Tetramethylpyrazine Reduces Epileptogenesis Progression in Electrical Kindling Models by Modulating Hippocampal Excitatory Neurotransmission
Tetramethylpyrazine Reduces Epileptogenesis Progression in Electrical Kindling Models by Modulating Hippocampal Excitatory Neurotransmission
复制标题
四甲基吡嗪通过调节海马兴奋性神经传递来减少电点燃模型中的癫痫发生进展。
DOI：
10.1021/acschemneuro.9b00575
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发表时间：
2019-12-01
影响因子：
5
通讯作者：
Yu, Jie
中科院分区：
文献类型：
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作者：
Jin, Yan;Cai, Song;Yu, Jie
抗癫痫药物(AEDs)是临床治疗边缘性癫痫的主要药物。然而，药物耐药性的高发生率和用于抑制癫痫病理进展的药物有限，构成了癫痫治疗的主要障碍。在本实验中，我们观察了川芎中的主要生物活性生物碱川芎嗪(TMP)对TLE大鼠急性海马和角膜电点燃模型癫痫发作的影响。在小鼠海马区点燃模型中，TMP剂量依赖性地限制了癫痫发作的进展，并缩短了后放电持续时间(ADS)。TMP(20，50 mg/kg，i.p)组小鼠长期处于癫痫进展的阶段1，需要额外的刺激来诱导阶段2-5的癫痫表型。TMP(50 mg/kg)也可抑制6赫兹角膜点燃进程。相反，TMP不能逆转全身性癫痫(GS)模型或最大电休克(MES)或戊四氮(PTZ)诱导的癫痫模型的表型。此外，膜片钳记录显示川芎素(10μM)对CA1区神经元的固有特性没有影响，但抑制了Schaffer侧支-CA1通路中(I)自发兴奋性突触后电流(SEPSC)的频率、(Ii)成对脉冲比(PPR)和(Iii)长时程增强(LTP)的诱导。TMP抑制钙通道的活性，但不抑制钠通道的活性。综上所述，这些结果表明，TMP具有抗癫痫作用，可能是通过其对钙通道的抑制作用来抑制兴奋性突触传递；这些特性使TMP有别于目前可用的AEDs。由于服用TMP的小鼠在物体识别和旷场测试中没有表现出任何神经损伤，这些数据支持TMP作为一种有前景的癫痫治疗方法的进一步发展。
Antiepileptic drugs (AEDs) are the primary agents prescribed for clinical management of limbic epilepsy. However, high incidence of pharmacoresistance and a limited armory of drugs for inhibiting the pathological progression of epilepsy pose major obstacles to managing epilepsy. Here, we investigated the effect of Tetramethylpyrazine (TMP), the main bioactive alkaloid isolated from the oriental medicine Ligusticum chuanxiong Hort., against the epileptogenesis progression of acute hippocampal and corneal (6 Hz) electrical kindling models of TLE. TMP dose-dependently limited the progression of seizures and reduced the after-discharge duration (ADDs) in a hippocampal mouse kindling model. Mice treated with TMP (20, 50 mg/kg, i.p.) remained in stage 1 of epileptic progression for a protracted period, requiring additional stimulation to induce stages 2-5 epileptic phenotypes. TMP (50 mg/kg) also inhibited 6 Hz corneal kindling progression. In contrast, TMP did not reverse the phenotypes induced in a generalized seizures (GS) model, or the maximal electroshock (MES) or pentylenetetrazole (PTZ)-induced models of epilepsy. Furthermore, patch clamp recordings revealed no effect of TMP (10 μM) on CA1 hippocampal neurons' intrinsic properties but suppressed the (i) frequency of spontaneous excitatory post synaptic currents (sEPSCs), (ii) paired pulse ratio (PPR), and (iii) long-term potentiation (LTP) induction in the Schaffer collateral-CA1 pathway. TMP suppressed the activity of calcium, but not sodium, channels. Taken together, these results suggest that TMP has an anti-epileptogenic effect, likely through suppression of excitatory synaptic transmission by its effects on inhibition of calcium channels; these traits distinguish TMP from currently available AEDs. As mice administered TMP did not show any neurologic impairment in the object recognition and open field tests, the data support further development of TMP as a promising treatment for epilepsy.