利多卡因对小鼠短暂全脑缺血后学习记忆障碍和胆碱能系统损害的影响

目的:观察利多卡因对不同ApoE基因型小鼠短暂全脑缺血后学习记忆障碍和中枢胆碱能系统损害的影响.方法:健康雄性C57BL/6J野生型小鼠(C57小鼠)和ApoE基因敲除型小鼠(ApoE小鼠)各随机分为3组:C57对照组(假手术操作,不夹闭双侧颈总动脉)C57缺血组(夹闭双侧颈总动脉17 min,经腹腔给予生理盐水)C57利多卡因组(夹闭双侧颈总动脉17 min,经腹腔给予利多卡因)ApoE对照组(处理同C57对照组)ApoE缺血组(处理同C57缺血组)ApoE利多卡因组(处理同C57利多卡因组).术后恢复7 d,从第8天起进行Morris水迷宫测试,连续5 d.术后第12天水迷宫测试后断头处死大鼠,分离双侧大脑皮层和海马测定乙酰胆碱酯酶、胆碱乙酰基转移酶活性和M受体结合活性.结果:(1)潜伏期:各缺血组均明显长于同品系相应的对照组,C57利多卡因组还明显长于C57缺血组[测试第3天(74.1±32.7)s比(49.2±19.5)s],但ApoE利多卡因组明显短于ApoE缺血组[测试第3～5天分别为(40.7±27.7)s比(84.7±26.8)s,(31.2±19.2)s比(72.1±33.0)s,和(28.0±22.1)s比(60.8±26.9)s](P＜0.05或0.01).两品系间比较,ApoE缺血组明显长于C57缺血组,但ApoE利多卡因组明显短于C57利多卡因组(P＜0.05或0.01).(2)有效搜索策略百分比:各缺血组均明显低于同品系相应的对照组,C57利多卡因组还明显低于C57缺血组[测试第3～5天分别为(18.2±11.7)%比(41.7±17.7)%,(22.7±20.8)%比(55.6±20.8)%,和(29.6±27.0)%比(66.7±21.7)%],但ApoE利多卡因组明显高于ApoE缺血组[测试第3～5天分别为(41.7±25.8)%比(15.6±12.9)%,(58.3±20.4)%比(18.8±11.6)%,和(66.7±30.3)%比(28.1±20.9)%](P＜0.01).两品系间比较,ApoE缺血组明显低于C57缺血组,但ApoE利多卡因组明显高于C57利多卡因组(P＜0.01).(3)胆碱能系统指标:各缺血组明显低于同品系相应的对照组,C57利多卡因组还明显低于C57缺血组,但ApoE利多卡因组明显高于ApoE缺血组(P＜0.05或0.01).两品系间比较,ApoE利多卡因组明显高于C57利多卡因组(P＜0.05或0.01).结论:短暂全脑缺血导致小鼠明显的脑损害,表现为学习记忆功能障碍和中枢胆碱能系统功能损害;ApoE小鼠学习记忆功能障碍的程度较C57小鼠更重.利多卡因加重了短暂全脑缺血所导致的C57小鼠脑损害,但可减轻ApoE小鼠的脑损害程度.

Effect of lidocaine on the impairment of learning and memory function and central cholinergic system after transient global cerebral ischemia in mice

