Necrostatin-1对小鼠脑外伤脑组织损害及行为学能力的影响

The effects of Necrostatin-1 on tissue damage and behavioral deficits in mice traumatic brain injury model

目的探讨细胞程序性坏死特异性抑制剂Necrostatin-1(Nec-1)对脑外伤导致的组织损伤和行为学能力(运动功能、学习能力)损害的影响。方法健康成熟雄性昆明小鼠(体重20～25g),采用改良的自由落体装置制作定量右侧脑外伤(Traumatic Brain Injury,TBI)模型,建模15min前同侧脑室分别注射溶剂二甲基亚砜(DMSO)和DMSO配制的Nec-1溶液分别建立脑外伤DMSO组和脑外伤Nec-1组,同时设立假手术组(Sham组),利用行为学试验(Motor Test和Morris水迷宫试验)评估TBI 2周内各组小鼠的运动功能和学习能力损害,利用脑组织缺损体积(Lesion Volume,LV)评价TBI 3周后脑皮质损伤程度。结果 (1)脑外伤后1周内能观察到小鼠运动能力评分降低明显(P<0.01),伤后2～7d各组运动评分均逐渐恢复。与DMSO组比较,Nec-1预给药能明显加快运动功能的恢复过程(P<0.05);(2)所有TBI小鼠与Sham组比较,在水迷宫定位航行试验中搜找平台时需要更长的潜伏期(P<0.05);Nec-1组在伤后第9～12d表现较短的潜伏期(P<0.05);(3)脑外伤导致各组小鼠脑组织的缺失(P<0.01),与DMSO组比较,Nec-1预处理明显减少了脑外伤后的脑组织损伤体积(P<0.05)。结论侧脑室预注射Nec-1抑制程序性坏死可减少小鼠脑外伤后脑组织缺损,促进活动功能、学习能力的恢复。

Objective To study the effects of specific Necroptosis inhibitor Necrostatin-1（Nec-1）on traumatic brain injury（TBI）caused tissue damage and behavioral deficits in our TBI model.Methods Mice were subjected to TBI in right hemisphere of the brain by using a weight-drop model.Necrostatin-1（Nec-1）or vehicle dimethyl sulfoxid（DMSO）were pretreated with intracerebroventricular（i.c.v.）injection in ipsilateral hemisphere 15 min before TBI.The lesion volume（LV）of brain tissue was determined to explore extent of tissue damage.TBI-induced behavior deficits were tested by motor test and morris water maze.Results（1）1～7 dafterTBI,motor test score decline was observed（P〈0.01）,then all groups＇ scores were grandually regained.Compared with DMSO group,Nec-1 pretreatment reduced TBI-induced motor function deficits（P〈0.05）.Treatment with Nec-1 attenuated TBI-induced motor function deficits.（2）Latencies to find the hidden platform in place navigation probe trails of morris water maze were sagnificantly prolonged 8～14 d after TBI（P〈0.05）.Compared with DMSO group,mice pretreated with Nec-1 showed a noteworthy decrease of the latencies 9～12 dafter TBI（P〈0.05）.（3）Brain lesions was observable 21 days after TBI（P〈0.01）.Compared with DMSO group,Nec-1 pretreatment significantly reduced TBI-induced lesion volume（P〈0.05）.Conclusion Nec-1 could suppress TBI-induced tissue damage and facilitate behavioral function recovery.