Effect of Lidocaine-induced Seizure on Spatial Learning Memory in Rats_West China Medical Journal

Authors：

WANG Xiaojia ¹ , ZHOU Cheng ² , HUANG Han ¹ ,  LI Yu ¹

1.Department of Anesthesiology; 2. Laboratory of Anesthesia and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

LI Yu, Email: xj.wang.anes@gmail.com

Keywords：

利多卡因; 惊厥; 海马; 神经毒性; 空间学习能力; 大鼠

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目的　研究利多卡因对海马的神经毒性是否会对大鼠空间学习记忆能力产生影响，并探讨大鼠空间学习能力的变化与海马CA3区锥体细胞数目的相关性。方法　将成年Wistar雄性大鼠随机分为基础值组（n=7）和利多卡因惊厥组（n=40）。基础值组大鼠静脉给予生理盐水后使用Y迷宫测定大鼠的空间学习能力。利多卡因惊厥组大鼠尾静脉持续输注利多卡因造成惊厥，待大鼠恢复正常运动以后放入鼠笼重新饲养。并于惊厥后第1、3、5、7天从中随机抓取大鼠测试其空间学习能力以及组织学改变。根据对应天数将利多卡因惊厥组的40只大鼠随机细分为Day-1、Day-3、Day-5、Day-7亚组，每亚组10只。所有大鼠在测定空间学习能力之后立即处死，取出大脑并做石蜡包埋，冠状面切片后进行组织学检测，显微镜下评估海马CA3区锥体细胞状态。结果　① 基础值组和Day-1、Day-3、Day-5、Day-7亚组大鼠的Y迷宫穿梭次数分别为（25.2 ± 3.7）、（27.1 ± 8.1）、（36.9 ± 9.9）、（38.7 ± 10.6）、（40.6 ± 16.3）次，除Day-1亚组与基础值组比较差异无统计学意义（P＞0.05）外，其余各亚组与基础值组差异均有统计学意义（P＜0.05）；② 与基础值组单位面积（10.3 ± 4.5）个（异常锥体）细胞比较，利多卡因惊厥组大鼠海马CA3区异常锥体细胞数增加，Day-1、Day-3、Day-5、Day-7亚组计数值分别为13.0 ± 7.2、15.6 ± 5.0、19.6 ± 8.1、18.1 ± 5.1，且与大鼠Y迷宫穿梭次数呈正相关（r=0.711，P＜0.05）。结论　利多卡因引起的惊厥使成年大鼠海马依赖性空间学习能力下降，利多卡因的神经毒性引起的海马异常锥体细胞增多可能是造成这一现象的一种原因。

Citation： WANG Xiaojia,ZHOU Cheng,HUANG Han,LI Yu. Effect of Lidocaine-induced Seizure on Spatial Learning Memory in Rats. West China Medical Journal, 2012, 27(4): 545-548. doi: Copy

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10.	West MJ. Regionally specific loss of neurons in the aging human hippocampus[J]. Neurobiol Aging, 1993, 14 (4): 287-293.
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12.	Johnson ME, Uhl CB, Spittler KH, et al. Mitochondrial injury and caspase activation by the local anesthetic lidocaine[J]. Anesthesiology, 2004, 101(5): 1184-1194.
13.	Royes LF, Fighem MR, Furian AF, et al. Involvement of NO in the convulsive behavior and oxidative damage induced by the intrastriatal injection of methylmalonate[J]. Neurosci Lett, 2005, 376(2): 116-120.
14.	邹晓毅, 蒋毅, 青霉素诱导的癫痫大鼠脑组织一氧化氮合成酶mRNA表达的初步研究[J]. 华西医学, 2007, 22(4): 812-813.
15.	Werdehausen R, Fazeli S, Braun S, et al. Apoptosis induction by different local anaesthetics in a neuroblastoma cell line[J]. Br J Anaesth, 2009, 103(5): 711-718.
16.	Onizuka S, Tamura R, Hosokawa N, et al. Local anesthetics depolarize mitochondrial membrane potential by intracellular alkalization in rat dorsal root ganglion neurons[J]. Anesth Analg, 2010, 111(3): 775-783.
17.	Onizuka S, Tamura R, Yonaha T, et al. Clinical dose of lidocaine destroys the cell membrane and induces both necrosis and apoptosis in an identied Lymnaea neuron[J]. J Anesth, 2011, 26(1): 54-61.
18.	Treves A, Rolls ET. Computational constraints suggest the need for two distinct input systems to the hippocampal CA3 network[J]. Hippocampus, 1992, 2(2): 189-199.
19.	Papp G, Witter MP, Treves A. The CA3 network as a memory store for spatial representations[J] Learn Mem, 2007, 14: 732-744.
20.	Kesner RP. Behavioral functions of the CA3 subregion of the hippocampus[J]. Learn Mem, 2007, 14(11): 771-781.
21.	Broadbent NJ, Squire LR, Clark RE. Reversible hippocampal lesions disrupt water maze performance during both recent and remote memory tests[J]. Learn Mem, 2006, 13(2):187-191.