OBJECTIVE: To evaluate the effects of lidocaine on the impairments of learning and memorial function and central cholinergic system after 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 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 (sham operation, neither BCCAO was performed nor pharmacologic intervention was given), C57 ischemia group (BCCAO for 17 minutes was performed and normal saline was given intraperitoneally), C57 lidocaine group (BCCAO for 17 minutes was performed and lidocaine was given intraperitoneally), ApoE control group (the same procedure as that of C57 control group), ApoE ischemia group (the same procedure as that of C57 ischemia group), ApoE lidocaine group (the same procedure as that of C57 lidocaine group). The mice were allowed to recover for 7 days. Morris water maze test were performed from the 8th postoperative day. Mice were tested four times daily for 5 consecutive days. The latency periods were recorded and the percentages of effective search strategies were calculated. On the 12th postoperative day after Morris water maze test, mice were decapitated under anesthesia. The cerebral cortex and hippocampus were removed quickly. The activities of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) as well as the binding activity of muscarinic receptor (M receptor) were assayed. RESULTS: (1) The latency periods were significantly longer in the ischemia groups than in the corresponding control groups (P<0.05 or 0.01). They were also significantly longer in C57 lidocaine group than in C57 ischemia group [on the 3rd day of test, (74.1+/-32.7)s vs (49.2+/-19.5)s] (P<0.05). However, they were significantly shorter in apoE lidocaine group than in apoE ischemia group [from the 3rd to the 5th days of test, (40.7+/-27.7)s vs (84.7+/-26.8)s, (31.2+/-19.2)s vs (72.1+/-33.0)s, and (28.0+/-22.1)s vs (60.8+/-26.9)s, respectively] (P<0.05 or 0.01). When compared between two strains, they were significantly longer in apoE ischemia group than in C57 ischemia group (P<0.05 or 0.01). However, they were significantly shorter in apoE lidocaine group than in C57 lidocaine group (P<0.01). (2) The percentages of effective search strategies were significantly lower in the ischemia groups than in the corresponding control groups (P<0.01). They were also significantly lower in C57 lidocaine group than in C57 ischemia group [from the 3rd to the 5th days of test, (18.2+/-11.7)% vs (41.7+/-17.7)%, (22.7+/-20.8)% vs (55.6+/-20.8)%, and (29.6+/-27.0)% vs (66.7+/-21.7)%, respectively] (P<0.01). However, they were significantly higher in apoE lidocaine group than in apoE ischemia group [from the 3rd to the 5th days of test, (41.7+/-25.8)% vs (15.6+/-12.9)%, 8.3+/-20.4)% vs (18.8+/-11.6)%, and (66.7+/-30.3)% vs (28.1+/-20.9)%, respectively] (P<0.01). When compared between two strains, they were significantly lower in apoE ischemia group than in C57 ischemia group (P<0.01). However, they were significantly higher in apoE lidocaine group than in C57 lidocaine group (P<0.01). (3) The parameters of central cholinergic system were significantly lower in the ischemia groups than in the corresponding control groups (P<0.05 or 0.01). They were also significantly lower in C57 lidocaine group than in C57 ischemia group [the activities of AChE of cerebral cortex and hippocampus, (0.44+/-0.09) U/mg protein vs (0.57+/-0.08) U/mg protein, and (0.73+/-0.21) U/mg protein vs (1.08+/-0.27) U/mg protein, respectively; the activities of ChAT of hippocampus, (80.60+/-6.55) pmol/mg protein/min vs (93.66+/-11.15) pmol/mg protein/min; and the binding activities of M receptor of cerebral cortex and hippocampus, (6.03+/-0.74) pmol/mg protein vs (7.49+/-0.48) pmol/mg protein, and (7.56+/-0.92) pmol/mg protein vs (10.65+/-3.35) pmol/mg protein, respectively] (P< 0.05 or 0.01). However, they were significantly higher in ApoE lidocaine group than in ApoE ischemia group [the activities of ChAT of cerebral cortex and hippocampus, (66.99+/-7.55) pmol/mg protein/min vs (46.23+/-4.96) pmol/mg protein/min, and (116.46+/-24.05) pmol/mg protein/min vs (92.08+/-16.33) pmol/mg protein/min, respectively] (P<0.05 or 0.01). When compared between two strains, they were significantly higher in ApoE lidocaine group than in C57 lidocaine group (P< 0.05 or 0.01). CONCLUSION: Transient global cerebral ischemia caused significant brain damages in both strains of mice, which were represented by decline of learning and memorial function and damage of the central cholinergic system. Compared with the C57 mice, the ApoE mice had enhanced susceptibility to global cerebral ischemic injury as shown by more severe decline of the learning and memorial function. In the C57 mice, lidocaine significantly worsened the ischemic brain damage. In the ApoE mice, however, lidocaine significantly alleviated the ischemic cerebral results.