title: Pathogenesis and pharmacology of epilepsy in the lithium-pilocarpine model.
abstract: To try to identify the critical structures during epileptogenesis, we used the lithium-pilocarpine model that reproduces most clinical and neuropathological features of temporal lobe epilepsy (TLE). We used imaging techniques as well as a disease modifying approach and pharmacological strategy. With [14C]-2-deoxyglucose autoradiography, we assessed changes in cerebral glucose utilization. T2-weighted magnetic resonance imaging (MRI, 4.7 T) allowed follow-up of structures involved in epileptogenesis. A potential disease-modifying effect was studied using preconditioning with brief seizures (amygdala kindling, maximal electroshocks) and pharmacological strategies including vigabatrin (250 mg/kg), caffeine (0.3 g/L in drinking water), topiramate (10-60 mg/kg), pregabalin (50 mg/kg followed by 10 mg/kg), or RWJ-333369 (10-120 mg/kg). In adult and PN21 rats that became epileptic, entorhinal, and piriform cortices were the initial structures exhibiting significant signal changes on MRI scans, from 6 h after status epilepticus (SE) onset, reflecting neuronal death. In PN21 rats that did not become epileptic, no signal occurred in parahippocampal cortices. In hippocampus, MRI signal change appeared 36-48 h after SE, and progressively worsened to sclerosis. During the latent and chronic phases, the metabolic level in the hilus of adult and PN21 epileptic rats was normal although neuronal loss reached 60-75%. Protection limited to CA1 and/or CA3 (caffeine, topiramate, vigabatrin, amygdala kindling) did not affect the latency to spontaneous seizures. Protection limited to the entorhinal and piriform cortices (pregabalin) delayed epileptogenesis. The combined protection of Ammon's horn and parahippocampal cortices (RWJ-333369) prolonged the latency before the onset of seizures in a dose-dependent manner or, in some cases, prevented the epilepsy. The entorhinal and piriform cortices are critically involved in the early phase of the epileptogenesis while the hilus may initiate and/or maintain epileptic seizures. Pharmacological protection of the basal cortices is necessary for a beneficial disease-modifying effect but this must be combined with protection of the hippocampus to prevent epileptogenesis in this model of TLE.
authors.affiliation: INSERM U 398, 405 and 666, Strasbourg, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: André
authors.forename: Céline
authors.initials: C
authors.lastname: Dubé
authors.forename: Jennifer
authors.initials: J
authors.lastname: François
authors.forename: Claire
authors.initials: C
authors.lastname: Leroy
authors.forename: Marie-Aude
authors.initials: MA
authors.lastname: Rigoulot
authors.forename: Catherine
authors.initials: C
authors.lastname: Roch
authors.forename: Izzie J
authors.initials: IJ
authors.lastname: Namer
authors.forename: Astrid
authors.initials: A
authors.lastname: Nehlig
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology; D001345:Autoradiography; D002452:Cell Count; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D003847:Deoxyglucose / Q000378:metabolism; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000706:statistics & numerical data; D004597:Electroshock; D018728:Entorhinal Cortex / Q000473:pathology / Q000503:physiopathology; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced* / Q000235:genetics* / Q000503:physiopathology; D005632:Fructose / Q000031:analogs & derivatives / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D007696:Kindling, Neurologic / Q000502:physiology; D018021:Lithium Chloride; D008279:Magnetic Resonance Imaging; D009833:Olfactory Pathways / Q000473:pathology / Q000503:physiopathology; D010862:Pilocarpine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced* / Q000235:genetics* / Q000503:physiopathology; D000077236:Topiramate; D020888:Vigabatrin / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D010862:Pilocarpine; D000077236:Topiramate; D005632:Fructose; D003847:Deoxyglucose; D018021:Lithium Chloride; D020888:Vigabatrin; D005947:Glucose