[1]徐晓科,蔡方成.新一代抗癫痫药对新生大鼠脑发育的影响[J].新乡医学院学报,2019,36(8):724-731.[doi:10.7683/xxyxyxb.2019.08.006]
　XU Xiao-ke,CAI Fang-cheng.Effect of new generation antiepileptic drugs on brain development of neonatal rats[J].Journal of Xinxiang Medical University,2019,36(8):724-731.[doi:10.7683/xxyxyxb.2019.08.006]
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新一代抗癫痫药对新生大鼠脑发育的影响
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《新乡医学院学报》[ISSN:1004-7239/CN:41-1186/R]

卷:
36
期数:
2019年8
页码:
724-731
栏目:
基础研究
出版日期:
2019-08-05

文章信息/Info

Title:
Effect of new generation antiepileptic drugs on brain development of neonatal rats
作者:
徐晓科1; 蔡方成2
（1.西安市儿童医院神经内科,陕西　西安　710002；2.重庆医科大学附属儿童医院神经内科，重庆　400014）
Author(s):
XU Xiao-ke1; CAI Fang-cheng2
（1.Department of Neurology,Xi′an Children′s Hospital,Xi′an 710002,Shaanxi Province,China；2.Department of Neurology,Children′s Hospital of Chongqing Medical University,Chongqing 400014,China）
关键词:
新生儿; 奥卡西平; 左乙拉西坦; 托吡酯; 脑损伤
Keywords:
neonatal; oxcarbazepine; levetiracetam; topiramate; brain damage
分类号:
R651.1+5
DOI:
10.7683/xxyxyxb.2019.08.006
文献标志码:
A
摘要:
目的　探讨新一代抗癫痫药一次性单药或联合苯巴比妥（PB）用药对新生大鼠脑发育的影响。方法　将健康清洁级7日龄Wistar大鼠270只随机分为对照组、奥卡西平（OXC）30组、OXC60组、托吡酯（TPM）组、左乙拉西坦（LEV）组、PB组、PB+OXC30组、PB+TPM组和PB+LEV组，每组30只。OXC30组、OXC60组、TPM组、LEV组和PB组大鼠分别灌胃OXC 187.5 mg·kg-1、OXC 375.0 mg·kg-1、TPM 62.5 mg·kg-1、LEV 375.0 mg·kg-1、PB 62.5 mg·kg-1；PB+OXC30组、PB+TPM组和PB+LEV组大鼠均腹腔注射PB 62.5 mg·kg-1，4 h后，再分别灌胃OXC 187.5 mg·kg-1、TPM 62.5 mg·kg-1、LEV 375.0 mg·kg-1；对照组大鼠腹腔注射生理盐水0.1 mL。每组取10只大鼠测给药前后体质量及给药后脑质量；给药后24 h，每组取10只大鼠采用苏木精-伊红（HE）、尼氏染色观察大鼠脑组织病理学改变；给药后16 d，每组取10只大鼠行Morris水迷宫试验检测大鼠学习记忆能力;水迷宫试验结束后次日处死大鼠，取脑组织观察病理学改变，并进行颞叶皮层及海马下托复合体神经细胞计数。结果　用药前各组大鼠体质量比较差异无统计学意义（P>0.05）；给药后24 h，OXC60组、PB+OXC30组、PB+TPM组、PB+LEV组及PB组大鼠体质量均低于对照组（P<0.05）；OXC30组、TPM组、LEV组与对照组大鼠体质量比较差异无统计学意义（P>0.05）。PB+OXC30组、PB+TPM组、PB+LEV组与PB组大鼠体质量比较差异均无统计学意义（P>0.05）。OXC60组、PB+OXC30组大鼠脑质量显著低于对照组（P<0.05）；其余各给药组大鼠脑质量与对照组比较差异均无统计学意义（P>0.05）。PB+OXC30组、PB+TPM组、PB+LEV组大鼠脑质量与PB组比较差异均无统计学意义（P>0.05）。给药后 24 h，HE染色可见，各给药组大鼠脑组织颞叶皮层结构未见明显异常。OXC60组、PB组、PB+OXC30组、PB+TPM组及PB+LEV组大鼠脑组织海马下托复合体出现部分细胞核固缩、深染，核周空泡，细胞皱缩等病理学改变，且PB+OXC30组病变严重程度明显大于PB组；OXC30、TPM、LEV组大鼠脑组织海马下托均未见明显病理改变。尼氏染色显示，OXC60组、PB+OXC30组、PB+TPM组及PB+LEV组大鼠脑组织颞叶皮层少数神经细胞尼氏小体减少，部分溶解消失；OXC60组和PB组大鼠海马下托可见尼氏小体减少，部分溶解。给药后23 d，PB+OXC30组大鼠脑组织颞叶皮层可见退行性红色神经细胞明显增多；PB+TPM组、PB+LEV组及OXC60组大鼠脑组织病理学改变有所恢复。OXC60组和PB+OXC30组大鼠穿越平台次数少于对照组 (P<0.05)。OXC30组、TPM组、LEV组、PB组、PB+TPM组和PB+LEV组与对照组大鼠穿越平台次数比较差异无统计学意义（P>0.05）；PB+OXC30组、PB+TPM组和PB+LEV组与PB组大鼠穿越平台次数比较差异无统计学意义（P>0.05）。第1、2、3、4天，各给药组与对照组大鼠寻台潜伏期比较差异均无统计学意义（P>0.05）。PB+OXC30组大鼠第5天寻台潜伏期长于对照组（P<0.05），其余各给药组与对照组大鼠第5天寻台潜伏期比较差异均无统计学意义（P>0.05）。第1、2、3、4、5天，PB+OXC30组、PB+TPM组、PB+LEV组与PB组大鼠寻台潜伏期比较差异无统计学意义（P>0.05）。各给药组与对照组大鼠颞叶皮层神经细胞计数比较差异均无统计学意义（P>0.05）。PB+OXC30组大鼠海马下托区神经细胞计数少于对照组（P<0.05），其余各组大鼠海马下托区神经细胞计数与对照组比较差异均无统计学意义（P>0.05）。PB+OXC30组、PB+TPM组、PB+LEV组与PB组大鼠海马下托区神经细胞计数比较差异无统计学意义（P>0.05）。结论　一次性使用375.0 mg·kg-1 OXC可导致新生健康大鼠急性期脑损伤和远期空间记忆能力稍减弱；较低剂量（187.5 mg·kg-1）的OXC不会引起发育未成熟脑出现明显损伤，但却能明显加重PB引起的脑损伤，且遗留持久性脑损伤和记忆功能障碍;抢救剂量的LEV （375.0 mg·kg-1）和TPM (62.5 mg·kg-1）不存在脑损伤危险，也不加重PB引起的损伤。
Abstract:
Objective　To investigate the effect of new generation of antiepileptic drugs alone or combined with phenobarbital (PB) on the brain development of newborn rats.Methods　Two hundred and seventy healthy cleaning seven days old Wistar rats were randomly divided into control group,oxcarbazepine (OXC)30 group,OXC60 group,topiramate (TPM) group,levetiracetam (LEV) group,PB group,PB+OXC30 group,PB+TPM group and PB+LEV group,with 30 rats in each group.The rats in OXC30 group,OXC60 group,TPM group,LEV group and PB group were given OXC 187.5 mg·kg-1,OXC 375.0 mg·kg-1,TPM 62.5 mg·kg-1,LEV 375.0 mg·kg-1,PB 62.5 