孕期补充叶酸对丙戊酸钠诱导仔鼠的早期生理发育和行为发育的影响

The effects of folic acid on valproate-induced postnatal physiological and neurobehavioral development

目的探讨孕期补充叶酸对丙戊酸钠诱导出生后仔鼠的影响。方法健康成年ICR雌、雄鼠按4∶2进行交配,将孕鼠随机分为对照组、丙戊酸钠组(VPA)和叶酸补充组(FA+VPA)。在受孕第12.5天,VPA组和FA+VPA组腹腔注射丙戊酸钠500 mg/kg,其中FA+VPA组需提前1小时灌胃叶酸3 mg/kg,对照组腹腔注射等量生理盐水。所有孕鼠在分娩后仔代均调整为8只。检测仔鼠出生后早期的生长发育情况,以及青春期探索和认知相关试验(旷场试验、水迷宫试验)。结果 VPA组仔鼠的平面翻正达标的时间显著延迟(P<0.05),FA+VPA组的睁眼时间较VPA组明显提前(P<0.05)。旷场试验中,VPA组雌鼠的中间时间所占总时间的比值较对照组有着显著性减少(P<0.05),仔代雄鼠间差异无统计学意义。水迷宫试验中,与对照组相比,VPA组雄鼠的游泳路程在第二天和第五天显著增加(P<0.05),同时雄鼠的穿越平台次数显著减少(P<0.05),而雌鼠没有显著性差异;与VPA组相比,FA+VPA组雌鼠游泳路程在第五天显著降低(P<0.05),雄鼠没有明显差异。结论孕期补充叶酸可能减缓丙戊酸钠诱导仔鼠神经发育毒性,以及改善雌性仔鼠的学习记忆能力。

Objective To investigate the effects of folic acid supplementation on newborn mouse induced by valproate.Methods The adult ICR mice were allowed free access to food and water at all times,and four females were housed overnight with two males for mating purposes. All pregnant mice were randomly divided into three groups： control group,sodium valproate group（ VPA） and folic acid supplementation group（ FA＋VPA）. At the 12.5th days after conception,VPA group and VPA＋FA group were injected with sodium valproate at the dose of 500 mg/kg. However the FA＋VPA group was intragastrically administration with folic acid at the dose of 3 mg/kg one hour earlier. The control group were injected with normal saline. The growth and development of the offspring were detected,including adolescent exploration and cognitive tests（ open field test,Morris water maze）.Results VPA group was significantly delayed in the time of surface righting compared with the control group（ P0.05）. The time of eye opening in VP ＋VPA group was significantly earlier than that in VPA group（ P0.05）.In the open-field test,the middle time ratio of the total time in the VPA group was significantly lower than that in the control group in female mice（ P 0. 05）,but there was no significant difference between male. In the water maze test,the swimming distance of the VPA group was significantly higher than that of the control group on the second and fifth day in male mice（ P0.05）,and the frequency of crossing the platform in the VPA group was significantly decreased（ P 0. 05）,but there was no significant difference between female mice. Compared with VPA group,swimming distance of FA＋VPA group was significantly lower than that of VPA group in female mice（ P 0. 05）,and it was no significant difference in male. Conclusions Supplementation of folic acid during pregnancy may attenuate postnatal neurotoxicity induced by sodium valproate,and improve the learning and memory ability of female offspring.