吡拉格雷对脑缺血再灌注不同时间点神经炎症及巨噬细胞M1/M2极化的影响  

Effects of pyragrel on neuroinflammation and M1/M2 polarization of macrophages at different time points of cerebral ischemia-reperfusion

作　　者：周珮珮 崔亚娇 赵炎[3] 何广卫[3] 孙志[1] 吴玉林[4] 杜书章[1] ZHOU Pei-pei;CUI Ya-jiao;ZHAO Yan;HE Guang-wei;SUN Zhi;WU Yu-lin;DU Shu-zhang(Department of Pharmacy/He-nan Provincial Key Laboratory of Precision Clinical Pharmacy,the First Affliated Hospital of Zhengzhou University,Zhengzhou HE-NAN 450052,China;Department of Pharmacy,He-nan Chest Hospital,Zhengzhou HE-NAN 450000,China;Hefei Medical Industry Pharmaceutical Co.,Ltd.,Hefei ANHUI 230000,China;China Pharmaceutical University,Nanjing JIANGSU211198,China)

机构地区：[1]郑州大学第一附属医院药学部/河南省精准临床药学重点实验室,河南郑州450052 [2]河南省胸科医院药学部,河南郑州450000 [3]合肥医工医药有限公司,安徽合肥230000 [4]中国药科大学,江苏南京211198

出　　处：《中国新药与临床杂志》2023年第10期675-679,共5页Chinese Journal of New Drugs and Clinical Remedies

基　　金：国家“重大新药创制”重大专项候选药物(2009ZX09103);郑州大学第一附属医院院内基金。

摘　　要：目的探讨吡拉格雷对脑缺血模型大鼠再灌注不同时间点神经炎症及巨噬细胞M1/M2极化的影响。方法雄性SD大鼠分为假手术组,模型组,奥扎格雷(18 mg·kg^(-1))组,吡拉格雷低、中、高剂量(10.8、18、30 mg·kg^(-1))组。采用改良线栓法建立大鼠大脑中动脉栓塞模型,脑缺血2 h再灌注24、48、72、168 h。造模缺血2 h后立即给药,依据复灌注不同时间点每日尾静脉给予对应剂量药物,通过ELISA检测脑组织肿瘤坏死因子(TNF)-α和白细胞介素(IL)-10水平,以TNF-α/IL-10比值代表巨噬细胞M1/M2极化水平。结果与假手术组相比,模型组在缺血2 h再灌注24、48、72、168 h四个时间点的TNF-α显著升高(P<0.05),48、72、168 h时间点的IL-10水平及M1/M2比值显著升高(P<0.05),72 h时TNF-α、IL-10水平达峰值。与模型组相比,奥扎格雷组和吡拉格雷中、高剂量组再灌注四个时间点TNF-α水平均显著降低(P<0.05),再灌注72、168 h的IL-10水平显著升高,M1/M2比值显著降低(P<0.01);吡拉格雷低剂量组再灌注72、168 h TNF-α水平及M1/M2比值显著降低,IL-10水平显著升高(P<0.05)。吡拉格雷中、高剂量组各指标与奥扎格雷组相当(P>0.05)。结论吡拉格雷可减轻缺血再灌注损伤大鼠的神经炎症,诱导巨噬细胞由促炎性M1向抑炎性M2表型的极化。AIM To investigate the effects of pyragrel on neuroinflammation and M1/M2 polarization of macrophages at different time points during reperfusion in rats with cerebral ischemia.METHODS Male SD rats were divided into sham group,model group,ozagrel group(18 mg kg^(-1)),and pyragrel low,medium,and high dose(10.8,18,30 mg·kg^(-1))groups.The model of middle cerebral artery occlusion in rats was established using a modified thread occlusion method,with cerebral ischemia for 2 h and reperfusion for 24,48,72,168 h.The drug was administered in the tail vein immediately after the completion of the modeling for 2 h of ischemia,and the corresponding dose of drug was administered daily according to the different time points of reperfusion.Tumor necrosis factor(TNF)-α and interleukin(IL)-10 levels in brain tissue were detected by ELISA.The TNF-α/IL-10 ratio represents the M1/M2 polarization level of macrophages.RESULTS Compared with the sham group,the levels of TNF-αin the model group increased significantly at reperfusion 24,48,72,168 h after 2 h of ischemia(P<0.05).The IL-10 levels and M1/M2 ratios increased significantly at reperfusion 72,168 h(P<0.05),and TNF-α and IL-10 reached its peak at reperfusion 72 h.Compared with the model group,TNF-α levels decreased at four time points after reperfusion in the ozagrel group and the pyragrel middle and high dose groups(P<0.05),the levels of IL-10 increased and ratios of M1/M2 decreased significantly at reperfusion 72,168 h(P<0.01).TNF-α level and M1/M2 ratio decreased at reperfusion 72,168 h in the pyragrel low dose groups(P<0.05),and level of IL-10 increased(P<0.05).The indicators in the pyragrel medium and high dose groups were comparable to those in the ozagrel group(P>0.05).CONCLUSION Pyragrel can alleviate neuroinflammation in rats with ischemia reperfusion injury and induce the polarization of macrophages from pro-inflammatory M1 to anti-inflammatory M2 phenotype.

关 键 词：吡拉格雷 脑缺血 再灌注损伤 神经炎症性疾病 巨噬细胞活化 

分 类 号：R971[医药卫生—药品]