The pilocarpine model of temporal lobe epilepsy

Montreal Neurological Institute and Departments of Neurology & Neurosurgery and Physiology, McGill University, Montreal, QC, Canada.
Journal of Neuroscience Methods (Impact Factor: 2.05). 08/2008; 172(2):143-57. DOI: 10.1016/j.jneumeth.2008.04.019
Source: PubMed


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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Available from: Giulia Curia, Oct 06, 2015
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    • "In addition, previous studies analysed interictallike events originating from normal functioning networks rather than from structurally and functionally rewired networks following epileptogenesis. The chronic experimental model studied here mimics the structural network changes reported in human patients after epileptogenesis (Curia et al., 2008) and therefore is more likely to capture the relevant cellular mechanisms at the basis of epileptiform activity. The clinical translation of the synchronous activation of CA1 GABAergic neurons and resultant inhibition of principle cells observed here supports the hypothesis that "
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    ABSTRACT: Epilepsy is characterized by recurrent seizures and brief, synchronous bursts called interictal spikes that are present in-between seizures and observed as transient events in EEG signals. While GABAergic transmission is known to play an important role in shaping healthy brain activity, the role of inhibition in these pathological epileptic dynamics remains unclear. Examining the microcircuits that participate in interictal spikes is thus an important first step towards addressing this issue, as the function of these transient synchronizations in either promoting or prohibiting seizures is currently under debate. To identify the microcircuits recruited in spontaneous interictal spikes in the absence of any proconvulsive drug or anaesthetic agent, we combine a chronic model of epilepsy with in vivo two-photon calcium imaging and multiunit extracellular recordings to map cellular recruitment within large populations of CA1 neurons in mice free to run on a self-paced treadmill. We show that GABAergic neurons, as opposed to their glutamatergic counterparts, are preferentially recruited during spontaneous interictal activity in the CA1 region of the epileptic mouse hippocampus. Although the specific cellular dynamics of interictal spikes are found to be highly variable, they are consistently associated with the activation of GABAergic neurons, resulting in a perisomatic inhibitory restraint that reduces neuronal spiking in the principal cell layer. Given the role of GABAergic neurons in shaping brain activity during normal cognitive function, their aberrant unbalanced recruitment during these transient events could have important downstream effects with clinical implications. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Brain 08/2015; DOI:10.1093/brain/awv227 · 9.20 Impact Factor
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    • "We followed here a unique approach by initiating antiepileptogenic treatment after disease onset, thereby setting ourselves apart from most research efforts that initiate 'antiepileptogenic' treatments before, during, or shortly after a precipitating event. To ascertain whether a KD can prevent seizures and disease progression in a model of chronic epilepsy, we evaluated its effects in the rat pilocarpine model, which is characterized by an initial precipitating injury, a latent period, hippocampal sclerosis and reorganization of neuronal networks leading to spontaneous epileptogenicity in the limbic system (Curia et al., 2008). Spontaneous convulsive seizures in this model increase in severity and frequency over time and reflect ongoing disease progression and continuous epileptogenesis . "
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    ABSTRACT: Epilepsy is a highly prevalent seizure disorder which tends to progress in severity and become refractory to treatment. Yet no therapy is proven to halt disease progression or to prevent the development of epilepsy. Because a high fat low carbohydrate ketogenic diet (KD) augments adenosine signaling in the brain and because adenosine not only suppresses seizures but also affects epileptogenesis, we hypothesized that a ketogenic diet might prevent epileptogenesis through similar mechanisms. Here, we tested this hypothesis in two independent rodent models of epileptogenesis. Using a pentylenetetrazole kindling paradigm in mice, we first show that a KD, but not a conventional antiepileptic drug (valproic acid), suppressed kindling-epileptogenesis. Importantly, after treatment reversal, increased seizure thresholds were maintained in those animals kindled in the presence of a KD, but not in those kindled in the presence of valproic acid. Next, we tested whether a KD can halt disease progression in a clinically relevant model of progressive epilepsy. Epileptic rats that developed spontaneous recurrent seizures after a pilocarpine-induced status epilepticus were treated with a KD or control diet (CD). Whereas seizures progressed in severity and frequency in the CD-fed animals, KD-fed animals showed a prolonged reduction of seizures, which persisted after diet reversal. KD-treatment was associated with increased adenosine and decreased DNA methylation, the latter being maintained after diet discontinuation. Our findings demonstrate that a KD prevented disease progression in two mechanistically different models of epilepsy, and suggest an epigenetic mechanism underlying the therapeutic effects. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 08/2015; 99. DOI:10.1016/j.neuropharm.2015.08.007 · 5.11 Impact Factor
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    • "It prolonged the latency time to the occurrence of prodromal symptoms of seizures, status epilepticus, and death. Our results are in agreement with available data pointing out the efficacy of tiagabine in pilocarpine-induced seizures, e.g., in temporal lobe epilepsy model in rats [28] [29]. "
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    ABSTRACT: Tiagabine, a selective inhibitor of GABA transporter subtype 1 is used as an add-on therapy of partial seizures in humans but its mechanism of action suggests other potential medical indications for this drug. In this research we assess its pharmacological activity in several screening models of seizures, pain, anxiety and depression in mice. For pharmacological tests tiagabine was administered intraperitoneally 60min before the assay. Behavioral tests were performed using models of chemically and electrically induced seizures, thermal acute pain and formalin-induced tonic pain. Anxiolytic-like properties were evaluated using the four plate test and the elevated plus maze test. Antidepressant-like activity was assessed in the forced swim test. In addition, to exclude false positive results in these assays, the influence of tiagabine on animals' locomotor activity and motor coordination was investigated, too. Tiagabine demonstrated anticonvulsant properties in chemically induced seizures (pentylenetetrazole and pilocarpine seizures). At the dose of 100mg/kg it also elevated the seizure threshold for electrically induced seizures by 31.6% (p<0.01), but it had no activity in the maximal electroshock seizure test. Tiagabine showed anxiolytic-like and antidepressant-like effects. Although it apparently reduced animals' nociceptive responses in pain tests, these activities rather resulted from its sedative and motor-impairing properties demonstrated in the locomotor activity and the rotarod tests, respectively. The results obtained in the present study suggest that tiagabine, apart its anticonvulsant effect, has anxiolytic-like, sedative and antidepressant-like properties. In view of this, it can be potentially used in the treatment of anxiety and mood disorders. Copyright © 2014. Published by Elsevier Urban & Partner Sp. z o.o.
    Pharmacological reports: PR 06/2015; 67(3). DOI:10.1016/j.pharep.2014.11.003 · 1.93 Impact Factor
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