title: Seizures triggered by pentylenetetrazol in marmosets made chronically epileptic with pilocarpine show greater refractoriness to treatment.
abstract: The efficiency of most of the new antiepileptic drugs (AEDs) on clinical trials still falls short the success reported in pre-clinical studies, possibly because the validity of the animal models is insufficient to fully represent the human pathology. To improve the translational value for testing AEDs, we propose the use of non-human primates. Here, we suggest that triggering limbic seizures with low doses of PTZ in pilocarpine-treated marmosets might provide a more effective basis for the development of AED. Marmosets with epileptic background were more susceptible to seizures induced by PTZ, which were at least 3 times longer and more severe (about 6 times greater frequency of generalized seizures) in comparison to naïve peers. Accordingly, PTZ-induced seizures were remarkably less attenuated by AEDs in epileptic than naïve marmosets. While phenobarbital (40mg/kg) virtually abolished seizures regardless of the animal's background, carbamazepine (120mg/kg) and valproic acid (400mg/kg) could not prevent PTZ-induced seizures in epileptic animals with the same efficiency as observed in naïve peers. VPA was less effective regarding the duration of individual seizures in epileptic animals, as assessed in ECoG (p=0.05). Similarly following CBZ treatment, the behavioral manifestation of generalized seizures lasted longer in epileptic (p<0.05), which were also more frequent than in the naïve group (p<0.05). As expected, epileptic marmosets experiencing stronger seizures showed more NPY- and ΔFosB-immunostained neurons in a number of brain areas associated with the generation and spread of limbic seizures. Our results suggest that PTZ induced seizures over an already existing epileptic background constitutes a reliable and controllable mean for the screening of new AEDs.
authors.affiliation: Departamento de Fisiologia, Universidade Federal de São Paulo, Rua Pedro de Toledo 669, 3 andar, São Paulo, SP 04039-032, Brazil.
authors.forename: Josy Carolina C
authors.initials: JC
authors.lastname: Pontes
authors.affiliation: Hospital Israelita Albert Einstein, Avenida Albert Einstein, 627, São Paulo, SP 05652-000, Brazil.
authors.forename: Thiago Z
authors.initials: TZ
authors.lastname: Lima
authors.affiliation: Brain Institute, Universidade Federal do Rio Grande do Norte, Avenida Nascimento de Castro, 2155, Natal, RN 59056-450, Brazil.
authors.forename: Claudio M
authors.initials: CM
authors.lastname: Queiroz
authors.affiliation: Departamento de Fisiologia, Universidade Federal de São Paulo, Rua Pedro de Toledo 669, 3 andar, São Paulo, SP 04039-032, Brazil.
authors.forename: Simone M
authors.initials: SM
authors.lastname: Cinini
authors.affiliation: Departamento de Fisiologia, Universidade Federal de São Paulo, Rua Pedro de Toledo 669, 3 andar, São Paulo, SP 04039-032, Brazil.
authors.forename: Miriam M
authors.initials: MM
authors.lastname: Blanco
authors.affiliation: Departamento de Fisiologia, Universidade Federal de São Paulo, Rua Pedro de Toledo 669, 3 andar, São Paulo, SP 04039-032, Brazil. Electronic address: lemello@unifesp.br.
authors.forename: Luiz E
authors.initials: LE
authors.lastname: Mello
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002144:Callithrix; D002220:Carbamazepine / Q000494:pharmacology; D002908:Chronic Disease; D004195:Disease Models, Animal; D000069280:Electrocorticography; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D009478:Neuropeptide Y / Q000378:metabolism; D010433:Pentylenetetrazole; D010634:Phenobarbital / Q000494:pharmacology; D010862:Pilocarpine; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D009478:Neuropeptide Y; D016760:Proto-Oncogene Proteins c-fos; D010862:Pilocarpine; D002220:Carbamazepine; D014635:Valproic Acid; D010433:Pentylenetetrazole; D010634:Phenobarbital
keywords: Animal model; Anti-epileptic drugs; Epilepsy; Pentylenetetrazole; Pharmacoresistance; Pilocarpine