The adenosine A1 receptor agonist WAG 994 suppresses acute kainic acid-induced status epilepticus in vivo.
The adenosine A1 receptor agonist WAG 994 suppresses acute kainic acid-induced status epilepticus in vivo.
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DOI：
10.1016/j.neuropharm.2020.108213
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发表时间：
2020-10-01
影响因子：
4.7
通讯作者：
Dulla CG
中科院分区：
文献类型：
--
作者：
Klaft ZJ;Duerrwald LM;Gerevich Z;Dulla CG
癫痫持续状态 (SE) 是一种神经急症，其特征是持续超过五分钟的持续癫痫发作，并且癫痫发作之间通常没有恢复。约 30% 的 SE 病例对苯二氮卓类药物和二线治疗无效。由于难治性 SE 的死亡率高达 70%，因此迫切需要新的治疗方法。几十年来，腺苷能的强大抗惊厥作用已为人所知，但转化为癫痫治疗却受到心血管副作用的阻碍。然而，与经典的 A1R 激动剂相比，选择性腺苷 A1 受体激动剂 SDZ WAG 994 (WAG) 显示出较低的心血管副作用，并且在人体临床试验中可以安全地全身给药。在这里，我们研究了 WAG 的体外和体内抗惊厥功效。 WAG 强烈抑制大鼠海马切片中高 K+ 诱导的持续癫痫样活动 (IC50 = 52.5 nM)。重要的是，WAG 在小鼠体内急性抑制红藻氨酸（20 mg/kg 腹腔注射）诱导的 SE。 SE 建立后，小鼠接受 3 次腹膜内注射。注射 WAG 或地西泮（DIA，5 mg/kg）。有趣的是，DIA 并没有减弱 SE，而大多数 WAG 治疗的小鼠（1 mg/kg）在注射 3 次后没有癫痫发作。当使用较低剂量的WAG（0.3 mg/kg）时，抗惊厥作用得以保留。重要的是，所有 WAG 治疗的小鼠都在红藻氨酸诱导的 SE 中存活下来。总之，我们首次报告具有可接受的人类副作用的 A1R 激动剂可以在体内强烈抑制已建立的 SE。我们的结果表明，WAG 停止或大大削弱了 SE，而 DIA 未能减轻该模型中的 SE。
Status epilepticus (SE) is a neurological emergency characterized by continuous seizure activity lasting longer than five minutes, often with no recovery between seizures. SE is refractory to benzodiazepine and second-line treatments in about 30% cases. Novel treatment approaches are urgently needed as refractory SE is associated with mortality rates of up to 70%. Robust adenosinergic anticonvulsant effects have been known for decades, but translation into seizure treatments was hampered by cardiovascular side effects. However, the selective adenosine A1 receptor agonist SDZ WAG 994 (WAG) displays diminished cardiovascular side effects compared to classic A1R agonists and was safely administered systemically in human clinical trials. Here, we investigate the anticonvulsant efficacy of WAG in vitro and in vivo. WAG robustly inhibited high-K+-induced continuous epileptiform activity in rat hippocampal slices (IC50 = 52.5 nM). Importantly, WAG acutely suppressed SE in vivo induced by kainic acid (20 mg/kg i.p.) in mice. After SE was established, mice received three i.p. injections of WAG or diazepam (DIA, 5 mg/kg). Interestingly, DIA did not attenuate SE while the majority of WAG-treated mice (1 mg/kg) were seizure-free after three injections. Anticonvulsant effects were retained when a lower dose of WAG (0.3 mg/kg) was used. Importantly, all WAG-treated mice survived kainic acid induced SE. In summary, we report for the first time that an A1R agonist with an acceptable human side-effect profile can acutely suppress established SE in vivo. Our results suggest that WAG stops or vastly attenuates SE while DIA fails to mitigate SE in this model.
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影响因子：
5.6
作者：
Klaft, Zin-Juan;Hollnagel, Jan-Oliver;Heinemann, Uwe
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