Edaravone and carnosic acid synergistically enhance the expression of nerve growth factor in human astrocytes under hypoxia/reoxygenation.
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.
Department of Vascular Biology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan. hidemi_yoshida@gakushikai.jp
Hidemi
H
Yoshida
Junsei
J
Mimura
Tadaatsu
T
Imaizumi
Tomoh
T
Matsumiya
Akira
A
Ishikawa
Norifumi
N
Metoki
Kunikazu
K
Tanji
Ken
K
Ota
Ryo
R
Hayakari
Kunio
K
Kosaka
Ken
K
Itoh
Kei
K
Satoh
D045784:Abietanes / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D000077553:Edaravone; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000096:biosynthesis*; D010936:Plant Extracts / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D045784:Abietanes; D000975:Antioxidants; D010936:Plant Extracts; D020932:Nerve Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C018381:salvin; D000077553:Edaravone; D000983:Antipyrine