贝伐珠单抗抑制大鼠创伤性脑损伤半暗带区BCFB破坏和减轻炎症损伤的机制研究  

The mechanism of Bevacizumab inhibiting the destruction of BCFB in penumbra of traumatic brain injury rats and alleviating inflammatory damage

作　　者：李海荣 陆兆丰[2] 刘梦佳 朱义通 杨家发 Li Hairong;Lu Zhaofeng;Liu Mengjia;Zhu Yitong;Yang Jiafa(School of Clinical Medicine,Henan University of Science and Technology Luoyang,Henan 471000,China)

机构地区：[1]河南科技大学临床医学院,河南471000 [2]河南科技大学第一附属医院开元急诊科

出　　处：《脑与神经疾病杂志》2024年第5期284-289,共6页Journal of Brain and Nervous Diseases

基　　金：河南省医学科技攻关计划省部共建重点项目(SBGJ202102198)。

摘　　要：目的评价贝伐珠单抗(BV)对创伤性脑损伤(TBI)大鼠半暗带区恢复血-脑脊液屏障(BCFB)完整性和减轻炎症损伤的效果,以及NF-κB/MMP-9途径在实验性TBI中的潜在作用。方法大鼠被随机分成创伤组(TBI组)、创伤后应用BV组(药物干预组,TBI+BV组)、假手术组(Sham组)。采用改进的菲尼自由落体法建立大鼠TBI模型,然后用BV抑制TBI中血管内皮生长因子(VEGF)的表达。通过蛋白印迹(Western blot)和免疫组化检测VEGF在各组大鼠中的表达,采用改良神经功能评分(mNSS)、伊文思蓝染色、脑组织含水量、酶联免疫吸附试验(ELISA)和Western blot研究了VEGF的抑制对炎症反应、BCFB完整性以及神经功能恢复的影响。结果研究发现TBI诱导损伤半暗带区VEGF升高,并导致紧密连接蛋白减少,破坏BCFB完整性和介导炎症损伤。与Sham组相比,TBI组及TBI+BV组mNSS评分明显升高,BCFB完整性被显著破坏(脑水肿程度增加和紧密连接蛋白下调),炎症因子白细胞介素-6(IL-6)、白细胞介素-10(IL-10)和转化生长因子β(TGF-β)明显升高。与TBI组相比,TBI+BV组NSS评分显著降低(P<0.05)、紧密连接蛋白显著升高(P<0.05)、脑组织含水量明显改善(P<0.05)、促炎因子IL-6显著下降,抗炎因子IL-10和TNF-β显著升高(P<0.05),Western blot分析表明,BV显著抑制NF-κB/MMP-9通路激活。结论BV通过恢复BCFB完整性、调节炎性因子表达降低炎症损伤、以及抑制NF-κB/MMP-9通路激活抵消TBI后神经损伤,对大鼠TBI有良好的治疗效果。Objective To evaluate the effect of bevacizumab on restoring blood-cerebrospinal fluid barrier(BCFB)integrity and attenuating inflammatory damage in the penumbra region of rats with traumatic brain injury(TBI),as well as the potential role of NF-k B/MMP-9 pathway in experimental TBI.Methods Rats were randomly divided into traumatic group(TBI group),bevacizumab application after traumatic group(drug intervention group,TBI+BV group),and sham-operated group(Sham group),the rat TBI model was established using modified Feeney's freefall method,then the expression of vascular endothelial growth factor(VEGF)in TBI was inhibited with bevacizumab.The expression of VEGF in rats in each group was detected by western blot and immunohistochemistry,and using modified neurological severity score(mNSS),evans blue extravasation,brain tissue water connectivity,enzyme-linked immunosorbent assay,western blot to study the effect of VEGF inhibition on inflammatory response,BCFB integrity,and neurological recovery.Results The study found that the expression of VEGF in injury penumbra region was increased by TBI,and the tight junctions were reduced that resulted in BCFB integrity destroyed and inflammation damage.Compared with the Sham group,the mNSS score in the TBI group and the TBI+BV group increased significantly,and the integrity of BCFB was significantly broken(the degree of cerebral edema was increased and the tight junctions were decreased),and the inflammatory factor IL-6,IL-10 and TGF-βwere significantly increased.Compared with the TBI group,the TBI+BV group NSS score was significantly reduced(P<0.05),the tight junctions were significantly increased(P<0.05),the water content of brain tissue has improved significantly(P<0.05),and the pro-inflammatory factor IL-6 decreased significantly,and the anti-inflammatory factor IL-10 and TGF-βincreased significantly(P<0.05),as well as western blot analysis showed that bevacizumab was significantly inactivated NFk B/MMP-9 pathway.Conclusion Bevacizumab can counteract brain edema by rest

关 键 词：贝伐珠单抗 血-脑脊液屏障 紧密连接蛋白 创伤性脑损伤 

分 类 号：R651[医药卫生—外科学]