APOE基因亚型对创伤性脑损伤后COG1410早期神经保护作用的影响

Effect of apolipoprotein E genotypes on early neuroprotective function of COG1410 after traumatic brain injury

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.