发育期大鼠高温致惊对其成年期惊厥性脑损伤的影响

Febrile seizures of rats during brain development enhance the future brain injury of seizures

目的 研究大鼠生后发育期惊厥对其成年后再次惊厥所致神经元损伤的影响。方法 选择生后早期 (15d)高热致惊厥、成年后 (生后 5 5d)再次卡因酸 (KA)致惊厥大鼠 (FK组 )模型 ,与单纯成年期卡因酸致惊厥大鼠 (K组 )比较 ,观察成年期惊厥后大鼠的学习、记忆、行为学改变 ,海马苔藓纤维发芽以及海马凋亡细胞数的变化。结果 成年期大鼠惊厥后 ,FK及K组大鼠惊厥发作的潜伏期差异无显著性 [(4 0± 6 )s与 (4 6± 6 )s,P >0 0 5 ]。Morris水迷宫测试平均寻找平台时间 ,FK组[(2 4 3± 2 7)s]、K组 [(16 9± 3 3)s]时间较单纯热性惊厥组 (F组 ) [(6 0± 2 0 )s]、对照组 (C组 )[(5 5± 2 3)s]明显延长 (P <0 0 1) ,而且FK组也明显长于K组 (P <0 0 1) ,F组与C组差异无显著性(P >0 0 5 )。海马齿状回颗粒细胞上层Timm染色强度 ,FK组 (中位数为 2 83)和K组 (中位数为 2 33)较F组 (中位数为 0 2 5 )明显增强 (P <0 0 1) ,而FK组明显强于K组 (P <0 0 5 )。成年期应用KA后3d ,FK组、K组大鼠海马凋亡细胞数 (中位数分别为 2 1 9、14 5 )较F组 (中位数为 0 7)大鼠明显增多(P <0 0 1) ,同时FK组凋亡细胞数显著多于K组 (P <0 0 1)。结论 尽管发育期大鼠热性惊厥不能导致海马神经元凋亡 ,但在第

Objective Seizure is one of the most common neurological diseases, with the highest incidence during the first year of life. It is unclear about the effect of the seizure during brain development, especially the febrile convulsion. Therefore, the authors compared the brain injury of the kainate-induced seizure in adult rats between the rats with (group FK) and without febrile (group K) convulsion in early development time, and intend to determine whether and how the seizure during the brain development has the long term effect on the brain. Methods The febrile seizure model was established in the rats of postnatal 15 days by using hot water bath. The induced seizures lasted 1-2 minutes each time, once a day for 5 consecutive days. At the 55th day of postnatal, kainate was used to induce the rats (group FK) convulsion again ('two hit' model). The rats of group K only have 1 kainate-induced seizure during the adulthood (postnatal 55 days), and the rats of group F only have febrile seizures during the development. After the second time seizure, the seizure latent time, learning, memory and behavior changes were observed; meanwhile the mossy fiber sprouting in the hippocampus by Timm staining and apoptosis of neurons in the hippocampus by TUNEL were defined. Results After the second time seizure, the rats in both group FK and group K presented markedly abnormal behavior, such as irritability, wild running and jumping, and transient spontaneous seizure, but there was no difference in the latent time of seizure between the two groups [(40±6)s vs. (46±6)s, P>0.05]. The abnormal behavior gradually diminished in rats of group K after 5 days, while the abnormal behavior lasted until the sacrifice at the 65th day in rats of group FK. In Morris water maze test during the 60 to 65 days, the average searching platform latency (SPL) was significantly longer in rats of group FK [(24.3±2.7)s], group K [(16.9±3.3)s] (P<0.01) than rats of group F[(6.0±2.0)s], group C [(5.5±2.3)s, P<0.01], there was also significant difference between group FK and group K (P<0.01). No significant difference was seen between the rats of group F and group C. Mossy fiber sprouting has been found in supragranular layer of dentate in the rats of all groups, and increased markedly in rats of group FK and group K when compared with those in rats of group F [M=0.25,P<0.01]. The difference between group FK and group K was also significant (P<0.01). The apoptosis neurons in hippocampus in the rats of group FK and group K increased markedly [M=21.9, 14.5] compared to the rats of group F [M=0.7, P<0.01] 3 days after seizure, there was also significant difference between group FK and group K (P<0.01). Conclusion Although neuron apoptosis hasn′t been found in hippocampus during febrile seizures after 15-19 postnatal days, apoptosis neurons in hippocampus after serzure significantly increased in adult rats with the febrile seizure experience during the development, as well as mossy fibers sprouting in hippocampus. The rats with early seizures also presented marked defect of the space learning, memory and behavior. Therefore, seizures during the development might not induce marked neuron pathological injury, but seizures during the development increased the sensitivity of neuron injury to the later seizures during adulthood.