Elsevier

Neuropharmacology

Volume 69, June 2013, Pages 3-15
Neuropharmacology

Invited review
Defining “epileptogenesis” and identifying “antiepileptogenic targets” in animal models of acquired temporal lobe epilepsy is not as simple as it might seem

https://doi.org/10.1016/j.neuropharm.2012.01.022Get rights and content

Abstract

The “latent period” between brain injury and clinical epilepsy is widely regarded to be a seizure-free, pre-epileptic state during which a time-consuming cascade of molecular events and structural changes gradually mediates the process of “epileptogenesis.” The concept of the “latent period” as the duration of “epileptogenesis” implies that epilepsy is not an immediate result of brain injury, and that anti-epileptogenic strategies need to target delayed secondary mechanisms that develop sometime after an initial injury. However, depth recordings made directly from the dentate granule cell layers in awake rats after convulsive status epilepticus-induced injury have now shown that whenever perforant pathway stimulation-induced status epilepticus produces extensive hilar neuron loss and entorhinal cortical injury, hyperexcitable granule cells immediately generate spontaneous epileptiform discharges and focal or generalized behavioral seizures. This indicates that hippocampal injury caused by convulsive status epilepticus is immediately epileptogenic and that hippocampal epileptogenesis requires no delayed secondary mechanism. When latent periods do exist after injury, we hypothesize that less extensive cell loss causes an extended period during which initially subclinical focal seizures gradually increase in duration to produce the first clinical seizure. Thus, the “latent period” is suggested to be a state of “epileptic maturation,” rather than a prolonged period of “epileptogenesis,” and therefore the antiepileptogenic therapeutic window may only remain open during the first week after injury, when some delayed cell death may still be preventable. Following the perhaps unavoidable development of the first focal seizures (“epileptogenesis”), the most fruitful therapeutic strategy may be to interrupt the process of “epileptic maturation,” thereby keeping focal seizures focal.

This article is part of the Special Issue entitled ‘New Targets and Approaches to the Treatment of Epilepsy’.

Highlights

► “Epileptogenesis” and “epileptic maturation” defined. ► Animal models of acquired temporal lobe epilepsy with hippocampal sclerosis. ► Spontaneous granule cell layer events in epileptic rats. ► Hippocampal c-Fos expression after spontaneous epileptic seizures. ► “Keeping focal seizures focal” as a primary therapeutic strategy.

Section snippets

What is “epileptogenesis” exactly, and how can it be prevented?

Experimental and clinical studies have used antiepileptic drugs to abort post-injury epileptogenesis, but with minimal success (Dichter, 2009; Temkin, 2009; Löscher and Brandt, 2010; Pitkänen, 2010; Eastman et al., 2011; Langer et al., 2011). Although the right drugs may have been tested at the wrong doses, for the wrong duration, or at the wrong time after brain injury, it is also possible that antiepileptic drugs do not influence the injury-induced “epileptogenic” process. Because acquired

Animal models of acquired temporal lobe epilepsy with hippocampal sclerosis

If chemoconvulsant-induced status epilepticus causes widespread brain damage and seizures of unknown origin, why has “hippocampal epileptogenesis” been so widely assumed?

Although epilepsy can arise from a variety of brain regions, most experimental studies have focused on modeling acquired temporal lobe epilepsy (TLE) with hippocampal sclerosis. Acquired TLE is of particular interest experimentally for several reasons. First and foremost, the pattern of selective hippocampal formation pathology

The “latent period” and the implication that epileptogenesis involves an obligatory secondary mechanism

In our studies of epileptogenesis in kainate and pilocarpine-treated rats, we noted unexpectedly that spontaneous behavioral seizures nearly always began within the first week following status epilepticus (Sloviter et al., 2003; Harvey and Sloviter, 2005), before any secondary mechanism could have had time to develop, and this has now been confirmed by other laboratories (Goffin et al., 2007; Raol et al., 2006; Jung et al., 2007). Although the lack of any detectable seizure-free “latent period”

“Keeping focal seizures focal” as a primary therapeutic strategy

The concept of a virtually immediate “epileptogenic” change in network behavior, followed by a longer-lasting secondary process of “epileptic maturation,” suggests that “disease prevention” and “disease modification” are distinct therapeutic targets. Thus, antiepileptogenesis therapy might focus productively on neuroprotection, i.e., targeting potentially reversible neuronal injury during the immediate post-injury period (Langer et al., 2011; Jimenez-Mateos et al., 2011; Serrano et al., 2011).

