大鼠出生前接触苯妥英和褪黑素对仔代反射功能发育及自发运动的影响

中国临床药理学与治疗学 ›› 2004, Vol. 9 ›› Issue (5): 494-499.

大鼠出生前接触苯妥英和褪黑素对仔代反射功能发育及自发运动的影响

吴纯启, 王爱平, 廖明阳, 王治乔

军事医学科学院毒物药物研究所新药安全性评价研究室, 北京100850

收稿日期:2003-10-27 修回日期:2004-01-06 发布日期:2020-11-22
通讯作者: 吴纯启, 男, 博士, 助理研究员, 中国毒理学会生殖毒理学专业委员会委员, 主要从事新药临床前生殖毒理学研究。Tel:010-66931632 　E-mai l:wu940410@Yahoo.com

Effects of prenatal exposure to phenytoin and melatonin on the development of reflex function and locomotive activities of rat pups

WU Chun-Qi, WANG Ai-Ping, LIAO Ming-Yang, WANG Zhi-Qiao

Laboratory of Drug Safety Evaluation, Institute of Pharmacology and Toxicology, Academy of Military Medical Science,Beijing 100850, China

Received:2003-10-27 Revised:2004-01-06 Published:2020-11-22

摘要/Abstract

摘要： 目的探讨苯妥英(DPH) 神经发育毒性与胚胎脑组织中自由基产生和氧化应激反应的关系。方法 Wistar 孕鼠于妊娠d 11 ~ 14 经0, 100,200 mg·kg^-1 DPH 或合并40 mg·kg^-1褪黑素(MT) 染毒处理, 研究MT 对DPH 的仔代反射功能发育及自发运动损害作用的拮抗效应。结果孕鼠在染毒期及染毒后增重下降, 仔代体重减轻, 哺乳期死亡率增高;DPH 染毒仔鼠的转身运动增多, 空中翻正反射及游泳能力发育延迟, 成年后行走次数、站立次数、刻板动作等自发活动增多, 旋转手比率增多, 对阿朴吗啡“激发”反应性增强。MT 和DPH 合并处理可明显拮抗上述DPH 仔鼠的行为异常。结论氧化性损伤在DPH 神经发育毒性发生中发挥重要作用, 而MT 可拮抗其毒性作用。

关键词: 苯妥英, 褪黑素, 神经发育毒性, 氧化性损伤, 拮抗效应

Abstract: AIM: To explore the relationship between the developmental neurotoxicity (DNT) induced by prenatal phenytoin(DPH) exposure and free radicals and oxidative stress initiated in the embryonic brain. METHODS: PregnantWistar rats were administered DPH by gavage on gestation days (GD) 11-14 in doses of 0, 100, 200 mg·kg^-1 and or 40 mg·kg^-1 MT (melatonin). RESULTS: DPH treated dams showed a dose related decrease in weight gain throughout the treatment period. Offspring had significantly lowered birth weight along with increased mortality.During the neonatal period, the pups exposed in uterus to DPH showed a significant increase in pivoting locomotion, and delayed in air righting reflex and swimming development.As adults, these pups showed an increased ambulation, rearing, stereotype events and rotational behavior.Furthermore, prenatal DPH exposure resulted in a dose-response shift to the left for locomotor activity of F1 DPH pups after stimulated by 0.2 and 2.0 mg·kg^-1 apomorphine. CONCLUSION: Co-administration of MT and DPH to dams significantly antagonized or protected most of the postnatal adverse effects induced by prenatal DPH exposure in F1 pups, which suggest that DNT induced by prenatal DPH exposure may be evoked and mediated via oxidative stress.

Key words: phenytoin, melatonin, developmental neurotoxicity, oxidative stress, antagonism

中图分类号:

R965.1

吴纯启, 王爱平, 廖明阳, 王治乔. 大鼠出生前接触苯妥英和褪黑素对仔代反射功能发育及自发运动的影响[J]. 中国临床药理学与治疗学, 2004, 9(5): 494-499.

WU Chun-Qi, WANG Ai-Ping, LIAO Ming-Yang, WANG Zhi-Qiao. Effects of prenatal exposure to phenytoin and melatonin on the development of reflex function and locomotive activities of rat pups[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2004, 9(5): 494-499.

