The adenosine A1 receptor agonist WAG 994 suppresses acute kainic acid-induced status epilepticus in vivo

Neuropharmacology. 2020 Oct 1;176:108213. doi: 10.1016/j.neuropharm.2020.108213. Epub 2020 Jun 29.

Abstract

Status epilepticus (SE) is a neurological emergency characterized by continuous seizure activity lasting longer than 5 min, often with no recovery between seizures (Trinka et al., 2015). 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.

Keywords: Adenosine; Adenosine A1 receptor; Anticonvulsant; Drug resistance; Epilepsy; Status epilepticus.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural