Molecular biomarkers of epileptogenesis.
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ABSTRACT:
SUBMITTER: Lukasiuk K
PROVIDER: S-EPMC3996120 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The last decade has witnessed a significant shift on our understanding of the relationship between psychiatric disorders and epilepsy. While traditionally psychiatric disorders were considered as a complication of the underlying seizure disorder, new epidemiologic data, supported by clinical and experimental research, have suggested the existence of a bidirectional relation between the two types of conditions: not only are patients with epilepsy at greater risk of experiencing a psychiatric disorder, but patients with primary psychiatric disorders are at greater risk of developing epilepsy. Do these data suggest that some of the pathogenic mechanisms operant in psychiatric comorbidities play a role in epileptogenesis? The aim of this article is to review the epidemiologic data that demonstrate that primary psychiatric disorders are more frequent in people who develop epilepsy, before the onset of the seizure disorder than among controls. The next question looks at the available data of pathogenic mechanisms of primary mood disorders and their potential for facilitating the development and/or exacerbation in the severity of epileptic seizures. Finally, we review data derived from experimental studies in animal models of depression and epilepsy that support a potential role of pathogenic mechanisms of mood disorders in the development of epileptic seizures and epileptogenesis. The data presented in this article do not yet establish conclusive evidence of a pathogenic role of psychiatric comorbidities in epileptogenesis, but raise important research questions that need to be investigated in experimental, clinical, and population-based epidemiologic research studies.
| S-EPMC3996129 | biostudies-literature
Project description:The present study tested a hypothesis that early identification of injury severity with quantitative magnetic resonance imaging (MRI) provides biomarkers for predicting increased seizure susceptibility and epileptogenesis after traumatic brain injury (TBI). TBI was induced by lateral fluid percussion injury (FPI) in adult rats. Quantitative T2, T1?, and diffusion were assessed with MRI at 9 days, 23 days, or 2 months post-TBI in the perilesional cortex, thalamus, and hippocampus. Seizure susceptibility was assessed at 12 months after TBI using the pentylenetetrazol seizure-susceptibility test. At 9 and 23 days post-TBI, a change in T1? of the perilesional cortex showed the greatest predictive value for increased seizure susceptibility at 12 months post-TBI [area under the curve (AUC), 0.929 and 0.952, respectively; p<0.01]. At 2 months post-TBI, Dav in the thalamus was the best of the biomarkers analyzed (AUC, 0.988; p<0.05). The highest predictive value of all biomarkers was achieved by combining the measurement of Dav in the perilesional cortex and the thalamus at 2 months post-TBI (AUC, 1.000; p<0.01). Our results provide proof-of-concept evidence that clinically relevant MRI biomarkers predict increased seizure susceptibility after experimental TBI.
| S-EPMC3713441 | biostudies-literature
Project description:Descriptions of epileptic seizures and epilepsy date back to antiquity, and research into fundamental mechanisms of epilepsy in animal models, as well as patients, has been carried out for over a century. Studies of epileptogenesis, however, as distinct from ictogenesis, have been pursued for only a few decades, and antiepileptogenesis, the prevention of epilepsy or its progression, and the reversal of the epileptogenic process or cure, are relatively recent interests of the basic research community. The goal to develop antiepileptogenic interventions would be greatly facilitated by the identification of reliable biomarkers of epileptogenesis that could be used to create cost-effective, high-throughput screening models for potential antiepileptogenic compounds, as well as enrich patient populations and serve as surrogate endpoints for clinical trials. Without such biomarkers, the cost for clinical validation of antiepileptogenic interventions would be prohibitive. Epileptogenic mechanisms, antiepileptogenic interventions, and biomarkers are likely to be specific for the many different causes of epilepsy, which include genetic influences, cell loss and synaptic plasticity, malformations of cortical development, and autoimmune disorders, to name but a few. A high priority is currently being placed on investigations to elucidate fundamental mechanisms of epileptogenesis and identify biomarkers for specific models of human epilepsy, such as mesial temporal lobe epilepsy with hippocampal sclerosis, traumatic brain injury, and a variety of pediatric diseases, including tuberous sclerosis and West syndrome.
