摘要目的:探讨白藜芦醇抑制新生大鼠生发基质出血（germinal matrix hemorrhage，GMH）后神经炎症和改善受损神经功能的作用。方法:采用7日龄SD大鼠脑实质注射细菌性胶原酶方法制备GMH模型。108只大鼠随机分为18组，每组6只，包括4个假手术组、GMH（12 h、24 h、72 h、7 d）组、3个GMH+药物（二甲基亚砜）对照组、GMH+白藜芦醇（10、100、1 000 mg/kg）组（其中最佳剂量共3组）、2个GMH+白藜芦醇+白藜芦醇抑制剂（EX527）组。采用负向趋地试验和翻正反射试验评估大鼠短期神经行为；采用水迷宫、失足试验、旋转试验评估大鼠长期神经行为；采用免疫荧光方法评估大鼠脑血肿周围炎性指标分泌情况；采用蛋白印迹试验评估大鼠脑内目标蛋白表达情况。结果:GMH发生后24 h内源性去乙酰化酶1（sirtuin-1，SIRT1）下降至最低，然后逐渐上升；磷酸化核转录因子κB（nuclear factor kappa B，NF-κB）于12 h开始升高，7 d降至正常；与GMH+药物对照组及其他剂量组比较，GMH+白藜芦醇100 mg/kg组48 h及72 h短期行为学得分更高；与GMH+药物对照组比较，GMH+白藜芦醇100 mg/kg组22 d后水迷宫、失足试验、旋转试验得分更高；免疫荧光染色显示，GMH+白藜芦醇100 mg/kg组大鼠脑血肿周围白细胞介素1β、髓过氧化物酶阳性细胞数低于GMH+药物对照组和GMH+白藜芦醇+EX527组；蛋白印迹提示GMH+白藜芦醇100 mg/kg组大鼠脑内炎性因子白细胞介素1β、肿瘤坏死因子α和白细胞介素6下降，使用抑制剂EX527后可抵消白藜芦醇的作用。结论:白藜芦醇100 mg/kg可改善GMH大鼠短期和长期神经行为学功能，减少GMH大鼠脑血肿周围炎性指标阳性细胞数，其通过SIRT1/NF-κB途径抑制GMH大鼠脑内神经炎性指标的表达。

abstractsObjective:To study the roles of resveratrol in reducing neuroinflammation and improving neurobehavioral functions after germinal matrix hemorrhage (GMH) in neonatal rat model.Methods:GMH model was established intraparenchymally injecting bacterial collagenase in 7-day-old SD rats. 108 rats were randomly assigned into 18 groups (6 in each group), including 4 sham groups, GMH (12 h, 24 h, 72 h, 7 d) groups, 3 GMH+vehicle (dimethylsulfoxide, DMSO) groups, 5 GMH+resveratrol (10 mg/kg, 100 mg/kg, 1 000 mg/kg) groups and 2 GMH+resveratrol+EX527 (SIRT1 inhibitor) groups. Negative geotaxis and righting reflex tests were used to evaluate the short-term neurobehavior. Water maze, foot fault and Rotor-Rod tests were used to assess the long-term neurobehavior. Immunofluorescence was used to quantify the IL-1β and MPO positive cells (inflammatory markers) in peri-hematoma area. Western blot was used to evaluate the expression of relevant proteins in the brain.Results:Endogenous sirtuin-1(SIRT1) decreased to the lowest level at 24 h and then increased gradually. Phosphorylated NF-κB increased at 12 h, peaked at 72 h and returned to normal level at 7 d after GMH. Compared with the control group and other doses groups, GMH treated with resveratrol (100 mg/kg) had higher short-term behavioral scores at 48 h and 72 h. Compared with the control group, the resveratrol (100 mg/kg) group also had higher scores in water maze, foot fault and Rotor-Rod tests 22 days later. Immunofluorescence showed less positive IL-1β and MPO cells around hematoma in GMH+resveratrol group than both GMH+vehicle group and GMH+resveratrol+EX527 group. Western blot indicated that IL-1, TNF-α and IL-6 expressions were decreased in GMH+resveratrol group and Ex527 could offset the effects of resveratrol.Conclusions:Resveratrol (optimal dose: 100 mg/kg) can improve the short-term and long-term neurobehavioral functions of neonatal GMH rats. It can reduce GMH cells with positive inflammatory markers around the hematoma, possibly via inhibition of the SIRT1/NF-κB pathway. Resveratrol may be promising for the treatment of GMH patients.