Anti-epileptogenesis in rodent post-traumatic epilepsy models

Department of Neurobiology, Epilepsy Research Laboratory, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland.
Neuroscience Letters (Impact Factor: 2.03). 03/2011; 497(3):163-71. DOI: 10.1016/j.neulet.2011.02.033
Source: PubMed


Post-traumatic epilepsy (PTE) accounts for 10-20% of symptomatic epilepsies. The urgency to understand the process of post-traumatic epileptogenesis and search for antiepileptogenic treatments is emphasized by a recent increase in traumatic brain injury (TBI) related to military combat or accidents in the aging population. Recent developments in modeling of PTE in rodents have provided tools for identification of novel drug targets for antiepileptogenesis and biomarkers for predicting the risk of epileptogenesis and treatment efficacy after TBI. Here we review the available data on endophenotypes of humans and rodents with TBI associated with epilepsy. Also, current understanding of the mechanisms and biomarkers for PTE as well as factors associated with preclinical study designs are discussed. Finally, we summarize the attempts to prevent PTE in experimental models.

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Available from: Tamuna Bolkvadze, May 23, 2014
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    • "TBI triggers molecular changes at transcriptional, posttranslational, and epigenetic levels, some of which likely underlie the consequent circuitry reorganization. Recent data demonstrate also the development of several types of acquired channelopathies after TBI that can contribute to increased excitability [53]. Molecular and cellular plasticity can continue for weeks to months to years, and the pattern of changes is time-dependent, suggesting that the expression of treatment targets is also time-dependent. "
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    ABSTRACT: Traumatic brain injury (TBI) can cause a myriad of sequelae depending on its type, severity, and location of injured structures. These can include mood disorders, posttraumatic stress disorder and other anxiety disorders, personality disorders, aggressive disorders, cognitive changes, chronic pain, sleep problems, motor or sensory impairments, endocrine dysfunction, gastrointestinal disturbances, increased risk of infections, pulmonary disturbances, parkinsonism, posttraumatic epilepsy, or their combinations. The progression of individual pathologies leading to a given phenotype is variable, and some progress for months. Consequently, the different post-TBI phenotypes appear within different time windows. In parallel with morbidogenesis, spontaneous recovery occurs both in experimental models and in human TBI. A great challenge remains; how can we dissect the specific mechanisms that lead to the different endophenotypes, such as posttraumatic epileptogenesis, in order to identify treatment approaches that would not compromise recovery? This article is part of a Special Issue entitled “NEWroscience 2013”.
    Full-text · Article · Sep 2014 · Epilepsy & Behavior
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    • "Epileptic networks arise via numerous mechanisms (Pitkänen et al., 2011; Vezzani et al., 2011; Kim et al., 2012; Hildebrand et al., 2013; Rowley and Patel, 2013). Changes in neuronal properties and resulting alterations of network behavior constitute one of the important mechanisms of epileptogenesis (Yaari and Beck, 2002; Noam et al., 2011; Goldberg and Coulter, 2013). "
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    ABSTRACT: The mechanisms generating epileptic neuronal networks following insults such as severe seizures are unknown. We have previously shown that interfering with the function of the neuron-restrictive silencer factor (NRSF/REST), an important transcription factor that influences neuronal phenotype, attenuated development of this disorder. In this study, we found that epilepsy-provoking seizures increased the low NRSF levels in mature hippocampus several fold yet surprisingly, provoked repression of only a subset (∼10%) of potential NRSF target genes. Accordingly, the repressed gene-set was rescued when NRSF binding to chromatin was blocked. Unexpectedly, genes selectively repressed by NRSF had mid-range binding frequencies to the repressor, a property that rendered them sensitive to moderate fluctuations of NRSF levels. Genes selectively regulated by NRSF during epileptogenesis coded for ion channels, receptors, and other crucial contributors to neuronal function. Thus, dynamic, selective regulation of NRSF target genes may play a role in influencing neuronal properties in pathological and physiological contexts.
    Full-text · Article · Aug 2014 · eLife Sciences
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    • "The factors that lead to the establishment of the long-term epileptic state are not fully understood, but there is considerable evidence to suggest that seizures in the acute period may drive changes that will result in the development of PTE. Early use of AEDs may prevent these changes from occurring, reverse the process of early epileptogenesis related to injury, and prevent chronic epilepsy.38,97,98 "
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    ABSTRACT: Traumatic brain injury (TBI) leads to many undesired problems and complications, including immediate and long-term seizures/epilepsy, changes in mood, behavioral, and personality problems, cognitive and motor deficits, movement disorders, and sleep problems. Clinicians involved in the treatment of patients with acute TBI need to be aware of a number of issues, including the incidence and prevalence of early seizures and post-traumatic epilepsy (PTE), comorbidities associated with seizures and anticonvulsant therapies, and factors that can contribute to their emergence. While strong scientific evidence for early seizure prevention in TBI is available for phenytoin (PHT), other antiepileptic medications, eg, levetiracetam (LEV), are also being utilized in clinical settings. The use of PHT has its drawbacks, including cognitive side effects and effects on function recovery. Rates of recovery after TBI are expected to plateau after a certain period of time. Nevertheless, some patients continue to improve while others deteriorate without any clear contributing factors. Thus, one must ask, 'Are there any actions that can be taken to decrease the chance of post-traumatic seizures and epilepsy while minimizing potential short- and long-term effects of anticonvulsants?' While the answer is 'probably,' more evidence is needed to replace PHT with LEV on a permanent basis. Some have proposed studies to address this issue, while others look toward different options, including other anticonvulsants (eg, perampanel or other AMPA antagonists), or less established treatments (eg, ketamine). In this review, we focus on a comparison of the use of PHT versus LEV in the acute TBI setting and summarize the clinical aspects of seizure prevention in humans with appropriate, but general, references to the animal literature.
    Full-text · Article · Aug 2014 · Neuropsychiatric Disease and Treatment
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