期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 60, 期 -, 页码 282-291出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2013.02.029
关键词
Mild traumatic brain injury; Blood-brain barrier; Oxidative stress; Perivascular unit; Neuroinflammation; Primary blast; Free radicals
资金
- NIH/NIAAA [R21 AA020370-01A1, RO1 AA017398]
- U.S. Army Research Office project Army UNL Center of Trauma Mechanics [W911NF- 08-10483]
We investigate the hypothesis that oxidative damage of the cerebral vascular barrier interface (the blood-brain barrier, BBB) causes the development of mild traumatic brain injury (TBI) during a primary blast-wave spectrum. The underlying biochemical and cellular mechanisms of this vascular layer-structure injury are examined in a novel animal model of shock tube. We first established that low-frequency (123 kPa) single or repeated shock wave causes BBB/brain injury through biochemical activation by an acute mechanical force that occurs 6-24 h after the exposure. This biochemical damage of the cerebral vasculature is initiated by the induction of the free radical-generating enzymes NADPH oxidase 1 and inducible nitric oxide synthase. Induction of these enzymes by shock-wave exposure paralleled the signatures of oxidative and nitrosative damage (4-HNE/3-NT) and reduction of the BBB tight-junction (TJ) proteins occludin, claudin-5, and zonula occluden 1 in the brain microvessels. In parallel with TJ protein disruption, the perivascular unit was significantly diminished by single or repeated shock-wave exposure coinciding with the kinetic profile. Loosening of the vasculature and perivascular unit was mediated by oxidative stress-induced activation of matrix metalloproteinases and fluid channel aquaporin-4, promoting vascular fluid cavitation/edema, enhanced leakiness of the BBB, and progression of neuroinflammation. The BBB leakiness and neuroinflammation were functionally demonstrated in an in vivo model by enhanced permeativity of Evans blue and sodium fluorescein low-molecular-weight tracers and the infiltration of immune cells across the BBB. The detection of brain cell proteins neuron-specific enolase and sloop in the blood samples validated the neuroastroglial injury in shock-wave TBI. Our hypothesis that cerebral vascular injury occurs before the development of neurological disorders in mild TBI was further confirmed by the activation of caspase-3 and cell apoptosis mostly around the perivascular region. Thus, induction of oxidative stress and activation of matrix metalloproteinases by shock wave underlie the mechanisms of cerebral vascular BBB leakage and neuroinflammation. Published by Elsevier Inc.
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