title: Rapid epileptogenesis in the mouse pilocarpine model: video-EEG, pharmacokinetic and histopathological characterization.
abstract: Temporal lobe epilepsy (TLE) is the most common form of drug-resistant epilepsy and several rodent models allow studying the pathophysiology of this disorder. One of the best characterized models of TLE is the pilocarpine model. The model has been widely used in rats, but relatively few studies report data obtained with mice. This triggered the present study to perform a comprehensive characterization of the mouse pilocarpine model. We used male NMRI mice (28-32 g) and first established the dose-response relationship for pilocarpine (250-400 mg/kg; ip) to induce status epilepticus (SE). This enabled to define the optimal dose (300 mg/kg) producing the highest SE response (50%) associated with the best survival rate of the animals (90%). The impact of different durations of SE (0.5-3.0 h) on the time to the onset of the first spontaneous recurrent seizures (SRS) was recorded during 5-day continuous video monitoring following the SE. Virtually no "latent" period was observed as the seizures appeared already within 24-48 h after the pilocarpine-induced SE and 0.5 h duration of the SE was sufficient to trigger SRS. Pharmacokinetics assessment showed that these seizures were not associated with residual pilocarpine exposure as it was cleared from the blood and brain already within 24 h post-injection. Consistent with previous reports from the rat pilocarpine model we observed that the extent of hippocampal reorganization and neuronal loss correlates with the duration of SE. However, the shorter durations of SE (0.5-2.0 h) appeared to produce cell loss restricted mainly to the hilus of the dentate gyrus. Interestingly, we also observed that the number of seizures occurring within 5 days after SE appeared to correlate with the degree of hippocampal damage. Continuous 7-week video-EEG monitoring after the SE revealed that SRS were expressed in a particular pattern of clusters. Taken together, the current study provides an in-depth characterization of the mouse pilocarpine model and confirms several features of the epileptogenesis process previously reported from the rat pilocarpine model. However, the mouse pilocarpine model differs by the rapid onset of seizures and an apparent correlation between their numbers and the degree of histopathological changes. Our findings highlight that the pilocarpine model of TLE in mice is associated with brain pathology akin to different stages of human disease and may provide a valuable tool for the discovery of future antiepileptic drugs with disease-modifying properties.
authors.affiliation: UCB Pharma, CNS Research, Braine-l'Alleud, Belgium.
authors.forename: Manuela
authors.initials: M
authors.lastname: Mazzuferi
authors.forename: Gaurav
authors.initials: G
authors.lastname: Kumar
authors.forename: Chiara
authors.initials: C
authors.lastname: Rospo
authors.forename: Rafal M
authors.initials: RM
authors.lastname: Kaminski
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D003975:Diazepam / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004567:Electrodes, Implanted; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced* / Q000175:diagnosis*; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018721:Muscarinic Agonists / Q000493:pharmacokinetics* / Q000633:toxicity*; D010862:Pilocarpine / Q000493:pharmacokinetics* / Q000633:toxicity*; D013997:Time Factors; D014741:Video Recording
chemical_list: D000927:Anticonvulsants; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D018721:Muscarinic Agonists; D010862:Pilocarpine; D003975:Diazepam