利多卡因对不同载脂蛋白E基因型小鼠短暂全脑缺血后脑损害程度的影响

Effects of lidocaine on brain damage induced by transient global cerebral ischemia in mice of different apolipoprotein E genotypes

目的观察利多卡因对不同载脂蛋白E(apoE)基因型小鼠短暂全脑缺血后脑损害程度的影响。方法健康雄性C57BL/6J野生型小鼠(C57小鼠)和apoE敲除型小鼠(apoE小鼠)随机分为C57对照组(15只,假手术操作),C57缺血组(21只,夹闭双侧颈总动脉17min,经腹腔给予生理盐水),C57利多卡因组(22只,夹闭双侧颈总动脉17min,经腹腔给予利多卡因),apoE对照组(15只,处理同C57对照组),apoE缺血组(19只,处理同C57缺血组),apoE利多卡因组(16只,处理同C57利多卡因组)。术后第7天从各组随机选取小鼠28只进行神经病理检查。其余小鼠从术后第8天起进行Morris水迷宫测试,连续5d。结果(1)海马CA1区缺血神经元百分比分别为C57对照组0.3%±0.1%、C57缺血组19.3%±4.5%、C57利多卡因组36.9%±2.5%、apoE对照组0.6%±0.3%、apoE缺血组65.5%±2.2%、apoE利多卡因组39.4%±6.5%。各缺血组和利多卡因组均明显多于相应的对照组(均P<0.01),C57利多卡因组和apoE缺血组还明显多于C57缺血组(均P<0.01),但apoE利多卡因组明显少于apoE缺血组(P<0.01)。(2)潜伏期除apoE缺血组外,各组均随测试天数增多而明显缩短(P<0.05,0.01)。各缺血组和利多卡因组明显长于相应的对照组(P<0.05,0.01),C57利多卡因组和apoE缺血组还明显长于C57缺血组(P<0.05,0.01),但apoE利多卡因组明显短于C57利多卡因组和apoE缺血组(P<0.05,0.01)。(3)有效搜索策略百分比除C57利多卡因组和apoE缺血组外,各组均随测试天数增多而明显增加(P<0.05,0.01)。各缺血组和利多卡因组明显低于相应的对照组(P<0.05,0.01),C57利多卡因组和apoE缺血组还明显低于C57缺血组(P<0.05,0.01),但apoE利多卡因组明显高于C57利多卡因组和apoE缺血组(P<0.05)。结论短暂全脑缺血导致小鼠明显的脑损害,apoE小鼠脑损害的程度较C57小鼠更重;利多卡因加重了C57小鼠的脑损害,但可减轻apoE小鼠脑损害的程度。

Objective To evaluate the effects of lidocaine on changes of neuropathological outcome as well as the learning and memory abilities induced by transient global cerebral ischemia in mice of different apolipoprotein E genotypes. Methods Transient global ischemia was induced by bilateral common carotid arteries occlusion （BCCAO） for a period of 17 minutes. Healthy male C57BL/6J wild-type mice （C57 mice） and apolipoprotein E knockout mice （apoE mice） were randomly divided into six groups： C57 control group （n=15, undergoing sham operation, neither BCCAO was performed nor pharmacologic intervention was given）, C57 ischemia group （ n=21, BCCAO for 17 minutes was performed and normal saline was given intraperitoneally） , C57 lidocaine group （n=22, BCCAO for 17 minutes was performed and lidocaine was given intraperitoneally） , apoE control group （ n=15, undergoing the same procedure as that of the C57 control group）, apoE ischemia group （ n=19, undergoing the same procedure as that of the C57 ischemia group）, apoE lidocaine group （n=16, undergoing the same procedure as that of the C57 lidocaine group）. The mice were allowed to recover for 7 days. Twenty-eight mice were randomly selected from these 6 groups for neuropathological studies on the 7 th postoperative day. The percentage of ischemic neurons in the CAI region of hippocampus was calculated. Morris water maze tasks were performed for the rest mice from the 8 th postoperative day. Mice were tested four times daily for 5 consecutive days. The latency period was recorded and the percentage of effective search strategies were calculated. Results （1） The percentage of ischemic neurons in the CAI region of hippocampus was 0.3%±0.1% in the C57 control group, 19.3%±4.5% in the C57 ischemia group, 36.9%±2.5% in the C57 lidocaine group, 0.6%±0.3% in the apoE control group, 65.5%±2.2% in the apoE ischemia group, and 39.4%±6.5% in the apoE lidocaine group, significantly higher in the ischemia and lidocaine groups than in the corresponding control groups （ all P 〈0. 01 ）, significantly higher in the C57 lidocaine and apoE ischemia groups than in the C57 ischemia group （ both P 〈0.01 ）, however, significantly lower in the apoE lidocaine group than in the apoE ischemia group （both P〈0.01 ）. （2） The latency period decreased significantly along with the test days in all groups except in the apoE ischemia group （ P〈0.05 or 0.01 ） , significantly longer in the ischemia and lidocaine groups than in the corresponding control groups （ P〈0. 05 or 0.01 ）, significantly longer in the C57 lidocaine group than in the C57 ischemia group on the 3 rd day of test [73.1 （22.1-120. 1） s vs. 40.2 （28.4-91.1） s], and in the apoE ischemia group than in the C57 ischemia group on the 3 rd and4 th days of test [88.2 （41.0-120.1） s vs. 40.2 （28.4-91.1） s, and 78.2 （32.9-120.1） s vs. 46.3 （11.6-81.9） s] （P 〈0.05 or 0.01 ）, and ,however, significantly shorter in the apoE lidocaine group than in the C57 lidocaine group on the 3rd day of test [39,0 （15.5-103.5） s vs. 73.1 （22.1-120.1） s], and in the apoE lidocaine group than in the apoE ischemia group from the 3 rd to the 5 th days of test [ 39.0 （ 15.5-103.5） svs. 88.2 （41.0-120.1） s, 24.9 （11.8-68.0） s vs. 78.2 （32.9-120.1） s, and 29.1 （6.6-57.2） s vs. 66.3 （14.2-97.0） s respectively ] （ P 〈 0.05 or 0.01 ）. （3） The percentage of effective search strategy increased significantly along with the test day in all groups except in the C57 lidocaine and apoE ischemia groups （P 〈 0.05 or 0.01 ）, significantly lower in the ischemia and lidocaine groups than in the corresponding control groups （P 〈0.05 or 0.01 ）, significantly lower in the C57 lidocaine group than in the C57 ischemia group on the 4 th and 5 th days of test [25 （0-50）% vs. 50 （25-75）% and 37.5 （0-75）% vs. 50 （50-100）% ] , and in the apoE ischemia group than in the C57 ischemia group from the 3 rd to the Sth days of test [25 （0-25）% vs. 50 （25-75）%, 25 （0-25）% vs. 50 （25-75）%, and 25 （0- 50）% vs. 50 （50-100）% respectively] （P 〈0. 05 or 0.01 ）, and, however, significantly higher in the apoE lidocaine group than in the C57 lidocaine group [50 （0-75）% vs. 25 （0-50）% and 50 （25-100）% vs. 37.5. （0-75） % ], and in the apoE lidocaine group than in apoE ischemia group [ 50 （0-75） % vs. 25 （0-25）% and 50 （25-100）% vs. 25 （0-50）%] on the 4 th and 5th days of test （all P 〈0. 05）. Conclusion Transient global cerebral ischemia causess significant brain damage, which is more severe in the apoE mice than in the C57 mice. Lidocaine significantly worsens the ischemic brain damage in the C57 mice, and, however, significantly alleviates the ischemic cerebral result in the apoE mice.