1. 　Knudsen K, Suurkula MB, Blomberg S, et al. Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers[J]. Br J Anaesth, 1997, 78(5): 507-514.
2. 　Smith T. Systemic toxic effects of local anaesthetics[J]. Anaesth Intensive Care Med, 2007, 5(4): 132-136.
3. 　Blas-Valdivia V, Cano-Europa E, Hernández-García A, et al. Hippocampus and amygdala neurotoxicity produced by systemic lidocaine in adult rats[J]. Life Sci, 2007, 81(8): 691-694.
4. 　Tanaka K, Yamasaki M. Blocking of cortical inhibitory synapses by intravenous lidocaine[J]. Nature, 1966, 209 (5019): 207-208.
5. 　Ingvar M, Shapiro HM. Selective metabolic activation of the hippocampus during lidocaine-induced preseizure activity[J]. Anesthesiology, 1981, 54(1): 33-37.
6. 　Gilbert PE, Brushﬁeld AM. The role of the CA3 hippocampal subregion in spatial memory: a process oriented behavioral assessment[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2009, 33(5): 774-781.
7. 　王跃春, 王子栋. 动物学习能力的Y-型迷宫测试法[J]. 暨南大学学报(自然科学版), 2001, 22(5): 137-142.
8. 　Wlaź P, Löscher W. Weak anticonvulsant effects of two novel glycine B receptor[J]. Eur J Pharmacol, 1998, 342(1): 39-46.
9. 　Packard MG, McGaugh JL. Inactivation of hippocampus or caudate nucleus with lidocaine differentially affects expression of place and response learning[J]. Neurobiol Learn Mem, 1996, 65(1): 65-72.
10. 　West MJ. Regionally specific loss of neurons in the aging human hippocampus[J]. Neurobiol Aging, 1993, 14 (4): 287-293.
11. 　Gervasini G, Carrillo JA, Benitez J. Potential role of cerebral cytochrome P450 in clinical pharmacokinetics: modulation by endogenous compounds[J]. Clin Pharmacokinet, 2004, 43(11): 693-706.
12. 　Johnson ME, Uhl CB, Spittler KH, et al. Mitochondrial injury and caspase activation by the local anesthetic lidocaine[J]. Anesthesiology, 2004, 101(5): 1184-1194.
13. 　Royes LF, Fighem MR, Furian AF, et al. Involvement of NO in the convulsive behavior and oxidative damage induced by the intrastriatal injection of methylmalonate[J]. Neurosci Lett, 2005, 376(2): 116-120.
14. 　邹晓毅, 蒋毅, 青霉素诱导的癫痫大鼠脑组织一氧化氮合成酶mRNA表达的初步研究[J]. 华西医学, 2007, 22(4): 812-813.
15. 　Werdehausen R, Fazeli S, Braun S, et al. Apoptosis induction by different local anaesthetics in a neuroblastoma cell line[J]. Br J Anaesth, 2009, 103(5): 711-718.
16. 　Onizuka S, Tamura R, Hosokawa N, et al. Local anesthetics depolarize mitochondrial membrane potential by intracellular alkalization in rat dorsal root ganglion neurons[J]. Anesth Analg, 2010, 111(3): 775-783.
17. 　Onizuka S, Tamura R, Yonaha T, et al. Clinical dose of lidocaine destroys the cell membrane and induces both necrosis and apoptosis in an identied Lymnaea neuron[J]. J Anesth, 2011, 26(1): 54-61.
18. 　Treves A, Rolls ET. Computational constraints suggest the need for two distinct input systems to the hippocampal CA3 network[J]. Hippocampus, 1992, 2(2): 189-199.
19. 　Papp G, Witter MP, Treves A. The CA3 network as a memory store for spatial representations[J] Learn Mem, 2007, 14: 732-744.
20. 　Kesner RP. Behavioral functions of the CA3 subregion of the hippocampus[J]. Learn Mem, 2007, 14(11): 771-781.
21. 　Broadbent NJ, Squire LR, Clark RE. Reversible hippocampal lesions disrupt water maze performance during both recent and remote memory tests[J]. Learn Mem, 2006, 13(2):187-191.

West China Medical Journal

Effect of Lidocaine-induced Seizure on Spatial Learning Memory in Rats

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