A neuroprotective role of extracellular signal-regulated kinase in N-acetyl-O-methyldopamine-treated hippocampal neurons after exposure to in vitro and in vivo ischemia.

Abstract

In response to cerebral ischemia, neurons activate survival/repair pathways in addition to death cascades. Activation of cyclic AMP-response-element-binding protein (CREB) is linked to neuroprotection in experimental animal models of stroke. However, a role of the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MAPK/ERK or MEK), an upstream kinase for CREB, and its relation to CREB phosphorylation in neuroprotection in cerebral ischemia has not been delineated. Previously, we reported that N-acetyl-O-methyldopamine (NAMDA) significantly protected CA1 neurons after transient forebrain ischemia [J Neurosci 19 (1999b) 87.8]. The current study is to investigate whether NAMDA-induced neuroprotection occurs via the activation of ERK and its downstream effector, CREB. NAMDA induced ERK1/2 and CREB phosphorylation with increased survival of HC2S2 hippocampal neurons subjected to oxygen-glucose deprivation. These effects were reversed by U0126, a MEK kinase inhibitor. Similarly, animals treated with NAMDA following ischemia showed increased ERK and CREB phosphorylation in the CA1 subregion of the hippocampus during early reperfusion period with increased number of surviving neurons examined 7 days following ischemia. The NAMDA-induced neuroprotection was abolished by U0126 administered shortly after reperfusion. The results showed that the ERK-CREB signaling pathway might be involved in NAMDA-induced neuroprotection following transient global ischemia and imply that the activation of the pathway in neurons may be an effective therapeutic strategy to treat stroke or other neurological syndromes.

• Authors: E M Park, T H Joh, B T Volpe, C K Chu, G Song, S Cho
• Journal: Neuroscience (Neuroscience) Vol. 123 Issue 1 Pg. 147-54 ( 2004) ISSN: 0306-4522 [Print] United States
• PMID: 14667449 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclic AMP Response Element-Binding Protein
• Enzyme Inhibitors
• N-acetyl-3-O-methyldopamine
• Mitogen-Activated Protein Kinases
• Dopamine

Topics

• Animals
• Cell Hypoxia (drug effects, physiology)
• Cell Line
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Dopamine (analogs & derivatives, pharmacology, therapeutic use)
• Enzyme Inhibitors (pharmacology)
• Hippocampus (drug effects, enzymology)
• Ischemic Attack, Transient (drug therapy, enzymology, prevention & control)
• Male
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, physiology)
• Neurons (drug effects, enzymology)
• Rats
• Rats, Wistar