1-(2-氯)苯基-9-丁基-β-咔啉对小鼠的神经毒性作用  

Neurotoxic effects of 1-(2-chlorine)phenyl-9-butyl-β-carboline in mice

作　　者：张莉 布胡丽倩木·伊买尔江 马瑞佳 吾斯曼江·艾麦提 陈蓓[2] 王建华[2] ZHANG Li;Buhuliqianmu·Yimaierjiang;MA Rui-jia;Wusimanjiang·Aimaiti;CHEN Bei;WANG Jian-hua(College of Pharmacy,Xinjiang Medical University,Xinjiang Urumqi 830054,China;Department of Pharmacy,First Affiliated Hospital of Xinjiang Medical University,Xinjiang Urumqi 830054,China)

机构地区：[1]新疆医科大学药学院,新疆乌鲁木齐830054 [2]新疆医科大学第一附属医院药学部,新疆乌鲁木齐830054

出　　处：《中国医院药学杂志》2022年第9期879-883,共5页Chinese Journal of Hospital Pharmacy

基　　金：省部共建中亚高发病成因与防治国家重点实验室开放课题资助项目(编号:SKL-HIDCA-2019-24);国家自然科学基金项目(编号:81860666)。

摘　　要：目的:探讨去氢骆驼蓬碱衍生物1-(2-氯)苯基-9-丁基-β-咔啉(简称“DH-330”)对小鼠神经行为损伤的影响及可能机制,为系列衍生物的开发提供依据。方法:将昆明小白鼠随机分为4组,分别为空白对照组(0.9%NaCl溶液)、低剂量组(69.44 mg·kg^(-1)DH-330)、中剂量组(208.33 mg·kg^(-1)DH-330)和高剂量组(347.22 mg·kg^(-1)DH-330),连续灌胃给药28 d,采用Morris水迷宫实验测试神经行为;通过免疫吸附测定法(ELISA)测定小鼠脑组织中ROS、GSH、MAO、AChE、5-HT含量,同时采用透射电镜对小鼠海马组织超微结构进行观察。结果:Morris水迷宫实验:高剂量DH-330对小鼠的空间学习记忆能力造成影响,主要表现为高剂量组小鼠的逃避潜伏期及总行程显著长于对照组(P<0.05),而穿台次数及靶象限停留时间显著少于对照组(P<0.05)。生化指标结果:与对照组比较,DH-330高剂量组小鼠脑内ROS、5-HT水平显著升高(P<0.05);GSH、AChE、MAO含量显著降低(P<0.05)。海马超微结构:高剂量DH-330可导致海马组织中细胞结构损伤,主要表现为异染色质多黑、线粒体出现空泡化等现象。结论:DH-330可致小鼠神经行为系统损伤,其机制可能是通过抑制小鼠脑内AChE、MAO及GSH含量,促使ROS、5-HT水平升高,导致氧化平衡状态改变及单胺类神经递质含量升高,从而诱导神经行为毒性。OBJECTIVE The effects of 1-(2-chlorine)phenyl-9-butyl-β-carboline derivative(DH-330)on neurobehavioral injury in mice and its possible mechanism were investigted,so as to provide basis for the development of series of derivatives.METHODS Kunming white mice were randomly divided into 4 groups:blank control group(0.9%NaCl solution),low dose group(69.44 mg·kg^(-1)DH-330),medium dose group(208.33 mg·kg^(-1)DH-330)and high dose group(347.22 mg·kg^(-1)DH-330),and administered intragastrically for 28 consecutive days.Morris water maze test was used to detect mental behaviors.The contents of ROS,GSH,MAO,AChE and 5-HT in mice brain were determined by ELISA,and the ultrastructure of mouse hippocampus was observed under a transmission electron microscope.RESULTS Morris water maze experiment:the effects of high dose DH-330 on spatial learning and memory ability of mice were mainly manifested as longer escape latency and total travel,and less crossing times and residence time of mice in the high dose group than those in the control group(P<0.05).Biochemical index results:compared with those in the control group,the levels of ROS and 5-HT in the brain of DH-330 high dose group were significantly increased(P<0.05);the contents of GSH,AChE and MAO were significantly decreased(P<0.05).Ultrastructure of hippocampus:transmission electron microscopy showed that high dose DH-330 could cause cell structure damage in hippocampus,mainly manifested as black heterochromatin and mitochondria vacuolation phenomenon.CONCLUSION DH-330 may induce neurobehavioral damage in mice by inhibiting the contents of AChE,MAO and GSH in brain and increasing the levels of ROS and 5-HT resulting in the changes in oxidative balance and content increase of monoamine neurotransmitters,thereby inducing neurobehavioral toxicity.

关 键 词：去氢骆驼蓬碱衍生物 神经毒性 MORRIS水迷宫 

分 类 号：R994.6[医药卫生—毒理学]