Caveats and clarifications

Several caveats and clarifications relate to our analyses and assertions. First, in terms of clarifications, we emphasize that acquired epilepsies involve a variety of insults that presumably produce clinically distinct epilepsies that originate in different locations and exhibit different latencies to clinical seizures. We do not suggest that there must be one common epileptogenic mechanism, and we recognize that future studies using chronic depth recording will need to determine whether other

Acknowledgements

We thank Drs. Wolfgang Löscher (University of Veterinary Medicine Hannover), Daniel H. Lowenstein (University of California, San Francisco), Robert Schwarcz (University of Maryland), H. Steve White (University of Utah), and Hitten Zaveri (Yale University) for useful discussions and constructive criticism of the manuscript. Grant sponsor: National Institute of Neurological Disorders and Stroke, NIH; Grant NS18201.

References (90)

  • M. Langer et al.

    Therapeutic window of opportunity for the neuroprotective effect of valproate versus the competitive AMPA receptor antagonist NS1209 following status epilepticus in rats

    Neuropharmacology

    (2011)
  • J.P. Leite et al.

    Spontaneous recurrent seizures in rats: an experimental model of partial epilepsy

    Neurosci. Biobehav. Rev.

    (1990)
  • J.P. Leite et al.

    New insights from the use of pilocarpine and kainate models

    Epilepsy Res.

    (2002)
  • L.E. Mello et al.

    Lack of Fos-like immunoreactivity after spontaneous seizures or reinduction of status epilepticus by pilocarpine in rats

    Neurosci. Lett.

    (1996)
  • A. Pitkänen et al.

    Anti-epileptogenesis in rodent post-traumatic epilepsy models

    Neurosci. Lett.

    (2011)
  • J.L. Poirier et al.

    Differential progression of Dark Neuron and Fluoro-Jade labelling in the rat hippocampus following pilocarpine-induced status epilepticus

    Neuroscience

    (2000)
  • M. Rattka et al.

    Enhanced susceptibility to the GABA antagonist pentylenetetrazole during the latent period following a pilocarpine-induced status epilepticus in rats

    Neuropharmacology

    (2011)
  • T. Ravizza et al.

    Inflammation and prevention of epileptogenesis

    Neurosci. Lett.

    (2011)
  • C. Richichi et al.

    Mechanisms of seizure-induced ‘transcriptional channelopathy’ of hyperpolarization-activated cyclic nucleotide gated (HCN) channels

    Neurobiol. Dis.

    (2008)
  • J.E. Schwob et al.

    Widespread patterns of neuronal damage following systemic or intracerebral injections of kainic acid: a histological study

    Neuroscience

    (1980)
  • A.K. Shetty

    Progress in cell grafting therapy for temporal lobe epilepsy

    Neurotherapeutics

    (2011)
  • R.S. Sloviter

    Possible functional consequences of synaptic reorganization in the dentate gyrus of kainate-treated rats

    Neurosci. Lett.

    (1992)
  • R.S. Sloviter

    Apoptosis: a guide for the perplexed

    Trends Pharmacol. Sci.

    (2002)
  • R.S. Sloviter

    The neurobiology of temporal lobe epilepsy: too much information, not enough knowledge

    C. R. Biol.

    (2005)
  • R.S. Sloviter

    Progress on the issue of excitotoxic injury modification vs. real neuroprotection; implications for post-traumatic epilepsy

    Neuropharmacology

    (2011)
  • W.A. Turski et al.

    Limbic seizures produced by pilocarpine in rats: behavioural, electroencephalographic and neuropathological study

    Behav. Brain Res.

