Dexmedetomidine Protects SK-N-SH Nerve Cells from Oxidative Injury by Maintaining Iron Homeostasis
Ferroptosis is characterized by the accumulation of iron-derived reactive oxygen species (ROS). Ferroptosis causes neuronal death in multiple neurological disorders. Dexmedetomidine (Dex), an extensively used anesthetic, has neuroprotective effects against ROS, but its effect on iron metabolism rema...
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Published in | Biological & pharmaceutical bulletin Vol. 43; no. 3; pp. 424 - 431 |
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Main Authors | , , |
Format | Journal Article |
Language | English Japanese |
Published |
Japan
The Pharmaceutical Society of Japan
01.03.2020
Pharmaceutical Society of Japan Japan Science and Technology Agency |
Subjects | |
Online Access | Get full text |
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Summary: | Ferroptosis is characterized by the accumulation of iron-derived reactive oxygen species (ROS). Ferroptosis causes neuronal death in multiple neurological disorders. Dexmedetomidine (Dex), an extensively used anesthetic, has neuroprotective effects against ROS, but its effect on iron metabolism remains unknown. In this study, SK-N-SH cells were treated with Dex for 24 h before treatment with 100 µM tert-butyl hydroperoxide (t-BHP; an ROS inducer) for 1 h. Afterward, intracellular ROS and labile ferrous iron [Fe(II)] levels were assessed. Dex hindered the increase in cellular ROS and labile Fe(II) levels caused by t-BHP, although Dex alone had no effect on labile Fe(II) level. t-BHP increased the expression of iron importers, transferrin receptor-1 and divalent metal transporter-1, and iron regulatory protein 1 and 2. These effects were abrogated by Dex treatment and SP-1 knockdown. t-BHP increased the phosphorylation of c-Jun N-terminal kinase (JNK) and signal transducer and activator of transcription 4 (STAT4), the primary up-stream activators of SP-1, but Dex decreased this. This study, for the first time, revealed that the antioxidative effect of Dex is partly associated to the inhibition of intracellular iron accumulation induced by t-BHP. Dex regulates iron metabolism by regulating iron importers and exporters through JNK/Sp1 and Stat4/Sp1 signaling. It is worth investigating whether Dex can protect neurons from ferroptosis. |
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ISSN: | 0918-6158 1347-5215 |
DOI: | 10.1248/bpb.b19-00711 |