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      The evolution of the pilocarpine animal model of status epilepticus

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          Abstract

          The pilocarpine animal model of status epilepticus is a well-established, clinically translatable model that satisfies all of the criteria essential for an animal model of status epilepticus: a latency period followed by spontaneous recurrent seizures, replication of behavioural, electrographic, metabolic, and neuropathological changes, as well as, pharmacoresistance to anti-epileptic drugs similar to that observed in human status epilepticus. However, this model is also characterized by high mortality rates and studies in recent years have also seen difficulties in seizure induction due to pilocarpine resistant animals. This can be attributed to differences in rodent strains, species, gender, and the presence of the multi-transporter, P-glycoprotein at the blood brain barrier. The current paper highlights the various alterations made to the original pilocarpine model over the years to combat both the high mortality and low induction rates. These range from the initial lithium-pilocarpine model to the more recent Reduced Intensity Status Epilepticus (RISE) model, which finally brought the mortality rates down to 1%. These modifications are essential to improve animal welfare and future experimental outcomes.

          Abstract

          Pilocarpine, Animal model, Status epilepticus, Seizure, Neuroscience, Behavioral neuroscience, Cellular neuroscience, Cognitive neuroscience, Molecular neuroscience, Systems neuroscience, Health sciences.

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          The pilocarpine model of temporal lobe epilepsy

          Giulia Curia, Daniela Longo, Giuseppe Biagini … (2008)
          Understanding the pathophysiogenesis of temporal lobe epilepsy (TLE) largely rests on the use of models of status epilepticus (SE), as in the case of the pilocarpine model. The main features of TLE are: (i) epileptic foci in the limbic system; (ii) an “initial precipitating injury”; (iii) the so-called “latent period”; and (iv) the presence of hippocampal sclerosis leading to reorganization of neuronal networks. Many of these characteristics can be reproduced in rodents by systemic injection of pilocarpine; in this animal model, SE is followed by a latent period and later by the appearance of spontaneous recurrent seizures (SRSs). These processes are, however, influenced by experimental conditions such as rodent species, strain, gender, age, doses and routes of pilocarpine administration, as well as combinations with other drugs administered before and/or after SE. In the attempt to limit these sources of variability, we evaluated the methodological procedures used by several investigators in the pilocarpine model; in particular, we have focused on the behavioural, electrophysiological and histopathological findings obtained with different protocols. We addressed the various experimental approaches published to date, by comparing mortality rates, onset of SRSs, neuronal damage, and network reorganization. Based on the evidence reviewed here, we propose that the pilocarpine model can be a valuable tool to investigate the mechanisms involved in TLE, and even more so when standardized to reduce mortality at the time of pilocarpine injection, differences in latent period duration, variability in the lesion extent, and SRS frequency.
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            Drug resistance in brain diseases and the role of drug efflux transporters.

            Heidrun Potschka, Wolfgang Löscher (2005)
            Resistance to drug treatment is an important hurdle in the therapy of many brain disorders, including brain cancer, epilepsy, schizophrenia, depression and infection of the brain with HIV. Consequently, there is a pressing need to develop new and more effective treatment strategies. Mechanisms of resistance that operate in cancer and infectious diseases might also be relevant in drug-resistant brain disorders. In particular, drug efflux transporters that are expressed at the blood-brain barrier limit the ability of many drugs to access the brain. There is increasing evidence that drug efflux transporters have an important role in drug-resistant brain disorders, and this information should allow more efficacious treatment strategies to be developed.
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              A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group.

              Brent Faught, Craig Ramsay, V. CALABRESE … (1998)
              Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg per kilogram of body weight) followed by phenytoin (18 mg per kilogram), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg per kilogram), and phenytoin (18 mg per kilogram). Patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicated by coma and ictal discharges on the electroencephalogram, with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after the beginning of the drug infusion and there was no return of seizure activity during the next 40 minutes. Analyses were performed with data on only the 518 patients with verified generalized convulsive status epilepticus as well as with data on all 570 patients who were enrolled. Three hundred eighty-four patients had a verified diagnosis of overt generalized convulsive status epilepticus. In this group, lorazepam was successful in 64.9 percent of those assigned to receive it, phenobarbital in 58.2 percent, diazepam plus phenytoin in 55.8 percent, and phenytoin in 43.6 percent (P=0.02 for the overall comparison among the four groups). Lorazepam was significantly superior to phenytoin in a pairwise comparison (P=0.002). Among the 134 patients with a verified diagnosis of subtle generalized convulsive status epilepticus, no significant differences among the treatments were detected (range of success rates, 7.7 to 24.2 percent). In an intention-to-treat analysis, the differences among treatment groups were not significant, either among the patients with overt status epilepticus (P=0.12) or among those with subtle status epilepticus (P=0.91). There were no differences among the treatments with respect to recurrence during the 12-hour study period, the incidence of adverse reactions, or the outcome at 30 days. As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam plus phenytoin, it is easier to use.
              Article 0 comments Cited 154 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Ahmad Tarmizi Che Has
                Journal
                Journal ID (nlm-ta): Heliyon
                Journal ID (iso-abbrev): Heliyon
                Title: Heliyon
                Publisher: Elsevier
                ISSN (Electronic): 2405-8440
                Publication date PMC-release: 28 July 2020
                Publication date Collection: July 2020
                Publication date (Electronic): 28 July 2020
                Volume: 6
                Issue: 7
                Electronic Location Identifier: e04557
                Affiliations
                [1]Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia
                Author notes
                [∗ ]Corresponding author. ahmadtarmizi@ 123456usm.my
                Article
                Publisher ID: S2405-8440(20)31401-8 Publisher ID: e04557
                DOI: 10.1016/j.heliyon.2020.e04557
                PMC ID: 7393986
                PubMed ID: 32775726
                SO-VID: bc637b97-11b0-44bf-8051-282e353e304a
                Copyright © © 2020 Published by Elsevier Ltd.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 5 May 2020
                Date revision received : 5 July 2020
                Date accepted : 22 July 2020
                Categories
                Subject: Article

                Keywords: pilocarpine,animal model,status epilepticus,seizure,neuroscience,behavioral neuroscience,cellular neuroscience,cognitive neuroscience,molecular neuroscience,systems neuroscience,health sciences
                Data availability:
                Keywords: pilocarpine, animal model, status epilepticus, seizure, neuroscience, behavioral neuroscience, cellular neuroscience, cognitive neuroscience, molecular neuroscience, systems neuroscience, health sciences

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