| S-EPMC3996117 | biostudies-literature
Project description:Whether long febrile seizures (FSs) can cause epilepsy in the absence of genetic or acquired predisposing factors is unclear. Having established causality between long FSs and limbic epilepsy in an animal model, we studied here if the duration of the inciting FSs influenced the probability of developing subsequent epilepsy and the severity of the spontaneous seizures. We evaluated if interictal epileptifom activity and/or elevation of hippocampal T2 signal on magnetic resonance image (MRI) provided predictive biomarkers for epileptogenesis, and if the inflammatory mediator interleukin-1beta (IL-1beta), an intrinsic element of FS generation, contributed also to subsequent epileptogenesis. We found that febrile status epilepticus, lasting an average of 64 min, increased the severity and duration of subsequent spontaneous seizures compared with FSs averaging 24 min. Interictal activity in rats sustaining febrile status epilepticus was also significantly longer and more robust, and correlated with the presence of hippocampal T2 changes in individual rats. Neither T2 changes nor interictal activity predicted epileptogenesis. Hippocampal levels of IL-1beta were significantly higher for >24 h after prolonged FSs. Chronically, IL-1beta levels were elevated only in rats developing spontaneous limbic seizures after febrile status epilepticus, consistent with a role for this inflammatory mediator in epileptogenesis. Establishing seizure duration as an important determinant in epileptogenesis and defining the predictive roles of interictal activity, MRI, and inflammatory processes are of paramount importance to the clinical understanding of the outcome of FSs, the most common neurological insult in infants and children.
| S-EPMC2906240 | biostudies-other
Project description:experimental group and control group in rat post-status epilepticus model. Keywords: parallel sample
2003-10-31 | GSE785 | GEO
Project description:experimental group and control group in rat post-status epilepticus model. Keywords: parallel sample
2003-10-30 | E-GEOD-785 | biostudies-arrayexpress
Project description:BackgroundUncovering the molecular mechanisms involved in epileptogenesis is critical to better understand the physiopathology of epilepsies and to help develop new therapeutic strategies for this prevalent and severe neurological condition that affects millions of people worldwide.ResultsChanges in the transcriptome of hippocampal cells from rats subjected to the pilocarpine model of epilepsy were evaluated by microarrays covering 34,000 transcripts representing all annotated rat genes to date. Using such genome-wide approach, differential expression of nearly 1,400 genes was detected during the course of epileptogenesis, from the early events post status epilepticus (SE) to the onset of recurrent spontaneous seizures. Most of these genes are novel and displayed an up-regulation after SE. Noteworthy, a group of 128 genes was found consistently hyper-expressed throughout epileptogenesis, indicating stable modulation of the p38MAPK, Jak-STAT, PI3K, and mTOR signaling pathways. In particular, up-regulation of genes from the TGF-beta and IGF-1 signaling pathways, with opposite effects on neurogenesis, correlate with the physiopathological changes reported in humans.ConclusionsA consistent regulation of genes functioning in intracellular signal transduction regulating neurogenesis have been identified during epileptogenesis, some of which with parallel expression patterns reported in patients with epilepsy, strengthening the link between these processes and development of epilepsy. These findings reveal dynamic molecular changes occurring in the hippocampus that may serve as a starting point for designing alternative therapeutic strategies to prevent the development of epilepsy after acquired brain insults.
| S-EPMC2859406 | biostudies-literature
Project description:Purpose: to evaluate changes in the transcriptome of hippocampal cells during the course of epileptogenesis, from the early events post status epilepticus (SE) to the onset of recurrent spontaneous seizures. Experimental Design: Gene expression profiling was analyzed in hippocampi of rats subjected to the pilocarpine model of epilepsy at different times during the course of epileptogenesis: 3 days post-SE (3D), 7 days post-SE (7D), and immediately (up to 12h) after the first spontaneous seizure (Chronic). All three pilocarpine subgroups had a corresponding age-matched control group (saline-treated rats), from which normal hippocampi samples were obtained at the same experimental time points. Independent microarray hybridizations were carried out for each sample (n = 5, per experimental group) with oligonucleotide microarrays covering 34,000 transcripts representing most of the known and predictive genes of the rat genome (CodeLink™ Rat Whole Genome Bioarrays, GE Healthcare), following the manufacturer’s protocol. Results: differential expression of almost 1,400 genes was detected during the course of epileptogenesis, from the early events post status epilepticus (SE) to the onset of recurrent spontaneous seizures. Most of these genes are novel and displayed an up-regulation after SE. Noteworthy, a group of 128 genes functioning in neurogenesis, apoptosis, immune response, and intracellular signal transduction was found consistently hyper-expressed throughout epileptogenesis, indicating stable molecular alterations within the hippocampus. Those include modulation of the MAPK, Jak-STAT, PI3K, TGF-beta, and mTOR signaling pathways. Differential expression of genes from the p38 MAPK pathway, mediating inflammation and neurogenesis, was also confirmed by real-time PCR. These findings reveal dynamic molecular changes occurring in the hippocampus that may serve as a starting point for the generation of new hypothesis regarding the underlying mechanisms of epilepsy and for the designing of alternative therapeutic strategies. Keywords: gene expression changes during epileptogenesis.
