Department of Anatomy, Histology & Developmental Biology, School of Basic Medical Sciences , Shenzhen University Health Science Centre , Shenzhen 518055 , China.
Department of Pharmacology , University of Arizona College of Medicine and College of Pharmacy , Tucson , Arizona 85724 , United States.
ACS Chem Neurosci. 2019 Dec 18;10(12):4854-4863. doi: 10.1021/acschemneuro.9b00575. Epub 2019 Dec 6.
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 , 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 antiepileptogenic 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.
抗癫痫药物 (AEDs) 是治疗边缘性癫痫的主要临床药物。然而，抗药性发生率高和抑制癫痫病理进展的药物有限，这给癫痫的治疗带来了重大障碍。在这里，我们研究了四甲基吡嗪 (TMP) 的作用，TMP 是从东方药物中分离出来的主要生物活性生物碱，对抗颞叶癫痫的急性海马和角膜 (6 Hz) 电点燃模型的癫痫发生进展。TMP 剂量依赖性地限制了癫痫发作的进展，并减少了海马鼠点燃模型中的放电持续时间 (ADDs)。用 TMP (20、50 mg/kg，ip) 治疗的小鼠在癫痫进展的第 1 阶段持续时间较长，需要额外的刺激来诱导第 2-5 阶段的癫痫表型。TMP (50 mg/kg) 也抑制了 6 Hz 角膜点燃的进展。相比之下，TMP 不能逆转全身性癫痫 (GS) 模型、最大电休克 (MES) 或戊四氮 (PTZ) 诱导的癫痫模型诱导的表型。此外，膜片钳记录显示 TMP (10 μM) 对 CA1 海马神经元的内在特性没有影响，但抑制了 (i) 自发性兴奋性突触后电流 (sEPSCs) 的频率，(ii) 成对脉冲比 (PPR)，和 (iii) 在 Schaffer 侧枝-CA1 通路中的长时程增强 (LTP) 诱导。TMP 抑制钙通道，但不抑制钠通道的活性。综上所述，这些结果表明，TMP 具有抗癫痫发生的作用，可能是通过抑制钙通道来抑制兴奋性突触传递；这些特性将 TMP 与现有的 AEDs 区分开来。由于给予 TMP 的小鼠在物体识别和旷场测试中没有任何神经损伤，这些数据支持进一步开发 TMP 作为治疗癫痫的一种有前途的治疗方法。
