Examination of the antiepileptic effects of valacyclovir using kindling mice― search for novel antiepileptic agents by drug repositioning using a large medical information database
Examination of the antiepileptic effects of valacyclovir using kindling mice― search for novel antiepileptic agents by drug repositioning using a large medical information database
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使用点燃小鼠检查伐昔洛韦的抗癫痫作用——利用大型医学信息数据库通过药物重新定位寻找新型抗癫痫药物
DOI：
10.1016/j.ejphar.2021.174099
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发表时间：
2021
影响因子：
5
通讯作者：
Ishizawa Keisuke
中科院分区：
文献类型：
--
作者：
Takahashi Shimon;Takechi Kenshi;Jozukuri Natsumi;Niimura Takahiro;Chuma Masayuki;Goda Mitsuhiro;Zamami Yoshito;Izawa-Ishizawa Yuki;Imanishi Masaki;Horinouchi Yuya;Ikeda Yasumasa;Tsuchiya Koichiro;Yanagawa Hiroaki;Ishizawa Keisuke
尽管有20多种临床抗癫痫药物，但约30%的癫痫患者对抗癫痫药物治疗无反应。因此，重要的是开发通过新机制发挥作用的抗癫痫产品。在本研究中，我们评估了来自全球最大的数据库之一的数据，以确定具有抗癫痫作用的药物，随后试图了解抗癫痫药物和伐昔洛韦联合使用点燃模型在癫痫发作中的作用。为了诱导小鼠点燃，每48小时给予一次剂量为40 mg/kg的戊四唑。在点燃小鼠注射抗癫痫药物前30 min口服伐昔洛韦，并在戊四氮给药后20 min监测行为癫痫发作。此外，c-Fos在点燃小鼠海马齿状回的表达进行了测量。伐昔洛韦对戊四氮诱发的点燃发作有抑制作用。此外，同时使用左乙拉西坦和伐昔洛韦引起更有效的抑制癫痫发作活动，无论是丙戊酸还是地西泮增强点燃小鼠的抗癫痫发作作用。此外，点燃小鼠显示齿状回中c-Fos水平增加。同时使用左乙拉西坦和伐昔洛韦可显著抑制c-Fos表达的增加。本研究的结果表明，左乙拉西坦和伐昔洛韦的组合有可能对戊四氮诱导的点燃癫痫发作的抗惊厥作用。这些结果表明，伐昔洛韦可能有抗癫痫发作的患者。
Despite the availability of more than 20 clinical antiepileptic drugs, approximately 30% of patients with epilepsy do not respond to antiepileptic drug treatment. Therefore, it is important to develop antiepileptic products that function via novel mechanisms. In the present study, we evaluated data from one of the largest global databases to identify drugs with antiepileptic effects, and subsequently attempted to understand the effect of the combination of antiepileptic drugs and valacyclovir in epileptic seizures using a kindling model. To induce kindling in mice, pentylenetetrazol at a dose of 40 mg/kg was administered once every 48 h. Valacyclovir was orally administered 30 min before antiepileptic drug injection in kindled mice, and behavioral seizures were monitored for 20 min following pentylenetetrazol administration. Additionally, c-Fos expression in the hippocampal dentate gyrus was measured in kindled mice. Valacyclovir showed inhibitory effects on pentylenetetrazol-induced kindled seizures. In addition, simultaneous use of levetiracetam and valacyclovir caused more potent inhibition of seizure activity, and neither valproic acid nor diazepam augmented the anti-seizure effect in kindled mice. Furthermore, kindled mice showed increased c-Fos levels in the dentate gyrus. The increase in c-Fos expression was significantly inhibited by the simultaneous use of levetiracetam and valacyclovir. The findings of the present study indicate that a combination of levetiracetam and valacyclovir had possible anticonvulsive effects on pentylenetetrazol-induced kindled epileptic seizures. These results suggest that valacyclovir may have an antiseizure effect in patients with epilepsy.