title: Validation of the 6 Hz refractory seizure mouse model for intracerebroventricularly administered compounds.
abstract: The six hertz (6 Hz) refractory seizure model is considered an indispensable chain of the Anticonvulsant Screening Project. We here describe an adapted protocol using the intracerebroventricular (i.c.v.) delivery route, which will allow researchers to perform targetvalidation or proof-of-principle studies using promising compounds with unknown or limited blood-brain barrier permeability (e.g. neuropeptides and peptidomimetics) in this model. Seizures were induced by single application of a current intensity of 49 mA to i.c.v.-implanted NMRI mice using an ECT Unit 57800 Ugo Basile stimulator. By applying these key parameters, c-Fos immunohistochemistry revealed the recruitment of the dentate gyrus, ratifying this model as a valuable tool for testing i.c.v. administered compounds against therapy-resistant seizures. This finding was further strengthened, since i.c.v. administration of levetiracetam suppressed 6 Hz-evoked seizure severity but sodium phenytoin did not. We also propose to use "seizure duration" as an alternative, accurate parameter to express the results within this model.
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neurosciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium. Electronic address: Laura.Walrave@vub.ac.be.
authors.forename: Laura
authors.initials: L
authors.lastname: Walrave
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neurosciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium. Electronic address: Katrien.Maes@vub.ac.be.
authors.forename: Katrien
authors.initials: K
authors.lastname: Maes
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neurosciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium. Electronic address: Jessica.Coppens@vub.ac.be.
authors.forename: Jessica
authors.initials: J
authors.lastname: Coppens
authors.affiliation: Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neurosciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium. Electronic address: Eduard-Mihai.Bentea@vub.ac.be.
authors.forename: Eduard
authors.initials: E
authors.lastname: Bentea
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neurosciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium. Electronic address: Ann.Van.Eeckhaut@vub.ac.be.
authors.forename: Ann
authors.initials: A
authors.lastname: Van Eeckhaut
authors.affiliation: Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neurosciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium. Electronic address: Ann.Massie@vub.ac.be.
authors.forename: Ann
authors.initials: A
authors.lastname: Massie
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neurosciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium. Electronic address: Joeri.Van.Liefferinge@vub.ac.be.
authors.forename: Joeri
authors.initials: J
authors.lastname: Van Liefferinge
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neurosciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium. Electronic address: Ilse.Smolders@vub.ac.be.
authors.forename: Ilse
authors.initials: I
authors.lastname: Smolders
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002199:Capillary Permeability; D002408:Catheters, Indwelling; D003315:Cornea; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D000077287:Levetiracetam; D051379:Mice; D010672:Phenytoin / Q000008:administration & dosage; D010889:Piracetam / Q000008:administration & dosage / Q000031:analogs & derivatives; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; D016760:Proto-Oncogene Proteins c-fos; D000077287:Levetiracetam; D010672:Phenytoin; D010889:Piracetam
keywords: 6Hz model; Intracerebroventricular administration; Levetiracetam; Phenytoin; Refractory seizures; Seizure duration