奥格列汀和去铁胺联合用药对小鼠急性脑出血的神经保护作用  

Augmented neuroprotective effect of combined use of omarigliptin and deferoxamine on acute intracerebral hemorrhage in mice

作　　者：刘阳 张艳 薛孟周 LIU Yang;ZHANG Yan;XUE Mengzhou(The Second Affiliated Hospital of Zhengzhou University,Zhengzhou 450003,China;Qianxinan Prefecture People’s Hospital,Xingyi 562400,China)

机构地区：[1]郑州大学第二附属医院,河南郑州450003 [2]黔西南州人民医院,贵州兴义562400

出　　处：《中国实用神经疾病杂志》2024年第5期534-541,共8页Chinese Journal of Practical Nervous Diseases

基　　金：国家自然科学基金面上项目(编号:8207052870)。

摘　　要：目的 探讨脑出血(ICH)成年C57/BL雄性小鼠采用奥格列汀(MK3102)联合去铁胺(DFO)治疗的疗效。方法 将胶原酶立体定向输入到小鼠的纹状体中诱导ICH。ICH后2 h给小鼠进行灌胃,药物为奥格列汀[7 mg/(kg·d)]、去铁胺[100 mg/(kg·d),腹腔注射],分别进行单药注射和联合治疗,连续3 d;ICH对照组使用生理盐水处理。3 d后处死小鼠,检查铁沉积、小胶质细胞活化/巨噬细胞活化、神经元死亡、脑损伤区域、神经功能缺损、血-脑屏障的通透性。结果 全身给药奥格列汀和(或)去铁胺后,通过对普鲁士蓝染色、AIFM2、GPX4免疫组化染色、免疫印迹蛋白等试验,结果显示脑出血用药治疗后铁死亡程度减低,免疫荧光染色结果显示,ICH后活化小胶质细胞/巨噬细胞数量和中性粒细胞浸润数量、神经元死亡数量均明显降低;同时,与ICH对照组相比,在奥格列汀和(或)去铁胺治疗后,ICH引起的神经功能缺损以及脑损伤区域均明显改善。此外,与单一治疗组相比,联合治疗在改善铁死亡及神经保护方面显示出更好的效果。结论 联合治疗可显著改善ICH后的铁死亡,抑制小胶质细胞/巨噬细胞的活化,降低血-脑屏障的通透性,减少神经元死亡数量,减轻脑损伤区域,改善ICH后神经功能缺损。Objective To investigate the therapeutic effect of the combination of omarigliptin(MK3102)and deferoxamine(DFO)in adult C57/BL male mice with intracerebral hemorrhage(ICH).Methods Collagenase was stereotactically injected into the striatum of mice to induce ICH.Two hours after ICH,mice were given oral gavage with the drug omarigliptin(7 mg/(kg·d))and intraperitoneal injection of deferoxamine(100mg/(kg·d))for single drug injection and combination therapy,respectively,for three consecutive days.The ICH control group was treated with physiological saline.Mice were euthanized for 3 days to examine iron deposition,activation of microglia/macrophages,neuronal death,brain injury areas,neurological deficits,and blood-brain barrier permeability.Results After systemic administration of omarigliptin and/or deferoxamine,Perls staining,AIFM2,GPX4 immunohistochemistry staining,Western Blot and other tests were performed.The results showed that the degree of ferroptosis was reduced after treatment for intracerebral hemorrhage.Immunofluorescence staining showed that after drug treatment,the number of activated microglia/macrophages,cell death,and neuronal death were significantly reduced after ICH.Meanwhile,compared with the ICH control group,the neurological deficits and brain injury areas caused by ICH were significantly improved after treatment with omarigliptin and/or deferoxamine.In addition,compared to the single treatment group,combination therapy showed better effects in improving ferroptosis and neuroprotection.Conclusion Combination therapy can significantly improve ferroptosis after ICH,inhibit the activation of microglia/macrophages,reduce the permeability of the blood-brain barrier,reduce the number of neuronal deaths,alleviate brain injury areas,and improve neurological deficits after ICH.

关 键 词：奥格列汀 去铁胺 脑出血 神经保护 小鼠 

分 类 号：R-332[医药卫生]