Vartanian Mark G, Radulovic Louis L, Kinsora Jack J, Serpa Kevin A, Vergnes Marguerite, Bertram Edward, Taylor Charles P
Department of CNS Biology, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
Epilepsy Res. 2006 Mar;68(3):189-205. doi: 10.1016/j.eplepsyres.2005.11.001. Epub 2005 Dec 5.
Pregabalin (Lyrica) is a novel amino acid compound that binds with high affinity to the alpha2-delta (alpha2-delta) auxiliary protein of voltage-gated calcium channels. In vivo, it potently prevents seizures, pain-related behaviors and has anxiolytic-like activity in rodent models. The present studies were performed to determine the profile of pregabalin anticonvulsant activity in a variety of mouse and rat models. In the high-intensity electroshock test, pregabalin potently inhibited tonic extensor seizures in rats (ED50 = 1.8 mg/kg, PO), and low-intensity electroshock seizures in mice. It prevented tonic extensor seizures in the DBA/2 audiogenic mouse model (ED50 = 2.7 mg/kg, PO). Its time course of action against electroshock induced seizures in rats roughly followed the pharmacokinetics of radiolabeled drug in the brain compartment. At higher dosages (ED50 1= 31 mg/kg, PO), pregabalin prevented clonic seizures from pentylenetetrazole in mice. In a kindled rat model of partial seizures, pregabalin prevented stages 4-5 behavioral seizures (lowest effective dose = 10 mg/kg, IP), and also reduced the duration of electrographic seizures. Pregabalin was not active to prevent spontaneous absence-like seizures in the Genetic Absence Epilepsy in Rats from Strasbourg (GAERS) inbred Wistar rat strain. Pregabalin caused ataxia and decreased spontaneous locomotor activity at dosages 10-30-fold higher than those active to prevent seizures. These findings suggest that pregabalin has an anticonvulsant mechanism different from the prototype antiepileptic drugs and similar to that of gabapentin except with increased potency and bioavailability. In summary, our results show that pregabalin has several properties that favor treatment of partial seizures in humans.
普瑞巴林（乐瑞卡）是一种新型氨基酸化合物，它与电压门控钙通道的α2-δ（α2-δ）辅助蛋白具有高亲和力结合。在体内，它能有效预防啮齿动物模型中的癫痫发作、疼痛相关行为，并具有抗焦虑样活性。进行本研究以确定普瑞巴林在多种小鼠和大鼠模型中的抗惊厥活性特征。在高强度电休克试验中，普瑞巴林能有效抑制大鼠的强直性伸展性癫痫发作（ED50 = 1.8 mg/kg，口服）以及小鼠的低强度电休克癫痫发作。它能预防DBA/2听源性癫痫小鼠模型中的强直性伸展性癫痫发作（ED50 = 2.7 mg/kg，口服）。其针对大鼠电休克诱发癫痫发作的作用时间过程大致遵循放射性标记药物在脑区的药代动力学。在较高剂量（ED50 = 31 mg/kg，口服）时，普瑞巴林能预防小鼠戊四氮诱发的阵挛性癫痫发作。在部分性癫痫的点燃大鼠模型中，普瑞巴林能预防4 - 5期行为性癫痫发作（最低有效剂量 = 10 mg/kg，腹腔注射），并缩短脑电图癫痫发作的持续时间。普瑞巴林对预防来自斯特拉斯堡的遗传性失神癫痫大鼠（GAERS）近交系Wistar大鼠品系中的自发性失神样癫痫发作无效。普瑞巴林在比预防癫痫发作有效剂量高10 - 30倍的剂量下会导致共济失调并降低自发运动活性。这些发现表明，普瑞巴林具有与原型抗癫痫药物不同的抗惊厥机制，与加巴喷丁类似，但效力和生物利用度有所提高。总之，我们的结果表明普瑞巴林具有多种有利于治疗人类部分性癫痫的特性。