    (1983)
  • P. Williams et al.

    The use of radiotelemetry to evaluate electrographic seizures in rats with kainate-induced epilepsy

    J. Neurosci. Methods

    (2006)
  • P. Andersen et al.

    Entorhinal activation of dentate granule cells

    Acta Physiol. Scand.

    (1966)
  • G. Biagini et al.

    Proepileptic influence of a focal vascular lesion affecting entorhinal cortex-CA3 connections after status epilepticus

    J. Neuropathol. Exp. Neurol.

    (2008)
  • I. Blümcke et al.

    A new clinico-pathological classification system for mesial temporal sclerosis

    Acta Neuropathol.

    (2007)
  • M.R. Bower et al.

    Changes in granule cell firing rates precede locally recorded spontaneous seizures by minutes in an animal model of temporal lobe epilepsy

    J. Neurophysiol.

    (2008)
  • A. Bragin et al.

    Epileptic afterdischarge in the hippocampal-entorhinal system: current source density and unit studies

    Neuroscience

    (1997)
  • A. Bragin et al.

    Chronic epileptogenesis requires development of a network of pathologically interconnected neuron clusters: a hypothesis

    Epilepsia

    (2000)
  • A. Bragin et al.

    Further evidence that pathologic high-frequency oscillations are bursts of population spikes derived from recordings of identified cells in dentate gyrus

    Epilepsia

    (2011)
  • A.V. Bumanglag et al.

    Minimal latency to hippocampal epileptogenesis and clinical epilepsy after perforant pathway stimulation-induced status epilepticus in awake rats

    J. Comp. Neurol.

    (2008)
  • B.S. Chang et al.

    Mechanisms of disease; epilepsy

    N. Engl. J. Med.

    (2003)
  • M.A. Dichter

    Emerging concepts in the pathogenesis of epilepsy and epileptogenesis

    Arch. Neurol.

    (2009)
  • M. Dragunow et al.

    Kindling stimulation induces c-fos protein(s) in granule cells of the rat dentate gyrus

    Nature

    (1987)
  • F. Du et al.

    Preferential neuronal loss in layer III of the medial entorhinal cortex in rat models of temporal lobe epilepsy

    J. Neurosci.

    (1995)
  • K.M. Earle et al.

    Incisural sclerosis and temporal lobe seizures produced by hippocampal herniation at birth

    A. M. A. Arch. Neurol. Psychiatry

    (1953)
  • C.L. Eastman et al.

    Antiepileptic and antiepileptogenic performance of carisbamate after head injury in the rat: blind and randomized studies

    J. Pharmacol. Exp. Ther.

    (2011)
  • L. El-Hassar et al.

    Hyperexcitability of the CA1 hippocampal region during epileptogenesis

    Epilepsia

    (2007)
  • J.A. French et al.

    Characteristics of medial temporal lobe epilepsy: I. results of history and physical examination

    Ann. Neurol.

    (1993)
  • K.A. Giblin et al.

    Is epilepsy a preventable disorder? New evidence from animal models

    Neuroscientist

    (2010)
  • J.A. Gorter et al.

    Progression of spontaneous seizures after status epilepticus is associated with mossy fibre sprouting and extensive bilateral loss of hilar parvalbumin and somatostatin-immunoreactive neurons

    Eur. J. Neurosci.

    (2001)
  • Cited by (79)

    • Biochemical aspects and therapeutic mechanisms of cannabidiol in epilepsy

      2022, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      We also examine possible CBD anticonvulsant mechanisms and CBD molecular targets in neurodegenerative disorders and epilepsy. Epileptogenesis describes the structural changes that lead to seizure activity in a normal brain (Sloviter and Bumanglag, 2013). At the cellular and molecular level, epileptogenesis refers to a process in which an initial injury causes brain damage and triggers a cascade of cellular and molecular changes that eventually induce maladaptive neural plasticity and the conversion of a normal brain to a state prone to generating seizures (Pitkänen et al., 2019).

    View all citing articles on Scopus
    View full text