丁酸钠预处理通过减轻血脑屏障损伤改善大鼠肠缺血再灌注诱导的认知障碍  

Sodium butyrate preconditioning improves cognitive impairment in-duced by intestinal ischemia/reperfusion by reducing blood-brain barrier damage in rats

作　　者：曹璐 王迎斌[2] 张伟[2] 刘艳 张丽[1] 张晶玉 CAO Lu;WANG Yingbin;ZHANG Wei;LIU Yan;ZHAN GLi;ZHANG Jingyu(The Lanzhou University Second Hospital,Lanzhou 730030,Gansu,China;Department of Anesthesiology,the Lanzhou University Second Hospital,Lanzhou 730030,Gansu,China)

机构地区：[1]兰州大学第二临床医学院,甘肃兰州730030 [2]兰州大学第二医院麻醉科,甘肃兰州730030

出　　处：《中国临床药理学与治疗学》2024年第6期637-644,共8页Chinese Journal of Clinical Pharmacology and Therapeutics

基　　金：甘肃省自然科学基金(23JRRA0988);兰州大学第二医院“萃英科技创新”计划(CY2022-MS-A20)。

摘　　要：目的:探究丁酸钠对大鼠肠缺血/再灌注后血脑屏障和认知功能的影响及其可能存在的机制。方法:将SD大鼠随机分为4组,每组12只,(1)假手术组(Sham组);(2)肠缺血/再灌注组(II/R组);(3)肠缺血/再灌注+丁酸钠组(NaB组):造模前1周NaB 500 mg·kg^(-1)·d^(-1)灌胃;(4)肠缺血/再灌注+丁酸钠+ITSA-1组(ITSA-1组):造模前1周NaB 500 mg·kg^(-1)·d^(-1)灌胃+前5 d、3 d、1 d ITSA-10.5 mg/kg腹腔注射。HE染色评估肠黏膜损伤;Morris水迷宫测试评估大鼠认知功能;透射电镜观察血脑屏障微结构改变;ELISA检测脑组织炎症因子IL-1β、IL-6、TNF-α和紧密连接蛋白Claudin5、ZO-1及基质金属蛋白酶-9(matrix me-talloproteinase-9,MMP-9)含量;Western Blot检测紧密连接蛋白Claudin5、ZO-1及亲环蛋白A(cy-clophilin A,CypA)、MMP-9水平。结果:与Sham组相比,II/R组大鼠Chiu's肠黏膜损伤评分较高(P<0.001);游泳路程增加(P<0.05),非平台象限占比增加(P<0.001),潜伏期延长(P<0.05);透射电镜下血脑屏障微结构改变;脑组织炎症因子IL-1β、IL-6、TNF-α增加(P<0.001),CypA、MMP-9表达增加(P<0.01),紧密连接蛋白Claudin5、ZO-1表达减少(P<0.01,P<0.001);与II/R组相比,NaB组神经炎症、血脑屏障损伤减轻,认知功能改善;ITSA-1组上述损伤与II/R组相似。结论:丁酸钠可通过减轻血脑屏障损伤改善大鼠II/R诱导的神经认知功能障碍,其机制可能与抑制CypA/MMP-9通路有关。AIM:To investigate the possible mech-anisms by observing the effects of sodium butyrate on the blood-brain barrier and cognitive function after intestinal ischemia/reperfusion in rats.METH-ODS:SD rats were randomly divided into 4 groups of 12 rats each,(1)sham-operated group(the Sham group);(2)intestinal ischemia/reperfusion group(the II/R group);(3)intestinal ischemia/re-perfusion+sodium butyrate group(the NaB group):gavage of NaB 500 mg·kg^(-1)·d^(-1)for 1 week before modeling;(4)intestinal ischemia/reperfusion+sodi-um butyrate+ITSA-1 group(the ITSA-1 group):NaB 500 mg·kg^(-1)·d^(-1)gavage 1 week before modeling+IT-SA-10.5 mg/kg intraperitoneal injection in the first 5 d,3 d and 1 d.Intestinal mucosal injury was eval-uated by HE staining.Morris water maze test evalu-ated the cognitive function of rats.The microstruc-ture of the blood-brain barrier was observed by transmission electron microscope.The levels of in-flammatory cytokines IL-1β,IL-6,TNF-α,Claudin5,ZO-1,and MMP-9 in brain tissue were detected by ELISA.Western blotting detected Claudin5,ZO-1,CypA,and MMP-9 levels.RESULTS:Compared with the Sham group,Chiu's score in the II/R group was increased(P<0.001).The swimming distance was increased(P<0.05),the proportion of the non-plat-form quadrant was increased(P<0.001),and the in-cubation period was prolonged(P<0.05).The micro-structure of the blood-brain barrier was changed under the transmission electron microscope.The inflammatory cytokines IL-1β,IL-6,and TNF-αwere increased(P<0.001),the expressions of CypA and MMP-9 were increased(P<0.01),and the expres-sions of Claudin5 and ZO-1 were decreased(P<0.01,P<0.001).Compared with the II/R group,neu-roinflammation,and blood-brain barrier damage were reduced,and cognitive function was im-proved in the II/R+NaB group.The above injuries in group II/R+NaB+ITSA-1 were similar to those in group II/R.CONCLUSION:Sodium butyrate can ameliorate II/R-induced neurocognitive dysfunction in rats by alleviating blood-brain barrier damage,possibly related to inhibiting

关 键 词：丁酸钠 血脑屏障 肠缺血/再灌注 认知功能障碍 

分 类 号：R965.2[医药卫生—药理学]