Department of Pharmacology & Therapeutics, Faculty of Pharmacy, Kuwait University, Kuwait.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, Kuwait.
Eur J Pharm Sci. 2019 Mar 15;130:21-26. doi: 10.1016/j.ejps.2019.01.011. Epub 2019 Jan 10.
The pharmacotherapeutic management of seizure disorders with currently available medications is not optimal due to side effects and failure of some patients to respond to all available medications. As such there is the need to develop new antiseizure drugs by looking at new chemical classes of compounds. We recently screened, in vitro, a new class of compounds, the oxazolidinones, for actions in the brain that may indicate potential for antiseizure activity. A few compounds were identified with such a potential. Here we tested whether one of these lead compounds, PH192, will exhibit in vivo antiseizure activity using chemically- and electrically- induced seizures models in mice and rats. Out of 5 compounds tested, all of them had minimal neurotoxicological effects in mice, with PH192 being the best, with comparable efficacy (ED) and toxicity (TD) to only levetiracetam. Intraperitoneal (IP) pretreatment with PH192 produced a dose-dependent protection of mice from seizures induced using the 6 Hz stimulation protocol with an estimated ED of 34.5 mg/kg in mice and about 90 mg/kg in rats and a neurotoxic dose >500 mg/kg in mice, yielding a calculated neuro (protective) index of >14.7. When pretreated with 100 mg/kg PH192 for 30 min, about 75% of mice were protected from 6 Hz-induced seizures. When rats were pretreated for 30 min with PH192, 66.6% of rats were protected from seizures induced using the 6 Hz stimulation protocol while 83.3% were protected using the maximal electroshock (MES) stimulation protocol. Pentylenetetrazole (PTZ) injection at 50, and 100 mg/kg produced stage 5 seizures in all rats. Thirty minutes IP pretreatment of rats with 100 mg/kg PH192 protected 80% of rats from the PTZ-induced seizures, a level of protection similar to that obtained with a reference antiepileptic drug (AED) phenytoin (40 mg/kg), that is used clinically for the treatment of various seizure disorders. The results of these studies indicate that PH192 protects against both chemically- and electrically-induced seizures with little central nervous system side effects. This suggests that the oxazolidinone pharmacophore has potential for discovering new antiepileptic drugs with possibly minimal central side effects.
由于副作用和一些患者对所有可用药物均无反应，目前可用药物对癫痫发作疾病的治疗效果并不理想。因此，需要通过寻找新的化合物化学类型来开发新的抗癫痫药物。最近，我们在体外筛选了一类新的化合物——恶唑烷酮，以寻找可能具有抗癫痫活性的脑内作用。有几种化合物具有这种潜力。在这里，我们使用化学和电诱导的癫痫发作模型在小鼠和大鼠中测试了这些先导化合物之一 PH192 是否具有体内抗癫痫活性。在测试的 5 种化合物中，所有化合物在小鼠中均具有最小的神经毒性作用，其中 PH192 效果最好，其疗效（ED）和毒性（TD）与左乙拉西坦相当。腹腔（IP）预处理 PH192 可使小鼠免受 6Hz 刺激方案诱导的癫痫发作，在小鼠中的估计 ED 为 34.5mg/kg，在大鼠中约为 90mg/kg，而在小鼠中的神经毒性剂量>500mg/kg，得出计算出的神经（保护）指数>14.7。当用 100mg/kg PH192 预处理 30 分钟时，约 75%的小鼠可免受 6Hz 诱导的癫痫发作。当用 PH192 预处理 30 分钟时，66.6%的大鼠可免受 6Hz 刺激方案诱导的癫痫发作，而 83.3%的大鼠可免受最大电休克（MES）刺激方案的癫痫发作。戊四氮（PTZ）注射 50 和 100mg/kg 可使所有大鼠出现 5 期癫痫发作。用 100mg/kg PH192 对大鼠进行 30 分钟的 IP 预处理可使 80%的大鼠免受 PTZ 诱导的癫痫发作，这种保护水平与参考抗癫痫药物（AED）苯妥英（40mg/kg）相似，临床上用于治疗各种癫痫发作疾病。这些研究的结果表明，PH192 可预防化学和电诱导的癫痫发作，且对中枢神经系统副作用较小。这表明恶唑烷酮药效团具有发现新的抗癫痫药物的潜力，且可能对中枢副作用最小。
