain ischemia.

Abstract

alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are responsible for excitotoxicity induced by ischemic injury in hippocampal CA1 neurons, whereas the molecular mechanisms responsible for their neurotrophic activities are much less studied. Here, we examined the neuroprotective effect of positive modeulation of AMPARs by coapplication of AMPA with PEPA, an allosteric potentiator of AMPARs. We showed that coapplication of AMPA with PEPA protected hippocampal CA1 neurons from brain ischemia-induced death. Coapplication of AMPA with PEPA could prevent downregulated expression of GluR2 subunit caused by ischemia and increase BDNF expression via Lyn-ERK1/2-CREB signaling. Furthermore, TrkB receptor-mediated PI3K/Akt signal pathway was activated after coapplication of AMPA with PEPA, which was related to MAPK pathway and protected CA1 neurons against ischemic insults through depression of JNK3 activity, release of cytochrome c to cytosol and depression of capase-3 activity. Our results revealed that positive modulation of AMPARs could exert neuroprotective effects and the possible signaling pathways underlied.

• Authors: Quan-Guang Zhang, Dong Han, Shu-Qun Hu, Chong Li, Chang-Zhou Yu, Ran Wang, Guang-Yi Zhang
• Journal: Hippocampus (Hippocampus) Vol. 20 Issue 1 Pg. 65-77 (Jan 2010) ISSN: 1098-1063 [Electronic] United States
• PMID: 19330848 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2009 Wiley-Liss, Inc.

Chemical References

• Cyclic AMP Response Element-Binding Protein
• RNA, Messenger
• Receptors, AMPA
• lyn protein-tyrosine kinase
• src-Family Kinases
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• glutamate receptor ionotropic, AMPA 2

Topics

• Animals
• Brain Ischemia (metabolism)
• CA1 Region, Hippocampal (metabolism)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gene Expression Regulation
• MAP Kinase Signaling System
• Male
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Neurons (metabolism)
• RNA, Messenger (metabolism)
• Rats
• Rats, Inbred Strains
• Receptors, AMPA (genetics, metabolism)
• Signal Transduction
• src-Family Kinases (metabolism)