title: Anticonvulsive Activity in Audiogenic DBA/2 Mice of 1,4-Benzodiazepines and 1,5-Benzodiazepines with Different Activities at Cerebellar Granule Cell GABAAReceptors.
abstract: Herein, we tested in a model of generalized reflex epilepsy in mice different 1,4-benzodiazepines and 1,5-benzodiazepines with agonistic activity at the GABAAreceptor population contributing to the peak component of the chloride current elicited by GABA in cerebellar granule cells (CGCs) in culture. The substances have all higher lipophilia than clobazam, an antiepileptic drug well known and used in human therapy. This ensures that they all can pass relatively easily the blood-brain barrier (BBB). The benzodiazepines were administered intraperitoneally (i.p.) and tested for their activity against sound-induced tonic and clonic seizures in a genetic model of experimental epilepsy, the DBA/2 mouse. Our data demonstrates an interesting inverse correlation between the ED50s and the efficacy (E %) of the drugs in increasing the peak chloride current elicited by GABA in cerebellar granule cells in culture. There is indication of the existence of a threshold of E % above which the increase of ED50with increasing E % becomes linear. This is statistically significant for the clonic phase, whereas it is at the limit of significance for the tonic one. A possible interpretation of these results is that in this epilepsy model, projections from the cerebellum exert a convulsion prevention activity.
authors.affiliation: Department of Physics, University of Genova, Via Dodecaneso 33, 16146, Genoa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Gatta
authors.affiliation: Department of Physics, University of Genova, Via Dodecaneso 33, 16146, Genoa, Italy. aroldo.cupello@unige.it.
authors.forename: Aroldo
authors.initials: A
authors.lastname: Cupello
authors.affiliation: Department of Pharmacy, Pharmaceutical Chemistry Section, University of Genova, 16132, Genoa, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Di Braccio
authors.affiliation: Department of Pharmacy, Pharmaceutical Chemistry Section, University of Genova, 16132, Genoa, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Grossi
authors.affiliation: Department of Physics, University of Genova, Via Dodecaneso 33, 16146, Genoa, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Robello
authors.affiliation: Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, 88100, Catanzaro, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Scicchitano
authors.affiliation: Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, 88100, Catanzaro, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Russo
authors.affiliation: Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, 88100, Catanzaro, Italy.
authors.forename: Giovambattista
authors.initials: G
authors.lastname: De Sarro
mesh_terms: D000200:Action Potentials; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D001569:Benzodiazepines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D004829:Epilepsy, Generalized / Q000188:drug therapy*; D051379:Mice; D008811:Mice, Inbred DBA; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; D002712:Chlorides; D011963:Receptors, GABA-A; D001569:Benzodiazepines
keywords: 1,4-Benzodiazepines and 1,5-benzodiazepines; Anticonvulsive action; Audiogenic DBA/2 mice; Cerebellar granule cells; Cerebellum; Epilepsy