Trans-2-ene-valproic acid is less behaviorally teratogenic than an equivalent dose of valproic acid in rats.
Trans-2-ene-valproic acid is less behaviorally teratogenic than an equivalent dose of valproic acid in rats.
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与同等剂量的丙戊酸相比，反式 2-烯丙戊酸对大鼠的行为致畸性较小。
DOI：
10.1002/tera.1420490608
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发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Vorhees,CV
中科院分区：
文献类型：
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作者：
FisherJr,JE;Acuff-Smith,KD;Schilling,MA;Nau,H;Vorhees,CV
尽管动物实验表明丙戊酸（VPA）的反式-2-烯代谢物（t-2-烯-VPA）在抗惊厥活性方面与母体化合物相当，但在检查产前暴露胎儿形态缺陷的研究中，其致畸性要低得多。这使得t-2-ene-VPA成为一种有吸引力的潜在抗癫痫药物。然而，尽管在产前暴露于VPA的大鼠中也观察到神经行为改变，即使剂量低于产生畸形的剂量，但之前尚未检查过t-2-ene-VPA的发育神经毒性。本研究评价了产前暴露于t-2-ene-VPA的长期行为影响。妊娠CD大鼠在妊娠第7-18天通过灌胃给予300或400 mg/kg t-2-ene-VPA，该剂量先前显示无致畸性。VPA组给予300 mg/kg剂量进行比较。两种化合物的药代动力学特征相似。产前暴露于VPA的后代的行为结果与之前的结果一致，即，与对照组相比，VPA后代表现出运动活动减少、游泳迷宫错误增加和触觉惊吓反应减少。在400 mg/kg t-2-ene-VPA组中，辛辛那提迷宫错误和听觉惊吓反应增加，而在300 mg/kg t-2-ene组中未检测到显著的行为影响。这些结果表明，t-2-ene-VPA的发育神经毒性低于VPA，但仍然显著。© 1994 Wiley利斯公司
Although animal experiments have shown the trans‐2‐ene metabolite (t‐2‐ene‐VPA) of valproic acid (VPA) to be pharmacologically equivalent to the parent compound in terms of anticonvulsant activity, it is considerably less teratogenic in studies which have examined prenatally exposed fetuses for morphological defects. This has made t‐2‐ene‐VPA an attractive potential antiepileptic agent. However, while neurobehavioral alterations have also been observed in rats prenatally exposed to VPA, even at doses below those which produce malformations, the developmental neurotoxicity of t‐2‐ene‐VPA had not previously been examined. The current study evaluated the long‐term behavioral effects of prenatal exposure to t‐2‐ene‐VPA. Pregnant CD rats were treated with 300 or 400 mg/kg t‐2‐ene‐VPA by gavage on days 7–18 of gestation, doses previously shown to produce no teratogenicity. A VPA group was administered 300 mg/kg for comparison. The pharmacokinetic profiles of the two compounds were similar. Behavioral findings in offspring prenatally exposed to VPA were consistent with previous findings, i.e., VPA offspring exhibited decreased locomotor activity, increased swimming maze errors, and reduced tactile startle responding compared to controls. In the 400 mg/kg t‐2‐ene‐VPA group, Cincinnati maze errors and auditory startle reactivity were increased, while no significant behavioral effects were detected in the 300 mg/kg t‐2‐ene group. These results indicate that the developmental neurotoxicity of t‐2‐ene‐VPA is lower than that of VPA but is still significant. © 1994 Wiley‐Liss, Inc.