(−)-Epicatechin, a Natural Flavonoid Compound, Protects Astrocytes Against Hemoglobin Toxicity via Nrf2 and AP-1 Signaling Pathways

Xi Lan, Xiaoning Han, Qian Li, Jian Wang

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


(−)-Epicatechin is a brain-permeable, natural product found at high concentrations in green tea and cocoa. Our previous research has shown that (−)-epicatechin treatment reduces hemorrhagic stroke injury via nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in vivo. However, the mechanism of action of this compound in modulation of oxidant stress and in protection against hemoglobin-induced astrocyte injury is unclear. Therefore, we explored the cellular and molecular mechanisms that underlie these protective effects in vitro. Mouse primary astrocytes isolated from wild-type mice and Nrf2 knockout (KO) mice were preconditioned with hemoglobin to simulate intracerebral hemorrhage (ICH) in vitro. Effects of (−)-epicatechin were measured by Western blotting, immunostaining, MTT assay, and reactive oxidant stress (ROS) assay. (−)-Epicatechin increased Nrf2 nuclear accumulation and cytoplasmic levels of superoxide dismutase 1 (SOD1) in wild-type astrocytes but did not increase SOD1 expression in Nrf2 knockout (KO) astrocytes. Furthermore, (−)-epicatechin treatment did not alter heme oxygenase 1 (HO1) expression in wild-type astrocytes after hemoglobin exposure, but it did decrease HO1 expression in similarly treated Nrf2 KO astrocytes. In both wild-type and Nrf2 KO astrocytes, (−)-epicatechin suppressed phosphorylated JNK and nuclear expression of JNK, c-jun, and c-fos, indicating that inhibition of activator protein-1 (AP-1) activity by (−)-epicatechin is Nrf2-independent. These novel findings indicate that (−)-epicatechin protects astrocytes against hemoglobin toxicity through upregulation of Nrf2 and inhibition of AP-1 activity. These cellular and molecular effects may partially explain the cerebroprotection as we previously observed for (−)-epicatechin in animal models of ICH.

Original languageEnglish (US)
Pages (from-to)7898-7907
Number of pages10
JournalMolecular Neurobiology
Issue number10
StatePublished - Dec 1 2017


  • (−)-Epicatechin
  • Heme oxygenase 1
  • Intracerebral hemorrhage
  • Nuclear factor erythroid 2-related factor 2
  • Reactive oxygen species

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience


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