Edaravone and carnosic acid synergistically enhance the expression of nerve growth factor in human astrocytes under hypoxia/reoxygenation.

Abstract

Edaravone is a brain-penetrant free radical scavenger that is known to ameliorate postischemic neuronal dysfunction. The transcription factor Nrf2 plays an important role in the coordinated expression of stress-inducible genes. Here we examined the effects of edaravone and carnosic acid (CA), an Nrf2-inducer, on the expression of nerve growth factor (NGF) in human astrocytes exposed to hypoxia/reoxygenation. Cultured astrocytes were exposed to hypoxia for up to 4.5 h and then treated with edaravone and/or CA under normoxia (reoxygenation) for up to 72 h. Edaravone (∼1 mM) and CA (∼50 μM) treatment synergistically enhanced NGF expression. Nrf2 knockdown by siRNA and the inhibition of JNK (c-Jun N-terminal kinase) by SP600125 decreased both CA-induced NGF expression and Nrf2 nuclear accumulation and suppressed their synergistic effect on NGF expression. In contrast, the MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase) inhibitor U0126 suppressed the synergism without inhibiting CA-induced NGF expression. These results suggest that the synergistic effects of CA and edaravone depend, at least partially, on JNK-dependent Nrf2 accumulation (induced by CA) and on MEK-dependent pathways (induced by edaravone). We conclude that the use of edaravone and CA in combination may have therapeutic potential in the treatment of brain damage, particularly ischemia/reperfusion injury.

• Authors: Hidemi Yoshida, Junsei Mimura, Tadaatsu Imaizumi, Tomoh Matsumiya, Akira Ishikawa, Norifumi Metoki, Kunikazu Tanji, Ken Ota, Ryo Hayakari, Kunio Kosaka, Ken Itoh, Kei Satoh
• Journal: Neuroscience research (Neurosci Res) Vol. 69 Issue 4 Pg. 291-8 (Apr 2011) ISSN: 1872-8111 [Electronic] Ireland
• PMID: 21241747 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Chemical References

• Abietanes
• Antioxidants
• Plant Extracts
• Nerve Growth Factor
• Extracellular Signal-Regulated MAP Kinases
• JNK Mitogen-Activated Protein Kinases
• salvin
• Edaravone
• Antipyrine

Topics

• Abietanes (pharmacology)
• Antioxidants (pharmacology)
• Antipyrine (analogs & derivatives, pharmacology)
• Astrocytes (drug effects, metabolism)
• Cell Survival (drug effects)
• Cells, Cultured
• Drug Synergism
• Edaravone
• Enzyme-Linked Immunosorbent Assay
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Humans
• Hypoxia-Ischemia, Brain (metabolism)
• Immunoblotting
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Nerve Growth Factor (biosynthesis)
• Plant Extracts (pharmacology)
• Reperfusion Injury (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects, physiology)