title: Neuropeptide FF receptors as novel targets for limbic seizure attenuation.
abstract: Neuropeptide Y (NPY) is a well established anticonvulsant and first-in-class antiepileptic neuropeptide. In this study, the controversial role of NPY1 receptors in epilepsy was reassessed by testing two highly selective NPY1 receptor ligands and a mixed NPY1/NPFF receptor antagonist BIBP3226 in a rat model for limbic seizures. While BIBP3226 significantly attenuated the pilocarpine-induced seizures, neither of the highly selective NPY1 receptor ligands altered the seizure severity. Administration of the NPFF1/NPFF2 receptor antagonist RF9 also significantly attenuated limbic seizure activity. To further prove the involvement of NPFF receptors in these seizure-modulating effects, low and high affinity antagonists for the NPFF receptors were tested. We observed that the low affinity ligand failed to exhibit anticonvulsant properties while the two high affinity ligands significantly attenuated the seizures. Continuous NPFF1 receptor agonist administration also inhibited limbic seizures whereas bolus administration of the NPFF1 receptor agonist was without effect. This suggests that continuous agonist perfusion could result in NPFF1 receptor desensitization and mimic NPFF1 receptor antagonist administration. Our data unveil for the first time the involvement of the NPFF system in the management of limbic seizures.
authors.affiliation: Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; Department of Neurology, UZ Gent, De Pintelaan 185, 9000, Ghent, Belgium.
authors.forename: Jeanelle
authors.initials: J
authors.lastname: Portelli
authors.affiliation: Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; Department of Neurology, UZ Gent, De Pintelaan 185, 9000, Ghent, Belgium.
authors.forename: Alfred
authors.initials: A
authors.lastname: Meurs
authors.affiliation: Laboratoire d'Innovation Thérapeutique, UMR 7200, CNRS, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67400 Illkirch Graffenstaden, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Bihel
authors.affiliation: Laboratoire d'Innovation Thérapeutique, UMR 7200, CNRS, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67400 Illkirch Graffenstaden, France.
authors.forename: Hassan
authors.initials: H
authors.lastname: Hammoud
authors.affiliation: Laboratoire d'Innovation Thérapeutique, UMR 7200, CNRS, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67400 Illkirch Graffenstaden, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Schmitt
authors.affiliation: Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
authors.forename: Joery
authors.initials: J
authors.lastname: De Kock
authors.affiliation: Biotechnologie and Cellular Signalling, UMR7242, CNRS, Université de Strasbourg, 300 bvd Sébastien Brant, 67412, Illkirch, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Utard
authors.affiliation: Biotechnologie and Cellular Signalling, UMR7242, CNRS, Université de Strasbourg, 300 bvd Sébastien Brant, 67412, Illkirch, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Humbert
authors.affiliation: Biotechnologie and Cellular Signalling, UMR7242, CNRS, Université de Strasbourg, 300 bvd Sébastien Brant, 67412, Illkirch, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bertin
authors.affiliation: Department of Neurology, UZ Gent, De Pintelaan 185, 9000, Ghent, Belgium.
authors.forename: Ine
authors.initials: I
authors.lastname: Buffel
authors.affiliation: Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
authors.forename: Jessica
authors.initials: J
authors.lastname: Coppens
authors.affiliation: Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Tourwe
authors.affiliation: Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Veronique
authors.initials: V
authors.lastname: Maes
authors.affiliation: Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: De Prins
authors.affiliation: Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
authors.forename: Tamara
authors.initials: T
authors.lastname: Vanhaecke
authors.affiliation: Center for Neurosciences, Department of Pharmaceutical Biotechnology and Molecular Biology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Massie
authors.affiliation: Department of Surgery and Interdisciplinary Neuroscience Program, University of Cincinnati Medical Center, 213 Albert Sabin Way, 670558 Cincinnati, OH, USA.
authors.forename: Ambikaipakan
authors.initials: A
authors.lastname: Balasubramaniam
authors.affiliation: Department of Neurology, UZ Gent, De Pintelaan 185, 9000, Ghent, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Boon
authors.affiliation: Laboratoire d'Innovation Thérapeutique, UMR 7200, CNRS, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67400 Illkirch Graffenstaden, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Bourguignon
authors.affiliation: Biotechnologie and Cellular Signalling, UMR7242, CNRS, Université de Strasbourg, 300 bvd Sébastien Brant, 67412, Illkirch, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Simonin
authors.affiliation: Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, 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: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D016466:CHO Cells; D003412:Cricetulus; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D010862:Pilocarpine; D017208:Rats, Wistar; D018013:Receptors, Neuropeptide / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; C092926:BIBP 3226; D004151:Dipeptides; D018013:Receptors, Neuropeptide; D017476:Receptors, Neuropeptide Y; C508361:adamantylcarbonyl-arginyl-phenylalaninamide; C083929:neuropeptide FF receptor; C097212:neuropeptide Y-Y1 receptor; D010862:Pilocarpine; D001120:Arginine; D000218:Adamantane
keywords: Epilepsy; Neuropeptide FF; Neuropeptide Y; RF9; Seizure