2010-02-09 | GSE14763 | GEO
Project description:Tuberous sclerosis complex (TSC), caused by heterozygous mutations in TSC1 or TSC2, frequently results in intractable epilepsy. Here, we made use of an inducible Tsc1-knockout mouse model, allowing us to study electrophysiological and molecular changes of Tsc1-induced epileptogenesis over time. We recorded from pyramidal neurons in the hippocampus and somatosensory cortex (L2/L3) and combined this with an analysis of transcriptome changes during epileptogenesis. Deletion of Tsc1 resulted in hippocampus-specific changes in excitability and adaptation, which emerged before seizure onset and progressed over time. All phenotypes were rescued after early treatment with rapamycin, an mTOR inhibitor. Later in epileptogenesis, we observed a hippocampal increase of excitation-to-inhibition ratio. These cellular changes were accompanied by dramatic transcriptional changes, especially after seizure onset. Most of these changes were rescued upon rapamycin treatment. Of the genes encoding ion channels or belonging to the Gene Ontology term action potential, 27 were differentially expressed just before seizure onset, suggesting a potential driving role in epileptogenesis. Our data highlight the complex changes driving epileptogenesis in TSC, including the changed expression of multiple ion channels. Our study emphasizes inhibition of the TSC/mTOR signaling pathway as a promising therapeutic approach to target epilepsy in patients with TSC.
| S-EPMC8675202 | biostudies-literature
Project description:Purpose: to evaluate changes in the transcriptome of hippocampal cells during the course of epileptogenesis, from the early events post status epilepticus (SE) to the onset of recurrent spontaneous seizures. Experimental Design: Gene expression profiling was analyzed in hippocampi of rats subjected to the pilocarpine model of epilepsy at different times during the course of epileptogenesis: 3 days post-SE (3D), 7 days post-SE (7D), and immediately (up to 12h) after the first spontaneous seizure (Chronic). All three pilocarpine subgroups had a corresponding age-matched control group (saline-treated rats), from which normal hippocampi samples were obtained at the same experimental time points. Independent microarray hybridizations were carried out for each sample (n = 5, per experimental group) with oligonucleotide microarrays covering 34,000 transcripts representing most of the known and predictive genes of the rat genome (CodeLink⢠Rat Whole Genome Bioarrays, GE Healthcare), following the manufacturerâs protocol. Results: differential expression of almost 1,400 genes was detected during the course of epileptogenesis, from the early events post status epilepticus (SE) to the onset of recurrent spontaneous seizures. Most of these genes are novel and displayed an up-regulation after SE. Noteworthy, a group of 128 genes functioning in neurogenesis, apoptosis, immune response, and intracellular signal transduction was found consistently hyper-expressed throughout epileptogenesis, indicating stable molecular alterations within the hippocampus. Those include modulation of the MAPK, Jak-STAT, PI3K, TGF-beta, and mTOR signaling pathways. Differential expression of genes from the p38 MAPK pathway, mediating inflammation and neurogenesis, was also confirmed by real-time PCR. These findings reveal dynamic molecular changes occurring in the hippocampus that may serve as a starting point for the generation of new hypothesis regarding the underlying mechanisms of epilepsy and for the designing of alternative therapeutic strategies. Keywords: gene expression changes during epileptogenesis. We performed a genome wide analysis of genes differentially expressed during epileptogenesis. Virtually, all possible changes in the rat transcriptome were monitored at distinct time points corresponding to the latent to chronic phase transition of the pilocarpine model of epilepsy, which is probably the most extensively studied chemically inductive model of TLE. Genes identified as being differentially expressed were classified based on their respective biological functions to envisage processes and pathways likely implicated in epileptogenesis, as well as their possible value as targets for therapy. Results were expressed as fold variation, and genes displaying greater than 2-fold changes in transcript abundance and p<0.01 were selected.
2010-02-09 | E-GEOD-14763 | biostudies-arrayexpress