N-乙酰半胱氨酸和氯胺酮联用对脑缺血再灌注损伤的影响

中国临床药理学与治疗学 ›› 2005, Vol. 10 ›› Issue (4): 428-431.

N-乙酰半胱氨酸和氯胺酮联用对脑缺血再灌注损伤的影响

虞希冲, 陈醒言, 周红宇, 林丹, 朱桐君

温州医学院药学院药理教研室, 温州 325035, 浙江

收稿日期:2005-01-08 修回日期:2005-04-05 出版日期:2005-04-26 发布日期:2020-11-19
通讯作者: 朱桐君,女, 硕士, 教授, 主要从事神经药理学和神经毒理学研究。Tel:0577-86689710
作者简介:虞希冲, 男, 硕士, 助教, 主要从事神经药理学研究。Tel:0577-86689710 E-mail:yuxc@wzmc.net。

Effects of combination of ketamine and N-acetylcysteine on brain damage following cerebral ischemia /reperfusion in mice

YU Xi-chong, CHEN Xian-yan, ZHOU Hong-yu, LIN Dan, ZHU Tong-jun

Department of Pharmacology, Wenzhou Medical College, Wenzhou325035, Zhejiang, China

Received:2005-01-08 Revised:2005-04-05 Online:2005-04-26 Published:2020-11-19

摘要/Abstract

摘要： 目的: 研究巯基供体物质 N-乙酰半胱氨酸(NAC) 和非竞争性NMDA 受体拮抗剂氯胺酮(KT) 联用对小鼠脑缺血再灌注损伤的影响。方法: 雄性ICR小鼠, 随机分为假手术组、生理盐水组(0.01L°g^-1) 、氯胺酮组(15 mg°kg^-1) 、N-乙酰半胱氨酸组(75 mg°kg^-1) 和联合组 (KT 15 mg°kg^-1+NAC75 mg°kg^-1)。参照蒋晓帆等建立的方法, 制备局灶性短暂性脑缺血再灌注模型(tMCAO), 再灌注后 6、24 h 测定神经行为缺陷评分, 处死 TTC 染色测定脑梗死面积百分比;制备不完全性脑缺血再灌注模型(2-VO), 在再灌注 0.5 、2 和 6 h 时取全脑制成 10%匀浆, 比色法测定 MDA 含量、SOD 和 GSH-Px 活力。结果: (1) 短暂性局灶性脑缺血再灌注后 6、24 h, 各组小鼠脑组织均有不同程度梗死灶、神经行为缺陷明显, 与生理盐水组比较, 药物联合组可显著改善缺血再灌注小鼠的神经行为缺陷(均为 P <0.01), 减少脑梗死面积百分比(均为 P <0.01), 药物单用对以上指标有轻度的改善作用(P>0.05)。(2) 联合用药可明显改善脑细胞损伤。(3) 与假手术组比较,不完全性全脑缺血再灌注损伤 0.5、2 和 6 h 后, 生理盐水组小鼠MDA 含量显著升高(均为 P <0. 01), SOD活性(均为 P <0.01) 和 GSH-Px 活性均显著降低(均为 P <0.01)。与生理盐水组比较, 联合组可显著地降低缺血再灌注小鼠脑组织MDA 含量、提高SOD活性和GSH-Px 活性(均为 P <0.05、P <0.01), 单用药组改善不明显。结论: 联合用药能显著减少小鼠脑缺血再灌注后 MDA 含量, 提高 GSH-Px 和SOD 的活力;改善神经行为缺陷和减少梗死面积百分比, 减轻神经细胞坏死。

