The effect of high mobility group box-1 protein on cerebral edema, blood-brain barrier, oxidative stress and apoptozis in traumatic brain injury

Objective: Traumatic brain injury (TBI) is one of the most important causes of morbidity and mortality especially among in young adults. While the primary injury due to mechanical impact is unavoidable, the secondary injury, which is formed as a result of primary injury and tought to occur due to neuroinflammation, can be prevented and thus the risk of mortality and morbidity can be reduced. The HMGB-1 protein, which is released to cytoplasm or extrasellular space from necrotic tissues after traumatic brain injury and tought to starts neuroinflammatory process, may direct the other secondary injury mechanisms. The aim of this study was to investigate the effects of HMGB-1 on its receptors TLR-4 and RAGE, cerebral edema, blood-brain barrier, oxidative stress and apoptosis in experimental traumatic brain injury. Materials and methods: A total of 30 adult male Sprague-Dawley rats, weighing 280-320 g with age of 10-12 weeks, were used for the experiments. The rats were randomly assigned to 3 groups: 1) Control, 2) TBI and 3) TBI + ethyl pyruvate group (n=10 for each group). Right parietal cortical contusion was made by using a weight-dropping TBI method. Brain samples were harvested from pericontisuonal area at 24 h after TBI. HMGB1, TLR-4, RAGE, occludin, claudin-5, ZO-1 levels are investigated by Western Blot analyses and immunohistochemistry examinations. To assess apoptosis, TUNNEL for immunohistochemistry and Western Blot for bax, bcl-2, caspase 3 were performed. In addition, total oxidant and antioxidant capacity and oxidative stress index were evaluated in blood samples. Also, brain water content for determining cerebral edema was calculated by weighing wet and dry weight of the brain tissue. Results: HMGB-1, TLR-4 and RAGE expressions increased after TBI. Major tight junction proteins in the blood-brain barrier including occludin, claudin-5 and ZO-1 expressions decreased after TBI and brain edema was found to be increased. Also proapoptotic bax and caspase 3 expressions increased, antiapoptotic bcl-2 levels decreased after TBI. Total oxidant status and oxidatif stress increased, total antioxidant status decreased after TBI. These effects came to similar levels as the sham group in the group treated with ethyl pyruvate, a HMGB-1 inhibitor. Conclusion : HMGB1 protein triggers secondary injury mechanisms by increasing blood-brain barrier dysfunction, cerebral edema, oxidative stress and apoptosis, so HMGB-1 protein plays a key role in the pathophysiology of traumatic brain injury. Our results suggest that HMGB-1 protein may be a potential target for the treatment of TBI. Key words: Apoptosis, brain edema, HMGB-1, traumatic brain injury