Cerebroprotection of flavanol (-)-epicatechin after traumatic brain injury via Nrf2-dependent and -independent pathways
Authors: Qian Li
Xi Lan
Fangxia Guan
Alexa Potts
Xiaoning Han
Jian Wang
Jing Xing
Tian Cheng
Cunfang Qi
Jieru Wan
Wenzhu Wang
Journal: Free Radical Biology and Medicine (2016)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: (-)-Epicatechin; NF-E2-related factor; Traumatic brain injury.
Affiliations: The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, PR China; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA., Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA., The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, PR China; School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450000, PR China. Electronic address: ., The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, PR China; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA. Electronic address: .

Abstract:  Traumatic brain injury (TBI), which leads to disability, dysfunction, and even death, is a prominent health problem worldwide with no effective treatment. A brain-permeable flavonoid named (-)-epicatechin (EC) modulates redox/oxidative stress and has been shown to be beneficial for vascular and cognitive function in humans and for ischemic and hemorrhagic stroke in rodents. Here we examined whether EC is able to protect the brain against TBI-induced brain injury in mice and if so, whether it exerts neuroprotection by modulating the NF-E2-related factor (Nrf2) pathway. We used the controlled cortical impact model to mimic TBI. EC was administered orally at 3h after TBI and then every 24h for either 3 or 7 days. We evaluated lesion volume, brain edema, white matter injury, neurologic deficits, cognitive performance and emotion-like behaviors, neutrophil infiltration, reactive oxygen species (ROS), and a variety of injury-related protein markers. Nrf2 knockout mice were used to determine the role of the Nrf2 signaling pathway after EC treatment. In wild-type mice, EC significantly reduced lesion volume, edema, and cell death and improved neurologic function on days 3 and 28; cognitive performance and depression-like behaviors were also improved with EC administration. In addition, EC reduced white matter injury, heme oxygenase-1 expression, and ferric iron deposition after TBI. These changes were accompanied by attenuation of neutrophil infiltration and oxidative insults, reduced activity of matrix metalloproteinase 9, decreased Keap 1 expression, increased Nrf2 nuclear accumulation, and increased expression of superoxide dismutase 1 and quinone 1. However, EC did not significantly reduce lesion volume or improve neurologic deficits in Nrf2 knockout mice after TBI. Our results show that EC protects the TBI brain by activating the Nrf2 pathway, inhibiting heme oxygenase-1 protein expression, and reducing iron deposition. The latter two effects could represent an Nrf2-independent mechanism in this model of TBI. 

Retracted: No

PubPeer comments:
 Fig. 3E 2 images have an apparent overlap (red boxes) with color brightness adjustment ![file] , 
 Corrected [4 September 2021] . ---------------- The authors regret After the publication of this article, the authors noticed that the representative images (E) in Fig. 3 and (C) in Fig. 4 were incorrect. The correct images are supplied below. The changes do not influence the quantified results or the conclusion of the paper. The authors would like to apologise for any inconvenience caused. Fig. 3 with correct images in E: ![] Fig. 4 with correct images in C: ![] , 
 Here are the original Figures 3E and 4C as reported in October 2018. Can the authors please comment how they managed to perform three experiments, but show three different parts of the same specimen, not just once but twice? ![file] ,