Department of Translational Research & Drug Development, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 7008558, Japan.
School of Pharmaceutical Sciences, Tsinghua University, Beijing 100082, China.
Int J Mol Sci. 2024 May 28;25(11):5889. doi: 10.3390/ijms25115889.
Epidural and subdural hematomas are commonly associated with traumatic brain injury. While surgical removal is the primary intervention for these hematomas, it is also critical to prevent and reduce complications such as post-traumatic epilepsy, which may result from inflammatory responses in the injured brain areas. In the present study, we observed that high mobility group box-1 (HMGB1) decreased in the injured brain area beneath the epidural hematoma (EDH) in rats, concurrent with elevated plasma levels of HMGB1. Anti-HMGB1 monoclonal antibody therapy strongly inhibited both HMGB1 release and the subsequent increase in plasma levels. Moreover, this treatment suppressed the up-regulation of inflammatory cytokines and related molecules such as interleukin-1-beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and inducible nitric oxide synthase (iNOS) in the injured areas. Our in vitro experiments using SH-SY5Y demonstrated that hematoma components-thrombin, heme, and ferrous ion- prompted HMGB1 translocation from the nuclei to the cytoplasm, a process inhibited by the addition of the anti-HMGB1 mAb. These findings suggest that anti-HMGB1 mAb treatment not only inhibits HMGB1 translocation but also curtails inflammation in injured areas, thereby protecting the neural tissue. Thus, anti-HMGB1 mAb therapy could serve as a complementary therapy for an EDH before/after surgery.
硬膜外和硬膜下血肿通常与创伤性脑损伤有关。虽然手术切除是这些血肿的主要干预措施，但预防和减少并发症也至关重要，如外伤性癫痫，这可能是受伤大脑区域的炎症反应所致。在本研究中，我们观察到大鼠硬膜外血肿（EDH）下损伤脑区的高迁移率族蛋白 B1（HMGB1）减少，同时血浆 HMGB1 水平升高。抗 HMGB1 单克隆抗体治疗强烈抑制 HMGB1 的释放和随后血浆水平的升高。此外，这种治疗抑制了损伤区域中炎症细胞因子和相关分子（如白细胞介素 1-β（IL-1β）、肿瘤坏死因子-α（TNF-α）和诱导型一氧化氮合酶（iNOS））的上调。我们使用 SH-SY5Y 的体外实验表明，血肿成分-凝血酶、血红素和亚铁离子-促使 HMGB1 从细胞核易位到细胞质，这一过程可被添加抗 HMGB1 mAb 抑制。这些发现表明，抗 HMGB1 mAb 治疗不仅抑制 HMGB1 易位，而且还能减轻损伤区域的炎症，从而保护神经组织。因此，抗 HMGB1 mAb 治疗可以作为手术前后 EDH 的辅助治疗。