参考文献

1 Kimmel CA.Current status of behavioral teratology:Science and regulation[J].CRC Rev Toxicol, 1988;19(1):1-10
2 Wells PG,Winn LM.Biochemical toxicology of chemical teratogenesis[J].Crit Rev Biochem Mol Biol, 1996;31(1):1-40
3 Hansen DK, Holson RR.Developmental neurotoxicity of antiepileptic drugs[A].In:Slikker WJ, Chang LW, eds.Handbook of developmental neurotoxicology[M].San Diego:Academic Press, 1998:643-60
4 Reiter RJ.Oxidative damage in the central nervous system:protection by melatonin[J].Prog Neurobiol, 1998;56(3):359-84
5 王爱平.生殖毒性试验[A].见:王治乔, 袁伯俊, 主编.新药临床前安全性评价与实践[M].北京:军事医学科学院出版社, 1997:117-51
6 Vorhees CV.Fetal anticonvulsant syndrome in rats:dose-and period-response relationship of prenatal diphenylhydantoin, trimethadione and phenobarbital exposure on the structural and functional development of the offspring[J].J Pharmacol Exp Ther, 1983;27(2):274-87
7 Pizzi W, Jersey RM.Effects of prenatal diphenylhydantoin treatment on reproductive outcome, development and behavior in rats[J].Neurotox Teratol, 1992;14(2):111-7
8 Chen YC, Pellis SM, Sirkin D, PotegalM, Teitelbaum P.Bandage-backfall: labyrinthine and non-labyrinthine components [J].Physiol Behav, 1986;37(3):805-14
9 Vorhees CV, Minck DR.Long-term effects of prenatal phenytoin exposure on offspring behavior in rats[J].Neurotoxcol Teratol, 1989;11(3):295-305
10 Minck DR, Erway LC, Vorhees CV.Reduction of otoconia in the inner ear of adult rats following prenatal exposure to phenytoin[J].Neurotoxicol Teratol, 1989;11(3):307-11
11 Gordon JH.Hypophysectomy-induced striatal hypersensitivity and mesolimbic hypersens-itivity to apomorphine[J].Pharmacol Biochem Behav, 1983;19(5):807-11
12 Yan GM, Irwin RP, Lin SZ, Weller M, Wood KA, Paul SM. Diphenylhydantoin induced apoptotic cell death of cultured rat cerebellar granule neurons[J].J Pharmacol Exp Ther, 1995; 274(6):983-90

[1]	邵明坤, 刘蓉, 孙品, 关水, 廖炳灿, 李莎, 丛滔, 梁凯, 马辉, 孙长凯. 褪黑素人体网络机制及其临床应用[J]. 中国临床药理学与治疗学, 2022, 27(9): 1031-1040.
[2]	李雪恒, 李龙. 褪黑素与特发性肺纤维化关系的研究进展[J]. 中国临床药理学与治疗学, 2022, 27(6): 715-720.
[3]	王睿, 潘进进, 李华, 袁予辉. 褪黑素调节肺动脉高压的作用与机制研究进展[J]. 中国临床药理学与治疗学, 2021, 26(4): 444-448.
[4]	崔海鞠, 马张庆, 杨魁, 汪五三, 许慧芳, 栾家杰. 褪黑素在非杓型自发性高血压大鼠体内的时辰药动学研究[J]. 中国临床药理学与治疗学, 2020, 25(12): 1337-1343.
[5]	张琛涵, 聂静云, 辛鹏飞, 柴琛, 李波. 褪黑素与胰腺疾病的研究进展[J]. 中国临床药理学与治疗学, 2020, 25(11): 1309-1314.
[6]	于瀚，钟相根，李耘州，许宗颖，石少华，邓秀兰. 褪黑素对肝内胆汁淤积大鼠肝组织NO、MDA、GSH及NADPH的影响[J]. 中国临床药理学与治疗学, 2019, 24(11): 1221-1226.
[7]	黄小燕, 郭歆, 余鹏, 刘智, 黄志军, 阳国平, 程泽能. 磷苯妥英钠注射液人体药代动力学研究[J]. 中国临床药理学与治疗学, 2014, 19(4): 419-423.
[8]	刘扬, 宋亚娟, 丁国华. 基因诊断在苯妥英治疗癫痫病中的应用[J]. 中国临床药理学与治疗学, 2009, 14(4): 465-470.
[9]	董乐妹, 吴建胜, 贾国葆, 方佩佩, 孙学成, 倪银. 褪黑素干预急性坏死性胰腺炎肺损伤及巨噬细胞移动抑制因子表达[J]. 中国临床药理学与治疗学, 2009, 14(3): 261-264.
[10]	余涓, 周宇, 郑祥, 陈崇宏. 脑缺血再灌注损伤后神经细胞凋亡与褪黑素的影响[J]. 中国临床药理学与治疗学, 2008, 13(7): 740-743.
[11]	吴建胜, 吴金明, 王旦, 黄庆科, 陈向荣, 黄智铭, 林向飞, 陈民新, 韩清锡. 褪黑素对大鼠应激性溃疡的保护及胃粘膜核因子-κB 活性的影响[J]. 中国临床药理学与治疗学, 2005, 10(2): 211-214.
[12]	蒲其松, 杨健全, 雷军, 李春平, 兰大荣, 张翔, 吴体成, 蔡春燕. 幼年家兔口服苯妥英锌 7 个月小脑生长发育的研究[J]. 中国临床药理学与治疗学, 2005, 10(11): 1294-1298.
[13]	霍展样, 刘东华, 刘晓丽. 褪黑素对小鼠反复脑缺血再灌注损伤学习记忆的改善作用及机制[J]. 中国临床药理学与治疗学, 2003, 8(5): 567-569.
[14]	蒲其松, 李保国, 张翔, 陈发国. 苯妥英锌对烧伤的临床治疗作用[J]. 中国临床药理学与治疗学, 2003, 8(2): 192-194.
[15]	戴伟娟, 郭子林, 刘宏, 宋爱芹, 王传功, 刘善庭. 苯妥英钠对鼠脑缺血再灌注时血浆细胞因子及内皮素的影响[J]. 中国临床药理学与治疗学, 2001, 6(2): 117-118.