Journal
NEUROSCIENCE RESEARCH
Volume 69, Issue 4, Pages 291-298Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neures.2010.12.016
Keywords
Edaravone; Carnosic acid; Nrf2; NGF; Ischemia; Reperfusion
Categories
Funding
- Japan Science and Technology Agency (JST) [H20-02-010]
- Grants-in-Aid for Scientific Research [20117010, 23590560] Funding Source: KAKEN
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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 carnosi: 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 (similar to 1 mM) and CA (similar to 50 mu M) treatment synergistically enhanced NGF expression. Nrf2 knockdown by siRNA aid 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. (c) 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
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