Journal
MOLECULAR NEUROBIOLOGY
Volume 54, Issue 10, Pages 7898-7907Publisher
HUMANA PRESS INC
DOI: 10.1007/s12035-016-0271-y
Keywords
(-)-Epicatechin; Heme oxygenase 1; Intracerebral hemorrhage; Reactive oxygen species; Nuclear factor erythroid 2-related factor 2
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Funding
- National Institute of Health [R01NS078026, R01AT007317]
- American Heart Association Mid-Atlantic Affiliate [13GRNT15730001, 15POST25090114, 14POST20140003]
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(-)-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.
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