title: Status epilepticus induction has prolonged effects on the efficacy of antiepileptic drugs in the 6-Hz seizure model.
abstract: Several factors may influence the efficacy of antiepileptic drugs (AEDs) in patients with epilepsy, and treatment resistance could be related to genetics, neuronal network alterations, and modification of drug transporters or targets. Consequently, preclinical models used for the identification of potential new, more efficacious AEDs should reflect at least a few of these factors. Previous studies indicate that induction of status epilepticus (SE) may alter drug efficacy and that this effect could be long-lasting. In this context, we wanted to assess the protective effects of mechanistically diverse AEDs in mice subjected to pilocarpine-induced SE in another seizure model. We first determined seizure thresholds in mice subjected to pilocarpine-induced SE in the 6-Hz model, 2 weeks and 8 weeks following SE. We then evaluated the protective effects of mechanistically diverse AEDs in post-SE and control animals. No major differences in 6-Hz seizure susceptibility were observed between control groups, while the seizure threshold of pilocarpine mice at 8 weeks after SE was higher than at 2 weeks and higher than in control groups. Treatment with AEDs revealed major differences in drug response depending on their mechanism of action. Diazepam produced a dose-dependent protection against 6-Hz seizures in control and pilocarpine mice, both at 2 weeks and 8 weeks after SE, but with a more pronounced increase in potency in post-SE animals at 2 weeks. Levetiracetam induced a potent and dose-dependent protection in pilocarpine mice, 2 weeks after SE, while its protective effects were observed only at much higher doses in control mice. Its potency decreased in post-SE mice at 8 weeks and was very limited (30% protection at the highest tested dose) in the control group. Carbamazepine induced a dose-dependent protection at 2 weeks in control mice but only limited effect (50% at the highest tested dose) in pilocarpine mice. Its efficacy deeply decreased in post-SE mice at 8 weeks after SE. Perampanel and phenytoin showed almost comparable protective effects in all groups of mice. These experiments confirm that prior SE may have an impact on both potency and efficacy of AEDs and indicate that this effect may be dependent on the underlying epileptogenic processes. This article is part of a Special Issue entitled "Status Epilepticus".
authors.affiliation: UCB Pharma, Braine-l'Alleud, Belgium.
authors.forename: Karine
authors.initials: K
authors.lastname: Leclercq
authors.affiliation: UCB Pharma, Braine-l'Alleud, Belgium. Electronic address: rafal.kaminski@ucb.com.
authors.forename: Rafal M
authors.initials: RM
authors.lastname: Kaminski
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D002220:Carbamazepine / Q000627:therapeutic use; D003975:Diazepam / Q000627:therapeutic use; D004195:Disease Models, Animal; D000077287:Levetiracetam; D008297:Male; D051379:Mice; D010672:Phenytoin / Q000627:therapeutic use; D010862:Pilocarpine / Q000633:toxicity; D010889:Piracetam / Q000031:analogs & derivatives / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D010862:Pilocarpine; D002220:Carbamazepine; D000077287:Levetiracetam; D010672:Phenytoin; D003975:Diazepam; D010889:Piracetam
keywords: Epilepsy; Pharmacoresistance; Pilocarpine; Status epilepticus; TLE; Two-hit