摘要
目的探讨载脂蛋白E(apolipoprotein E,APOE表示其基因,apo E表示其相应蛋白)基因亚型对创伤性脑损伤(traumatic brain injury,TBI)后apo E拟肽(COG1410)早期神经保护作用的影响。方法以APOE转基因鼠(ε3、ε4)及APOE敲除鼠[APOE(-/-)]作为研究对象,各型鼠随机分为TBI+COG1410组(30只)、TBI+生理盐水组(30只)和假手术组(10只),TBI+COG1410组和TBI+生理盐水组又分为3个亚组:1、3、7 d,每组10只,采用PSI脑损伤撞击器精确打击制备TBI模型,并于伤后30 min内首次经尾静脉注射COG1410(1 mg/kg)或生理盐水(同容积)。早期脑损伤检测指标包括伤后连续7 d的神经功能学测试(转棒时间),以及伤后1、3、7 d的脑水肿和淀粉样前体蛋白(amyloid precursor protein,APP)在创伤周围胼胝体区的半定量表达。结果在不同APOE基因型小鼠中,ε3鼠在伤后前3 d的转棒时间明显优于ε4鼠(P〈0.05)。而在TBI+COG1410组和TBI+生理盐水组的对比中,COG1410在ε3鼠中具有增加伤后4~7 d的转棒时间(P〈0.05),同时也可减轻伤后3、7 d的脑组织含水量(P〈0.05);而在ε4鼠和APOE(-/-)鼠中,COG1410不仅可以增加伤后1~7 d的转棒时间(P〈0.05),同时也可改善伤后1、3 d及7 d的脑组织含水量(P〈0.05);此外,COG1410可以减轻ε3鼠和APOE(-/-)鼠在伤后1、3、7 d的APP表达(P〈0.05),却在ε4鼠伤后1、3、7 d的APP表达中没有统计学差异(P〉0.05)。结论 APOEε4基因作为一种高危基因,在急性颅脑创伤中预示不良的预后;在APOEε3/3和APOEε4/4基因型中,COG1410均具有降低早期脑损伤、改善预后的作用。
Objective To investigate the effect of different apolipoprotein E (APOE = gene, apoE = protein) genotypes on the neuroprotective function of apoE mimetic peptide (COG1410) after early traumatic brain injury (TBI). Methods APOE targeted-replacement mice (ε3, ε4 ) and APOE knockout (APOE (-/-) mice were randomly allocated to a TBI + COG1410 group (n = 30), a TBI + normal saline group (n = 30) and a sham operation group (n = 10). The TBI + COG1410 group and the TBI + normal saline group each were further divided into 3 subgroups (1, 3 and 7 d ), with 10 mice in each subgroup. TBI model was established by precision strike with a head injury impaetor (PSI company, U. S. A) , and COG1410 solution or normal saline ( 1 mg/kg) was selectively administered through the tail vein within 30 min after TBI. Early TBI outcomes included neural function test (Rotorod latency) in the initial 7 days after TBI, cerebral edema and semi-quantitative expression of amyloid precursor protein (APP) in the pericontusional corpus callosum in 1, 3 and 7 d. Results Among the mice with different APOE genotypes, ε3 mice demonstrated superior rotorod latency in the first 3 days after TBI as compared to e4 mice (P 〈 0. 05 ). After intravenous administration of COG1410 ( 1 mg/kg), ε3 mice exhibited improved rotorod latency in 4 - 7 d after TBI (P 〈 0. 05 ), and decreased cerebral edema on the days 3 and 7 (P 〈 0. 05 ), while E4 mice and APOE (-/-) mice exhibited improved Rotorod latency in 7 days after TBI (P 〈 0. 05 ) and decreased cerebral edema on 1,3 and 7 d ( P 〈 0. 05 ). Moreover, COG1410 suppressed the APP expression in ε3 mice and APOE(-/-) mice in 1,3 and 7 d after TBI (P 〈 0. 05 ), but the APP levels had no statistically significant difference in ε4 mice. Conclusion APOEε4 gene as a high risk gene has a poor outcome in TB/. Moreover, apoE mimetic peptide can reduce early brain injury and improve the outcomes in the mice with APOEe3/3 genotype and APOEε4/4 genotype.
出处
《第三军医大学学报》
CAS
CSCD
北大核心
2015年第10期990-995,共6页
Journal of Third Military Medical University
基金
国家自然科学基金(81371319
81000528)
新世纪优秀人才支持计划(NCET-12-1057)
四川省科技厅杰出青年项目(2014JQ0022)
四川省科技厅项目(2009JY0126)~~