TY - JOUR
T1 - Cerebroprotection of flavanol (-)-epicatechin after traumatic brain injury via Nrf2-dependent and -independent pathways
AU - Cheng, Tian
AU - Wang, Wenzhu
AU - Li, Qian
AU - Han, Xiaoning
AU - Xing, Jing
AU - Qi, Cunfang
AU - Lan, Xi
AU - Wan, Jieru
AU - Potts, Alexa
AU - Guan, Fangxia
AU - Wang, Jian
N1 - Funding Information:
This study was supported by the National Natural Science Foundation of China ( 81071008 ), the Excellent Youth Foundation of Henan Scientific Committee ( 114100510005 ), the Technology Foundation for Selected Overseas Chinese Scholars , American Heart Association Grant 13GRNT15730001 , and National Institutes of Health Grants R01NS078026 and R01AT007317 . T.C. is the recipient of the China Scholarship Council Joint Ph.D. Training award.
Funding Information:
We thank Dr. Zengjin Yang for help with the stereology protocol, Drs. Raymond Koehler and Zengjin Yang for helpful discussions, and Claire Levine for assistance with manuscript editing.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - 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 3 h after TBI and then every 24 h 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.
AB - 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 3 h after TBI and then every 24 h 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.
KW - (-)-Epicatechin
KW - NF-E2-related factor
KW - Traumatic brain injury
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U2 - 10.1016/j.freeradbiomed.2015.12.027
DO - 10.1016/j.freeradbiomed.2015.12.027
M3 - Article
C2 - 26724590
AN - SCOPUS:84954509048
SN - 0891-5849
VL - 92
SP - 15
EP - 28
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -