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; 驚厥; 海馬; 神經毒性; 空間學習能力; 大鼠

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目的　研究利多卡因對海馬的神經毒性是否會對大鼠空間學習記憶能力產生影響，并探討大鼠空間學習能力的變化與海馬CA3區錐體細胞數目的相關性。方法　將成年Wistar雄性大鼠隨機分為基礎值組（n=7）和利多卡因驚厥組（n=40）。基礎值組大鼠靜脈給予生理鹽水后使用Y迷宮測定大鼠的空間學習能力。利多卡因驚厥組大鼠尾靜脈持續輸注利多卡因造成驚厥，待大鼠恢復正常運動以后放入鼠籠重新飼養。并于驚厥后第1、3、5、7天從中隨機抓取大鼠測試其空間學習能力以及組織學改變。根據對應天數將利多卡因驚厥組的40只大鼠隨機細分為Day-1、Day-3、Day-5、Day-7亞組，每亞組10只。所有大鼠在測定空間學習能力之后立即處死，取出大腦并做石蠟包埋，冠狀面切片后進行組織學檢測，顯微鏡下評估海馬CA3區錐體細胞狀態。結果　① 基礎值組和Day-1、Day-3、Day-5、Day-7亞組大鼠的Y迷宮穿梭次數分別為（25.2 ± 3.7）、（27.1 ± 8.1）、（36.9 ± 9.9）、（38.7 ± 10.6）、（40.6 ± 16.3）次，除Day-1亞組與基礎值組比較差異無統計學意義（P＞0.05）外，其余各亞組與基礎值組差異均有統計學意義（P＜0.05）；② 與基礎值組單位面積（10.3 ± 4.5）個（異常錐體）細胞比較，利多卡因驚厥組大鼠海馬CA3區異常錐體細胞數增加，Day-1、Day-3、Day-5、Day-7亞組計數值分別為13.0 ± 7.2、15.6 ± 5.0、19.6 ± 8.1、18.1 ± 5.1，且與大鼠Y迷宮穿梭次數呈正相關（r=0.711，P＜0.05）。結論　利多卡因引起的驚厥使成年大鼠海馬依賴性空間學習能力下降，利多卡因的神經毒性引起的海馬異常錐體細胞增多可能是造成這一現象的一種原因。

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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5.	Ingvar M, Shapiro HM. Selective metabolic activation of the hippocampus during lidocaine-induced preseizure activity[J]. Anesthesiology, 1981, 54(1): 33-37.
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7.	王躍春, 王子棟. 動物學習能力的Y-型迷宮測試法[J]. 暨南大學學報(自然科學版), 2001, 22(5): 137-142.
8.	Wla? 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.	鄒曉毅, 蔣毅, 青霉素誘導的癲癇大鼠腦組織一氧化氮合成酶mRNA表達的初步研究[J]. 華西醫學, 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, Brush?eld 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. 　王躍春, 王子棟. 動物學習能力的Y-型迷宮測試法[J]. 暨南大學學報(自然科學版), 2001, 22(5): 137-142.
8. 　Wla? 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. 　鄒曉毅, 蔣毅, 青霉素誘導的癲癇大鼠腦組織一氧化氮合成酶mRNA表達的初步研究[J]. 華西醫學, 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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