关键词: 脑缺血, 再灌注, N-乙酰半胱氨酸, 氯胺酮, 联合用药

Abstract: AIM: To evaluate the effects of the com-bination of ketamine (KT) and N-acetylcysteine (NAC) on damage following cerebral ischemia/reperfusion in ICR mice. METHODS: Male ICRmice were randomly divid-ed into seven groups:Sham group, NS (saline 0.1 ml°kg^-1) group, KT (15 mg°kg^-1) group, NAC (75 mg°kg^-1) group, NAC+KT (75+15 mg°kg^-1) group. (1) ICR mice underwent two hours cerebral ischemia by transient right middle cerebral artery occlusion (tMCAO) and followed 6 h and 24 h reperfusion. Then brainswere prepared for the determination of the infarction volume. Before the death, neurological deficits were scored. (2) ICRmice subjected to five minutes ischemia by two com-mon carotid arteries occlusion (2-VO) and followed 0.5, 2 and 6 h reperfusion.Brains were prepared for the deter-mination of the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and the content of MDA.RESULTS: (1) tMCAO produced severe neuro-logical deficits, decreased the average score and brought about large infarction volume. KT, NAC showed the im-provement of the average score and reduced infarction vol-ume to some extent, and KT +NAC improved significant-ly. (2) The content of the MDA, the activities of GSH-Px and SOD in 2-VO mice deteriorated sharply, KT, NAC reduced the content of the MDA, enhanced the ac-tivities of GSH-Px and SOD, NAC +KT significantly ameliorated the levels of MDA, increased the activity of SOD and GSH-Px. CONCLUSION: The damage of cerebral ischemia/reperfusion leads to the decrease of neurological score, the increase of infarction volume, the reduction of activities of SOD and GSH-Px and the eleva-tion of MDA.KT and NAC partly relieve the damage, and NAC and KT in combination attenuates the damage more effectively.

Key words: cerebral, ischemia, reperfusion, ke-tamine, N-acetylcysteine, combination drug therapy

中图分类号:

R965

虞希冲, 陈醒言, 周红宇, 林丹, 朱桐君. N-乙酰半胱氨酸和氯胺酮联用对脑缺血再灌注损伤的影响[J]. 中国临床药理学与治疗学, 2005, 10(4): 428-431.

YU Xi-chong, CHEN Xian-yan, ZHOU Hong-yu, LIN Dan, ZHU Tong-jun. Effects of combination of ketamine and N-acetylcysteine on brain damage following cerebral ischemia /reperfusion in mice[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2005, 10(4): 428-431.

参考文献

1 Trotti D, DanboltNC, bolterra A.Glutamate transporters are ox-idant-vulnerable:a molecular link between oxidative and excito-toxic neurodegeneration[J]. Tips, 1998;19:328-33
2 Schubert D, Piasechi D.Oxidative glutamate toxicity can be a component of the excitotoxicity cascade[J]. J Neurosci, 2001; 21:7455-62
3 Himi T, Ikeda M, Yasuhara T, Murota S.Oxidative neuronal death caused by glutamate uptake inhibition in cultured hip-pocampal neurons[J]. J Neurosci Res, 2003;71:679-88
4 蒋晓帆, 章翔, 薛箐辉, 张光政, 李兵, 白红民, 等.小鼠局灶性线栓脑缺血模型的建立[J]. 第四军医大学学报,2002;23:2133-6
5 杜冠华, 张均田.丹参酚 A 对小鼠缺血再灌注致学习记忆功能障碍的改善作用及作用机理[J]. 药学学报, 1995;30:184-90
6 Garcia JH, Wagner S, LiuKF, HuXJ.Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats[J]. Stroke, 1995;26:627-35
7 Chan PH.Role of oxidants in ischemic brain damage[J]. Stroke, 1996;27:1124-9
8 Tan S, Sagara Y, LiuY, Maher P, Schubert D.The regulation of reactive oxygen species production during programmed cell death[J]. J Cell Boil, 1998;141:1423-32
9 Wang H, Cheng E, Brooke S, Chang P, Sapolsky R.Over-ex-pression of antioxidant enzymes protects cultured hippocampus and cortical neurons from necrotic insults[J]. J Neurochem, 2003;87:1527-34
10 Crack PJ, Taylor JM, de Haan JB, Kola I, Hertzog P, Iannel-lo RC.Glutathione peroxidase-1 contributes to the nuroprectec-tion seen in the superoxide dismutase-1 transgenic mouse in re-sponse to ischemia/reperfusion injury[J]. J Cereb Blood Flow Metab, 2003;23:19-22
11 Xue QS, Yu BW, Wang ZJ, Chen HZ.Effects of ketamine, midazolam, thiopental, andpropofol on brain ischemia injury in rat cerebral cortical slices[J]. Acta Pharmacol Sin, 2004;25: 115-20
12 Rozza A, Masoero E, Favalli L, Lanza E, GovoniS, Rizzo V, et al.Influence of different anaesthetics on extracellular aminoacids in rat brain[J]. J Neurosci Methods, 2000;101: 165-9
13 Han D, Sen CK, Roy S, KobayashiMS, Tritschler HJ, Packer L.Protection against glutamate-induced cytotoxicity in C6 glial cells by thiol antioxidants[J]. Am J Phsiol, 1997;273:R1771-8
14 Aruoma OI, Halliwell B, Hoey BM, Butler J.The antioxidant action of N-acetylcysteine:its reactionwith hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid[J]. Free Radic Boil Med, 1989;6:593-7

