Ferrous Iron Induces Nrf2 Expression in Mouse Brain Astrocytes to Prevent Neurotoxicity

• Published in: Journal of biochemical and molecular toxicology 2016-08, Vol.30 (8), p.396-403
• Main Authors: Cui, Zhenwen, Zhong, Zhihong, Yang, Yong, Wang, Baofeng, Sun, Yuhao, Sun, Qingfang, Yang, Guo-yuan, Bian, Liuguan
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Astrocyte; Astrocytes - cytology; Astrocytes - drug effects; Astrocytes - metabolism; Cell Survival - drug effects; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cytotoxicity; Fe2; Ferrous Compounds - pharmacology; Gene Expression Regulation - drug effects; L-Lactate Dehydrogenase - secretion; Mice; Mice, Inbred C57BL; Neurotoxicity; NF-E2-Related Factor 2 - antagonists & inhibitors; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2; Oxidative Stress; Primary Cell Culture; Reactive Oxygen Species - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction
• ISSN: 1095-6670; 1099-0461
• DOI: 10.1002/jbt.21803

ABSTRACT Free radical damage caused by ferrous iron is involved in the pathogenesis of secondary brain injury after intracerebral hemorrhage (ICH). NF‐E2‐related factor 2 (Nrf2), a major phase II gene regulator that binds to antioxidant response element, represents an important cellular cytoprotective mechanism against oxidative damage. We hypothesized that Nrf2 might protect astrocytes from damage by Fe2+. Therefore, we examined cytotoxicity in primary astrocytes induced by iron overload and evaluated the effects of Fe2+ on Nrf2 expression. The results demonstrated that 24‐h Fe2+ exposure exerted time‐ and concentration‐dependent cytotoxicity in astrocytes. Furthermore, Fe2+ exposure in astrocytes resulted in time‐ and concentration‐dependent increases in Nrf2 expression, which preceded Fe2+ toxicity. Nrf2‐specific siRNA further knocked down Nrf2 levels, resulting in greater Fe2+‐induced astrocyte cytotoxicity. These data indicate that induction of Nrf2 expression could serve as an adaptive self‐defense mechanism, although it is insufficient to completely protect primary astrocytes from Fe2+‐induced neurotoxicity.