title: Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish.
abstract: Treatment-resistant seizures affect about a third of patients suffering from epilepsy. To fulfill the need for new medications targeting treatment-resistant seizures, a number of rodent models offer the opportunity to assess a variety of potential treatment approaches. The use of such models, however, has proven to be time-consuming and labor-intensive. In this study, we performed pharmacological characterization of the allylglycine (AG) seizure model, a simple in vivo model for which we demonstrated a high level of treatment resistance. (d,l)-Allylglycine inhibits glutamic acid decarboxylase (GAD) - the key enzyme in γ-aminobutyric acid (GABA) biosynthesis - leading to GABA depletion, seizures, and neuronal damage. We performed a side-by-side comparison of mouse and zebrafish acute AG treatments including biochemical, electrographic, and behavioral assessments. Interestingly, seizure progression rate and GABA depletion kinetics were comparable in both species. Five mechanistically diverse antiepileptic drugs (AEDs) were used. Three out of the five AEDs (levetiracetam, phenytoin, and topiramate) showed only a limited protective effect (mainly mortality delay) at doses close to the TD50 (dose inducing motor impairment in 50% of animals) in mice. The two remaining AEDs (diazepam and sodium valproate) displayed protective activity against AG-induced seizures. Experiments performed in zebrafish larvae revealed behavioral AED activity profiles highly analogous to those obtained in mice. Having demonstrated cross-species similarities and limited efficacy of tested AEDs, we propose the use of AG in zebrafish as a convenient and high-throughput model of treatment-resistant seizures.
authors.affiliation: Neuroscience TA, UCB Biopharma, Braine-l'Alleud, Belgium.
authors.forename: Karine
authors.initials: K
authors.lastname: Leclercq
authors.affiliation: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Afrikanova
authors.affiliation: Luxembourg Center for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
authors.forename: Melanie
authors.initials: M
authors.lastname: Langlois
authors.affiliation: Center for Neurosciences, C4N, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: De Prins
authors.affiliation: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Olivia E
authors.initials: OE
authors.lastname: Buenafe
authors.affiliation: Neuroscience TA, UCB Biopharma, Braine-l'Alleud, Belgium.
authors.forename: Chiara C
authors.initials: CC
authors.lastname: Rospo
authors.affiliation: Luxembourg Center for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
authors.forename: Ann
authors.initials: A
authors.lastname: Van Eeckhaut
authors.affiliation: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Peter A M
authors.initials: PA
authors.lastname: de Witte
authors.affiliation: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium; Luxembourg Center for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Crawford
authors.affiliation: Center for Neurosciences, C4N, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Smolders
authors.affiliation: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium; Chemical Neuroscience Group, Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway. Electronic address: c.v.esguerra@biotek.uio.no.
authors.forename: Camila V
authors.initials: CV
authors.lastname: Esguerra
authors.affiliation: Neuroscience TA, UCB Biopharma, Braine-l'Alleud, Belgium. Electronic address: rafal.kaminski@ucb.com.
authors.forename: Rafal M
authors.initials: RM
authors.lastname: Kaminski
mesh_terms: D000501:Allylglycine; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D003975:Diazepam / Q000627:therapeutic use; D004195:Disease Models, Animal; D005632:Fructose / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077287:Levetiracetam; D008297:Male; D051379:Mice; D010672:Phenytoin / Q000627:therapeutic use; D010889:Piracetam / Q000031:analogs & derivatives / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D000077236:Topiramate; D016896:Treatment Outcome; D014635:Valproic Acid / Q000627:therapeutic use; D015027:Zebrafish
chemical_list: D000927:Anticonvulsants; D000077236:Topiramate; D000501:Allylglycine; D005632:Fructose; D000077287:Levetiracetam; D014635:Valproic Acid; D010672:Phenytoin; D003975:Diazepam; D010889:Piracetam
keywords: Allylglycine; Antiepileptic drugs; Epilepsy; Seizures; Treatment resistance; Zebrafish