[1]	张华斌, 罗中旭, 钟民, 洪宗元, 王德国. 脊髓麻醉对大鼠急性心肌缺血再灌注室性心律失常的影响研究[J]. 中国临床药理学与治疗学, 2023, 28(3): 249-256.
[2]	侯小煜, 冷玉芳, 曹雪芬, 吕兴娇, 韩晓霞, Janvier NIBARUTA, 刘永强. 五味子乙素减轻小鼠肠缺血再灌注损伤的网络药理学分析及实验验证[J]. 中国临床药理学与治疗学, 2023, 28(2): 147-154.
[3]	李欣宇, 黄鑫. 美洛昔康的临床应用研究现状[J]. 中国临床药理学与治疗学, 2023, 28(2): 189-197.
[4]	曹雪芬, 冷玉芳, 韩晓霞, 侯小煜, 吕兴娇, Janvier NIBARUTA. 川芎嗪通过抑制NLRP3减轻肠缺血再灌注损伤的细胞焦亡[J]. 中国临床药理学与治疗学, 2023, 28(11): 1201-1208.
[5]	刘丹, 刘明, 金良友, 潘娟, 辛昊儒, 刘梦圆, 李鑫, 郑坤, 冯晓灵. 木香烃内酯抗肿瘤活性研究进展[J]. 中国临床药理学与治疗学, 2023, 28(10): 1168-1176.
[6]	张晶玉, 王一涵, 李珺, 金平, 申希平, 王迎斌, 刘婕婷. 自噬促进大鼠肠缺血再灌注损伤的细胞铁死亡[J]. 中国临床药理学与治疗学, 2023, 28(1): 36-41.
[7]	苏洋, 周峰, 丁金磊. 艾司氯胺酮复合舒芬太尼对胸腔镜肺癌根治术后情绪及镇痛的影响[J]. 中国临床药理学与治疗学, 2023, 28(1): 59-65.
[8]	王欣, 孙合亮, 张庆伟, 刘存明, 王忠云, 杨春. 小剂量艾司氯胺酮在胸腔镜下肺叶切除术患者术后镇痛中的作用[J]. 中国临床药理学与治疗学, 2022, 27(9): 998-1003.
[9]	张伟, 王迎斌, 曹璐, 刘艳, 张丽, 刘婕婷. 自噬在肠缺血再灌注损伤中的研究进展[J]. 中国临床药理学与治疗学, 2022, 27(9): 1061-1066.
[10]	华海燕, 严杰, 秦宇芬. 五味子乙素通过抑制心肌细胞凋亡减轻大鼠心肌缺血再灌注损伤的实验研究[J]. 中国临床药理学与治疗学, 2022, 27(8): 848-856.
[11]	韩晓霞, 冷玉芳, 吕兴娇, 侯小煜, 曹雪芬, Janvier NIBARUTA. 鸢尾素在脏器缺血/再灌注损伤中作用及机制的研究进展[J]. 中国临床药理学与治疗学, 2022, 27(8): 886-891.
[12]	梁美芳, 陈庆状, 杨沛群, 王勇. 基于真实世界的阿托伐他汀仿制药和原研药防治缺血性脑卒中/短暂性脑缺血发作的有效性和安全性比较[J]. 中国临床药理学与治疗学, 2022, 27(7): 785-792.
[13]	贾涛, 滕金亮. 新型麻醉镇痛药：艾司氯胺酮[J]. 中国临床药理学与治疗学, 2022, 27(7): 834-840.
[14]	沈燕平, 殷利军, 庄文明, 严海雅. 艾司氯胺酮预防无痛人工流产术中丙泊酚注射痛的有效剂量[J]. 中国临床药理学与治疗学, 2022, 27(6): 660-664.
[15]	任以行, 冷玉芳, 郭名君, 张健民, 石亚静, 陈凤, 刘馨. SIRT3在右美托咪定减轻小鼠肠缺血再灌注损伤中的作用及机制[J]. 中国临床药理学与治疗学, 2022, 27(3): 253-259.