title: Cerebroprotection of flavanol (-)-epicatechin after traumatic brain injury via Nrf2-dependent and -independent pathways.
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.
authors.affiliation: 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.
authors.forename: Tian
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Wenzhu
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Xing
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Cunfang
authors.initials: C
authors.lastname: Qi
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Lan
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jieru
authors.initials: J
authors.lastname: Wan
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Alexa
authors.initials: A
authors.lastname: Potts
authors.affiliation: 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: 13613813972@126.com.
authors.forename: Fangxia
authors.initials: F
authors.lastname: Guan
authors.affiliation: 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: jwang79@jhmi.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001929:Brain Edema / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002392:Catechin / Q000008:administration & dosage*; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D018696:Neuroprotective Agents / Q000008:administration & dosage; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D002392:Catechin; D051547:Heme Oxygenase-1
keywords: (-)-Epicatechin; NF-E2-related factor; Traumatic brain injury