二甲双胍对先兆子痫模型大鼠认知功能受损的影响

Effects of metformin on cognitive dysfunction in preeclampsia rats

背景:先兆子痫是妊娠期特有的多器官、多系统功能障碍综合征,其致病学说目前无定论,内皮功能障碍是基础研究应用较多的一种机制,因此选用N-硝基-L-精氨酸甲基进行先兆子痫造模,并选用二甲双胍进行治疗。目的:腹腔注射N-硝基-L-精氨酸甲基构建大鼠先兆子痫模型,探究二甲双胍对先兆子痫的疗效及其对大鼠认知功能的影响。方法:将妊娠大鼠随机分为对照组、模型组和治疗组,对照组无特殊处理,模型组于妊娠中后期腹腔注射N-硝基-L-精氨酸甲基,治疗组于妊娠中后期腹腔注射同剂量N-硝基-L-精氨酸甲基及二甲双胍灌胃。妊娠中后期每日测量孕鼠体质量并计算药物剂量。妊娠第19天、产后第10,30天测量尾动脉血压并采血,进行可溶性内皮素和胎盘生长因子水平检测;妊娠第19天收集24 h尿进行白蛋白和肌酐定量检测;产后第10,30天进行水迷宫实验,获得潜伏期、穿越平台次数和平台逗留时间。结果与结论:①N-硝基-L-精氨酸甲基可成功建立先兆子痫模型,产生高血压、蛋白尿、宫内生长受限和内皮功能障碍表现;②二甲双胍可改善N-硝基-L-精氨酸甲基诱导产生的上述先兆子痫样表现;③N-硝基-L-精氨酸甲基诱导的先兆子痫大鼠产后第10,30天均出现了认知功能受损的表现,二甲双胍治疗可一定程度上改善上述表现;④提示二甲双胍在先兆子痫的治疗和预防中有一定潜能,其作用机制有待进一步深入研究。

BACKGROUND:Preeclampsia is a unique syndrome of pregnancy involving multiple organ systems,with no final conclusion in its pathogenesis.Endothelial dysfunction is a mechanism that has been widely used in basic research.Therefore,NG-nitro-L-arginine methyl ester was used in this study for preeclampsia modeling,followed by treatment with metformin.OBJECTIVE:To establish the model of preeclampsia in rats by intraperitoneal injection of NG-nitro-L-arginine methyl ester,and to explore the effects of metformin on preeclampsia and cognitive function in rats.METHODS:Pregnant rats were randomly divided into control group,model group,and metformin group.The model group was intraperitoneally injected with NG-nitro-L-arginine methyl ester in the middle and late pregnancy,and the metformin group was intraperitoneally injected with the same dose of NG-nitro-L-arginine methyl ester and metformin in the middle and late pregnancy.Body mass of each pregnant rat was recorded and corresponding drug dose was calculated every day.Caudal artery blood pressure was measured,and soluble endothelin and placental growth factor levels were quantified on day 19 of gestation and on days 10 and 30 after delivery.On the 19th day of gestation,urine was collected for 24 hours for urinary albumin and creatinine quantification.The Morris water maze test was conducted on the 10th and 30th days after delivery to obtain the escape latency,number of platform crossings and the average time spent in the target site where the platform was located.RESULTS AND CONCLUSION:Intraperitoneal injection of NG-nitro-L-arginine methyl ester could successfully establish the preeclampsia model in rats,resulting in hypertension,proteinuria and intrauterine growth restriction and endothelial dysfunction.Metformin could improve the preeclampsia-like performance induced by NG-nitro-L-arginine methyl ester.NG-nitro-L-arginine methyl ester-induced preeclampsia rats presented with impaired cognitive function 10 and 30 days after delivery,and metformin treatment could improve the above performance to a certain extent.Therefore,metformin has certain potential in the treatment and prevention of preeclampsia,and its mechanism of action needs to be further studied.