mg·kg-1 by intragastric administration；the rats in PB+OXC30 group,PB+TPM group and PB+LEV group were given PB 62.5 mg·kg-1 by intraperitoneal injection,after 4 hours,the rats were given OXC 187.5 mg·kg-1,TPM 62.5 mg·kg-1 and LEV 375.0 mg·kg-1 respectively;the rats in the control group were intraperitoneally injected with 0.1 mL saline.The body weight and brain weight of rats in all groups(n=10) were measured before and after 24 hours administration；the histopathological changes of rats in each group(n=10) were observed by hematoxylin-eosin (HE) and Nissl staining at 24 hours after administration.The learning and memory ability of rats in each group(n=10) were tested by Morris water maze test on the 16th day after administration;the rats were sacrificed on the next day after the water maze test and the brain tissues were taken to observe the pathological changes,and the hippocampal neurons in temporal cortex and subhippocampal complex were counted.Results　There was no significant difference in body weight of rats in each group before administration (P>0.05);at the 24 hours after administration,the body weight of rats in OXC60 group,PB+OXC30 group,PB+TPM group,PB+LEV group and PB group was lower than that in the control group (P<0.05);there was no significant difference in the body weight of rats between OXC30 group,TPM group LEV group and control group (P>0.05).There was no significant difference in body weight between PB+OXC30 group,PB+TPM group，PB+LEV group and PB group(P>0.05).The brain weight of rats in OXC60 group and PB+OXC30 group was significantly lower than that in the control group (P<0.05),while there was no significant difference in the brain weight between other intervention groups and control group (P>0.05).There was no significant difference in the brain weight of rats between PB+OXC30 group,PB+TPM group,PB+LEV group and control group (P>0.05).At 24 hours after administration,HE staining showed that there was no significant abnormality in temporal cortex structure of brain tissue in all intervention groups.Some pathological changes such as nuclear pyknosis,hyperchromatism,perinuclear vacuoles and cell shrinkage were observed in the hippocampal substratum complex of rats in OXC60 group,PB group,PB+OXC30 group,PB+TPM group and PB+LEV group;and the severity of the lesions of rats in PB+OXC30 group was significantly higher than that in PB group.There were no obvious pathological changes in the subhippocampal substratum of rats in OXC30 group,TPM group and LEV group.Nissl staining showed that the Nissl bodies decreased in a small number of neurons in the temporal cortex of brain tissue of rats in OXC60 group,PB+OXC30 group,PB+TPM group and PB+LEV group and partial Nissl bodies dissolved;the Nissl bodies decreased in the hippocampal substratum of brain tissue of rats in OXC60 group and PB group and partial Nissl bodies dissolved.At 23 days after administration,the number of degenerative red neurons in temporal lobe cortex of brain tissue of rats increased in PB+OXC30 group,and the pathological changes of brain tissue of rats in PB+TPM group,PB+LEV group and OXC60 group recovered.Conclusion　One-time use of rescue dose (375.0 mg·kg-1) of OXC can cause acute stage brain injury and weak long-term spatial memory ability of neonatal rats.The low doses (187.5 mg·kg-1) of OXC dose not cause significant acute phase damage in immature brain,but it can aggravated the brain damage caused by PB,and leave persistent brain damage and memory dysfunction.The rescue dose of LEV (375.0 mg·kg-1) and TPM (52.5 mg·kg-1) do not present the risk of brain injury and do not aggravate the damage caused by PB.

