托吡酯伍用叶酸对慢性癫癎幼鼠脑神经元损伤的保护作用

目的：目前国内外鲜见托吡酯（TPM）对小儿慢性癫癎发作所致脑神经元损伤保护作用及发挥最佳保护作用的适宜剂量的研究；亦尚未发现 TPM 与叶酸（FA）合用对 TPM 神经元保护作用影响的相关报道。因此，取得 TPM 单药及伍用 FA 后对幼鼠慢性癫癎发作引起的脑神经元损伤的保护作用实验室证据将对儿科临床用药具有重要的指导意义。方法：将 3 周龄雄性 Wistar 大鼠随机分为 6 组：阴性对照组、阳性对照组、TPM-20 组、TPM-40 组、TPM-80 组和 TPM-40 + FA 组。阳性对照组和 TPM 4 个组先行戊四氮(PTZ)腹腔注射制造幼鼠慢性癫癎模型,再分别每日给予等量蒸馏水、TPM 20 mg/kg、40 mg/kg、80 mg/kg和TPM 40 mg/kg + FA 5 mg/kg灌胃；阴性对照组则先行生理盐水腹腔注射，再给予等量的蒸馏水灌胃。连续用药 2个月。观察大鼠行为、血清神经元特异性烯醇化酶(NSE)及海马区病理改变。结果：TPM 4个组大鼠惊厥发作次数，血清 NSE 水平及海马区神经元死亡程度较阳性对照组明显减轻。阴性对照组、阳性对照组、TPM-20 组、TPM-40 组、TPM-80 组、TPM-40+FA 组的惊厥发作次数依次为：0，48.4±3.7，44.7±2.9，44.3±3.1，42.7±3.2，40.8±3.7 次；血清NSE值依次为：18.72±2.95，35.71±5.97，27.40 ± 6.40，24.79±6.22，21.47±6.87，22.55±7.02 μg/L；海马CA3 区坏死神经元细胞百分比依次为：（5.8±1.9）％、（72.2±9.8）％、（43.9±7.1）％、（25.9±5.5）％、（10.5±4.2）％、（16.1±4.8）％；海马CA1 区坏死神经元细胞百分比依次为：（5.1±1.8）％、（65.6±8.1）％、（40.5±6.4）％、（23.1±5.2）％、（8.9±3.6）％、（14.9 ± 4.3）％。结论:：PM 对幼鼠慢性癫癎发作引起的脑神经元损伤具有保护作用，该作用存在剂量效应，TPM 80 mg/(kg.d) 保护作用最强；TPM 伍用 FA后，神经元保护作用加强。

Neuroprotective effects of topiramate and folic acid on young rats with kindling-induced epilepsy

OBJECTIVE: To study the neuroprotective effects of topiramate (TPM) alone or together with folic acid (FA) on young rats with kindling-induced epilepsy. METHODS: Rat models of epilepsy were prepared by pentylenetetrazol (PTZ)-induced kindling. Seventy-two 3-week-old male Wistar rats were randomly divided into 6 groups: four TPM-treated epilepsy groups (TPM 20, 40 or 80 mg/kg/d and TPM 40 mg/kg/d + FA 5 mg/kg/d), a positive control group (untreated epilepsy group) and a negative control group (normal control group). After two months of administration, behaviors of the rats were recorded; serum levels of neuron-specific enolase (NSE) were measured using ELISA; pathological changes in the hippocampus were observed. RESULTS: The frequency of convulsion seizures in the 20, 40 and 80 mg TPM treatment and TPM+FA groups was 44.7 +/- 2.9, 44.3 +/- 3.1, 42.7 +/- 3.2, and 40.8 +/- 3.7 respectively, which were significantly lower than that in the positive control group (48.4 +/- 3.7) (P <0.01). Twenty, forty and eighty mg TPM treatment and TPM+FA treatment significantly reduced NSE levels from 35.71 +/- 5.97 microg/L of the control group to 27.40+/- 6.40, 24.79 +/- 6.22, 21.47 +/- 6.87 and 22.55 +/- 7.02 microg/L respectively (P <0.05). Neuronal apoptosis in the CA3 and CA1 regions were alleviated in the four TPM treatment groups compared with positive control. The number of necrotic neurons was progressively reduced with the increased dose of TPM. The 40 mg TPM+FA treatment group showed less necrotic neurons in the CA3 and CA1 regions than the 40 mg TPM alone treatment group. CONCLUSIONS: TPM has protective effects against epilepsy-induced neuronal damage. The effect is dose-dependent. A combination of TPM and FA can produce a synergistic effect.