NF-κB mediates early blood-brain barrier disruption in a rat model of traumatic shock

Background Blood-brain barrier (BBB) disruption is associated with a large number of central nervous system and systemic disorders. The aim of the present study was to investigate the dynamic change of BBB changes during traumatic shock and resuscitation as well as the mechanisms involved. Methods The experiments were carried out on male Sprague Dawley rats anaesthetized with pentobarbital sodium. To produce traumatic shock, the rats were subjected to bilateral femoral traumatic fracture and blood withdrawal from the femoral artery to decrease mean arterial pressure (MAP) to 35 mmHg. Hypovolemic status (at a MAP of 35 to 40 mm Hg)was sustained for 1 h followed by fluid resuscitation with shed blood and 20 ml/kg of lactated Ringer's solution. Results The rats were sacrificed at 1 h, 2 h or 6 h after fluid resuscitation. BBB permeability studies showed that traumatic shock significantly increased brain water contents and sodium fluorescein leakage, which was aggravated by fluid resuscitation. Real time RT-PCR and westerm blot analyses revealed that Na+-K+-Cl- cotransporter-1 (NKCC1) and VEGF expression were up-regulated in cortical brain tissue of traumatic shock rats, and this change was accompanied by down-regulation of occludin and claudin-5. Traumatic shock also significantly increased the protein levels of NF-κB-p65 subunit. Of note, administration of NF-κB inhibitor PDTC effectively attenuated augmentation of the above changes. Conclusions Our results suggest that traumatic shock is associated with early BBB disruption, and inhibition of NF-κB may be an effective therapeutic strategy in protecting the BBB under traumatic shock conditions. Level of evidence This is a Basic Science paper and, therefore, does not require a level of evidence CORRESPONDING AUTHORS: Dr. Hong-ke Zeng, Department of Emergency and Critical Care Medicine, Guangdong General Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Er Road, Guangzhou 510080, Guangdong, China. The Second School of Clinical Medicine, Southern Medical University, 1063 Shatai Nan road, Guangzhou 510515, Guangdong, China. Tel: +86-020-83827812, Fax: +86-020-82827712, Email: zenghongke@vip.163.com. Conflicts of Interest: The authors declare no conflicts of interest. Funding disclosure: No funding was received for this work from National Institutes of Health (NIH); Wellcome Trust; and the Howard Hughes Medical Institute (HHMI). This work was supported by grants from Rui E (Rui Yi) Specialized Research Funds for Emergency Medical Research (R2014008) and the Basic Research Project of Knowledge Program of Shenzhen Science and Technology Innovation Commission (JCYJ20130401112547042). These funding agencies had no role in study design, collection/analyses of data, decision to publish, or manuscript preparation. © 2018 Lippincott Williams & Wilkins, Inc.

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