参考文献/References:

［1］　徐晓科,蔡方成,宋艳，等.常用抗惊厥治疗方案对新生鼠脑发育的影响［J］.第三军医大学学报，2010，32(18)：1981-1985.
［2］　GLASS H C,WIRRELL E.Controversies in neonatal seizure mana-gement［J］.J Child Neurol，2009，24(5):591-599.
［3］　GLIER C,DZIETKO M,BITTIGAU P,et al.Therapeutic doses of topiramate are not toxic to the developing brain［J］.Exp Neurol,2004，187(2):403-409.
［4］　MANTHEY D,ASIMIADOU S,STEFOVSKA V,et al.Sulthiame but not levetiracetam exerts neurotoxic effect in the developing rat brain［J］.Exp Neurol,2005，193(2):497-503.
［5］　SILVERSTEIN F S,FERRIERO D M.Off-label use of antiepileptic drugs for the treatment of neonatal seizures［J］.Pediatr Neurol,2008，39(2):77-79.
［6］　BLUME H K,GARRISON M M,CHRISTAKIS D A.Neonatal seizures:treatment and treatment variability in 31 United States pediatric hospitals［J］.J Child Neurol,2009，24(2):148-154.
［7］　魏泓.实验动物和动物实验技术［M］.北京：人民卫生出版社,1998:142-146.
［8］　LOSCHER W.The pharmacokinetics of antiepileptic drugs in rats:consequences for maintaining effective drug levels during prolonged drug administration in rat models of epilepsy［J］.Epilepsia,2007，48(7):1245-1258.
［9］　TECOMA E S.Oxcarbazepine［J］.Epilepsia,1999，40(Suppl 5):S37-S46.
［10］　SILVERSTEIN F S,JENSEN F E,INDER T,et al.Improving the treatment of neonatal seizures:National Institute of Neurological Disorders and Stroke workshop report［J］.J Pediatr,2008，153(1):12-15.
［11］　CHA B H,SILVEIRA D C,LIU X,et al.Effect of topiramate following recurrent and prolonged seizures during early development［J］.Epilepsy Res,2002，51(3):217-232.
［12］　朱海霞,蔡方成,张晓萍.治疗血浓度下抗癫痫药对未成熟脑发育影响的实验研究［J］.中华神经科杂志,2007,40(3):157-161.
［13］　朱海霞,蔡方成,张晓萍.长程服用苯巴比妥、氯硝安定、丙戊酸和托吡酯对未成熟脑发育影响的实验研究［J］.中华儿科杂志,2007,45(2):121-125.
［14］　KAINDL A M,ASIMIADOU S,MANTHEY D,et al.Antiepileptic drugs and the developing brain［J］.Cell Mol Life Sci,2006，63(4):399-413.
［15］　AYALA-GUERRERO F,MEXICANO G,CAMPOS-SEPULVEDA E,et al.Effect of oxcarbazepine pretreatment on convulsive activity and brain damage induced by kainic acid administration in rats［J］.Comp Biochem Physiol A Mol Integr Physiol,2008，151(3):471-476.
［16］　AKTAS Z,CANSU A,ERDOGAN D,et al.Retinal ganglion cell toxicity due to oxcarbazepine and valproic acid treatment in rat［J］.Seizure,2009，18(6):396-399.
［17］　WANG Y,ZHANG H N,NIU C H,et al.Population pharmacoki-netics modeling of oxcarbazepine to characterize drug interactions in Chinese children with epilepsy［J］.Acta Pharmacol Sin,2014，35(10):1342-1350.
［18］　TARTARA A,GALIMBERTI C A,MANNI R,et al.The pharmac-okinetics of oxcarbazepine and its active metabolite 10-hydroxy-carbazepine in healthy subjects and in epileptic patients treated with phenobarbitone or valproicacid［J］.Br J Clin Pharmacol,1993，36(4):366-368.
［19］　VERDRU P.Epilepsy in children:the evidence for new antiepi-leptic drugs［J］.Acta Neurol Scand Suppl,2005，181:17-20.

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更新日期/Last Update: 2019-08-05