Article

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: 2.06). 03/2011; 497(3):163-71. DOI: 10.1016/j.neulet.2011.02.033
Source: PubMed

ABSTRACT 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”.
    Epilepsy & Behavior 09/2014; 38. DOI:10.1016/j.yebeh.2014.01.013 · 2.06 Impact Factor
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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.
    eLife Sciences 08/2014; 3:e01267. DOI:10.7554/eLife.01267 · 8.52 Impact Factor
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    • "4–6). Therefore, although behavioral and imaging abnormalities would be predicted to occur in epilepsy (Golarai et al., 2001; Jones et al., 2008b; Pitk€ anen et al., 2011), similar changes induced by TBI may have confounded the sensitivity of our measures. Furthermore, the behavioral testing may have occurred at time-points not sensitive to changes related to PTE, and the behavioral tasks were not comprehensive to the entire spectrum of behaviors potentially associated with PTE. "
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    ABSTRACT: PURPOSE: Posttraumatic epilepsy (PTE) occurs in a proportion of traumatic brain injury (TBI) cases, significantly compounding the disability, and risk of injury and death for sufferers. To date, predictive biomarkers for PTE have not been identified. This study used the lateral fluid percussion injury (LFPI) rat model of TBI to investigate whether structural, functional, and behavioral changes post-TBI relate to the later development of PTE. METHODS: Adult male Wistar rats underwent LFPI or sham injury. Serial magnetic resonance (MR) and positron emission tomography (PET) imaging, and behavioral analyses were performed over 6 months postinjury. Rats were then implanted with recording electrodes and monitored for two consecutive weeks using video-electroencephalography (EEG) to assess for PTE. Of the LFPI rats, 52% (n = 12) displayed spontaneous recurring seizures and/or epileptic discharges on the video-EEG recordings. KEY FINDINGS: MRI volumetric and signal analysis of changes in cortex, hippocampus, thalamus, and amygdala, (18) F-fluorodeoxyglucose (FDG)-PET analysis of metabolic function, and behavioral analysis of cognitive and emotional changes, at 1 week, and 1, 3, and 6 months post-LFPI, all failed to identify significant differences on univariate analysis between the epileptic and nonepileptic groups. However, hippocampal surface shape analysis using large-deformation high-dimensional mapping identified significant changes in the ipsilateral hippocampus at 1 week postinjury relative to baseline that differed between rats that would go onto become epileptic versus those who did not. Furthermore, a multivariate logistic regression model that incorporated the 1 week, and 1 and 3 month (18) F-FDG PET parameters from the ipsilateral hippocampus was able to correctly predict the epileptic outcome in all of the LFPI cases. As such, these subtle changes in the ipsilateral hippocampus at acute phases after LFPI may be related to PTE and require further examination. SIGNIFICANCE: These findings suggest that PTE may be independent of major structural, functional, and behavioral changes induced by TBI, and suggest that more subtle abnormalities are likely involved. However, there are limitations associated with studying acquired epilepsies in animal models that must be considered when interpreting these results, in particular the failure to detect differences between the groups may be related to the limitations of properly identifying/separating the epileptic and nonepileptic animals into the correct group.
    Epilepsia 05/2013; 54(7). DOI:10.1111/epi.12223 · 4.58 Impact Factor
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