Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran;.
Department of Basic Sciences, Faculty of Veterinary Medicine, Amol University of Special Modern Technologies, Amol, Iran.
Iran Biomed J. 2021 May 1;25(3):213-9. doi: 10.29252/ibj.25.3.213.
Despite introduction of modern antiepileptic drugs, 30% of epileptic patients are still drug resistant. Remarkable three-dimensional spatial structure of 1-Adamantane carboxylic acid (AdCA), yet the simplicity of the molecule, makes AdCA a promising lead compound.
Sedative/motor impairment and 24-h mortality rate of AdCA were determined in mice. Impact of AdCA on (1) threshold and occurrence of clonic seizures induced by pentylenetetrazole (PTZ) in mice, (2) incidence of tonic seizures induced by maximal electroshock (MES) in mice, and (3) incidence of generalized seizures and duration of evoked afterdischarges in amygdala-kindled rats, were determined. The role of benzodiazepine receptors in the AdCA effect on clonic seizure threshold was also assessed.
AdCA showed sedative effect (median toxic dose [TD50] = 224.5 [190.2-289.9] mg/kg). Median lethal dose (LD50) = 805.5 (715.2–988.1) mg/kg was obtained for AdCA. The compound increased PTZ seizure threshold from 180 mg/kg (p < 0.05) and also inhibited the incidence of clonic seizures (ED50 = 256.3 [107.4-417.3] mg/kg). AdCA also decreased afterdischarge duration (p < 0.01) and the incidence of generalized seizures (ED50 < 50 mg/kg) in the kindled rats. However, AdCA did not protect mice against tonic seizures induced by MES. The benzodiazepine receptor antagonist flumazenil prevented the increase of seizure threshold by AdCA.
AdCA possesses anticonvulsant activity in kindling and PTZ models through the activation of benzodiazepine/GABAA receptors with acceptable therapeutic index.
尽管现代抗癫痫药物已经问世，但仍有 30%的癫痫患者对药物治疗无反应。1-金刚烷羧酸（AdCA）具有显著的三维空间结构，但其分子结构却非常简单，这使得 AdCA 成为一种很有前途的先导化合物。
在小鼠中测定 AdCA 的镇静/运动损伤和 24 小时死亡率。测定 AdCA 对以下方面的影响：（1）戊四氮（PTZ）诱导的小鼠阵挛性癫痫发作的阈值和发作率；（2）最大电休克（MES）诱导的小鼠强直发作的发生率；（3）杏仁核点燃大鼠的全身性癫痫发作发生率和诱发后放电持续时间。还评估了苯二氮䓬受体在 AdCA 对阵挛性癫痫发作阈值的影响中的作用。
AdCA 具有镇静作用（中位数毒性剂量[TD50] = 224.5[190.2-289.9]mg/kg）。获得 AdCA 的中位数致死剂量（LD50）= 805.5（715.2–988.1）mg/kg。该化合物使 PTZ 癫痫发作阈值增加至 180mg/kg（p<0.05），并抑制阵挛性癫痫发作的发生率（ED50 = 256.3[107.4-417.3]mg/kg）。AdCA 还降低了点燃大鼠的后放电持续时间（p<0.01）和全身性癫痫发作的发生率（ED50<50mg/kg）。然而，AdCA 不能保护小鼠免受 MES 诱导的强直发作。苯二氮䓬受体拮抗剂氟马西尼可预防 AdCA 引起的癫痫发作阈值升高。
AdCA 通过激活苯二氮䓬/GABAA 受体具有抗惊厥活性，在点燃和 PTZ 模型中具有可接受的治疗指数。
