Cerebroprotection of flavanol (-)-epicatechin after traumatic brain injury via Nrf2-dependent and -independent pathways
| Autor: | Jing Xing, Jian Wang, Cunfang Qi, Tian Cheng, Fangxia Guan, Qian Li, Xi Lan, Xiaoning Han, Wenzhu Wang, Alexa Potts, Jieru Wan |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Programmed cell death Traumatic brain injury NF-E2-Related Factor 2 Brain Edema Pharmacology medicine.disease_cause Biochemistry Neuroprotection Article Catechin Superoxide dismutase 03 medical and health sciences Mice 0302 clinical medicine Physiology (medical) Edema Brain Injuries Traumatic medicine Animals Humans chemistry.chemical_classification Mice Knockout Reactive oxygen species biology Chemistry medicine.disease Oxidative Stress 030104 developmental biology Neuroprotective Agents Gene Expression Regulation Anesthesia Knockout mouse biology.protein medicine.symptom Reactive Oxygen Species 030217 neurology & neurosurgery Oxidative stress Heme Oxygenase-1 Signal Transduction |
| Zdroj: | Free radical biologymedicine. 92 |
| ISSN: | 1873-4596 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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