依达拉奉对戊四氮或电休克致痫小鼠的急性和亚慢性抗惊厥作用及其与一氧化氮的关系。
Acute and Sub-chronic Anticonvulsant Effects of Edaravone on Seizure Induced by Pentylenetetrazole or Electroshock in Mice, Nitric Oxide Involvement.
机构信息
Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
出版信息
Iran J Med Sci. 2023 May;48(3):329-340. doi: 10.30476/ijms.2022.94177.2544.
BACKGROUND
Edaravone is an anti-stroke medication that may have nitric oxide (NO) modulating properties. This study evaluated the role of NO in the acute and sub-chronic anticonvulsant effects of edaravone in murine models of seizures induced by intraperitoneal (IP) or intravenous (IV) injections of pentylenetetrazole (PTZ) or electroshock (maximal electroshock seizure [MES]).
METHODS
132 male albino mice were randomly divided into 22 groups (n=6) and given IP injections of vehicle or edaravone either acutely or for eight days (sub-chronically). The seizure was induced by electroshock or PTZ (IP or IV). The following edaravone doses were used: 7.5, 10, 12.5 (acute); 5, 7.5, 10 (sub-chronic) in IP PTZ model; 5, 7.5, 10 in IV PTZ model; and 5, 10 mg/Kg in the MES. To evaluate NO involvement, 216 mice were randomly divided into 36 groups (n=6) and pretreated with vehicle, edaravone, a non-specific nitric oxide synthase (NOS) inhibitor: N(ω)-nitro-L-arginine methyl ester (L-NAME) (5 mg/Kg), a specific nNOS inhibitor: 7-nitroindazole (7-NI) (60 mg/Kg), or a combination of edaravone plus L-NAME or 7-NI, either acutely or for eight days before seizure induction. Doses of edaravone were as follows: in IP PTZ model: 12.5 (acute) and 10 (sub-chronic); in IV PTZ model: 10; and in the MES: 5 mg/Kg. Data were analyzed using the one-way analysis of variance (ANOVA) followed by Tukey's test (SPSS 18). P≤0.05 was considered statistically significant.
RESULTS
In the IP PTZ model, edaravone increased time latencies to seizures (P<0.001), prevented tonic seizures, and death. Edaravone increased the seizure threshold (P<0.001) in the IV PTZ model and shortened the duration of tonic hind-limb extension (THE) in the MES model (P<0.001). In comparison to mice treated with edaravone alone, adding L-NAME or 7-NI reduced seizure time latencies (P<0.001), reduced seizure threshold (P<0.001), and increased THE duration (P<0.001).
CONCLUSION
Edaravone (acute or sub-chronic) could prevent seizures by modulating NO signaling pathways.
背景
依达拉奉是一种抗中风药物，可能具有调节一氧化氮（NO）的特性。本研究评估了 NO 在依达拉奉对腹膜内（IP）或静脉内（IV）注射戊四氮（PTZ）或电休克（最大电休克发作[MES]）诱导的小鼠模型中的急性和亚慢性抗惊厥作用中的作用。
方法
132 只雄性白化小鼠随机分为 22 组（n=6），分别给予 IP 注射载体或依达拉奉，急性或 8 天（亚慢性）。通过电休克或 PTZ（IP 或 IV）诱导癫痫发作。使用以下依达拉奉剂量：7.5、10、12.5（急性）；5、7.5、10（IP PTZ 模型）；5、7.5、10（IV PTZ 模型）；和 5、10mg/Kg 在 MES 中。为了评估 NO 参与，216 只小鼠随机分为 36 组（n=6），分别用载体、依达拉奉、非特异性一氧化氮合酶（NOS）抑制剂：N（ω）-硝基-L-精氨酸甲酯（L-NAME）（5mg/Kg）、特异性 nNOS 抑制剂：7-硝基吲唑（7-NI）（60mg/Kg）预处理，或依达拉奉加 L-NAME 或 7-NI 的组合，无论是急性还是在癫痫发作诱导前 8 天。依达拉奉的剂量如下：在 IP PTZ 模型中：12.5（急性）和 10（亚慢性）；在 IV PTZ 模型中：10；和 MES：5mg/Kg。数据采用单因素方差分析（ANOVA）进行分析，然后用 Tukey 检验（SPSS 18）进行检验。P≤0.05 被认为具有统计学意义。
结果
在 IP PTZ 模型中，依达拉奉增加了癫痫发作的潜伏期（P<0.001），防止了强直性发作和死亡。依达拉奉增加了 IV PTZ 模型中的癫痫发作阈值（P<0.001），并缩短了 MES 模型中强直性后肢伸展（THE）的持续时间（P<0.001）。与单独给予依达拉奉的小鼠相比，添加 L-NAME 或 7-NI 可降低癫痫发作潜伏期（P<0.001），降低癫痫发作阈值（P<0.001），并延长 THE 持续时间（P<0.001）。
结论
依达拉奉（急性或亚慢性）可通过调节 NO 信号通路来预防癫痫发作。
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