Topic
Epileptogenesis
About: Epileptogenesis is a research topic. Over the lifetime, 4218 publications have been published within this topic receiving 170809 citations.
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TL;DR: Damage to the cortex ipsilateral to the injury was more severe and extended more caudally in epileptic animals than in those without epilepsy, and the extent and location of cortical damage and its association with a lowered seizure threshold and the occurrence of spontaneous seizures were investigated.
74 citations
TL;DR: The aim was to explore if glia activation during epileptogenesis, or in the chronic epileptic phase, can be used as a biomarker of tissue epileptogenicity (i.e., a measure of epilepsy severity) and to measure metabolite content in the rat hippocampus.
Abstract: Summary
Purpose: Long-lasting activation of glia occurs in brain during epileptogenesis, which develops after various central nervous system (CNS) injuries Glia is the cell source of the biosynthesis and release of molecules that play a role in seizure recurrence and may contribute to epileptogenesis, thus representing a putative biomarker of epilepsy development and severity In this study, we set up an in vivo longitudinal study using 1H-magnetic resonance spectroscopy (MRS) to measure metabolite content in the rat hippocampus that could reflect the extent and the duration of glia activation Our aim was to explore if glia activation during epileptogenesis, or in the chronic epileptic phase, can be used as a biomarker of tissue epileptogenicity (ie, a measure of epilepsy severity)
Methods: 1H-MRS measurements were done in the adult rat hippocampus every 24 h for 7 days after status epilepticus (SE) and in chronic epileptic rats, using a 7 T Bruker Biospec MRI (magnetic resonance imaging)/MRS scanner We studied changes in metabolite levels that reflect astrocytes (myo-inositol, mIns; glutathione, GSH), microglia/macrophage activation and the associated neuronal cell injury/dysfunction (lactate, Lac; N-acetyl-aspartate, NAA) 1H-MRS results were validated by post hoc immunohistochemistry using cell-specific markers Data analysis was done to determine whether correlations exist between the metabolite changes and spontaneous seizure frequency or the extent of neuronal cell loss
Key Findings: The analysis of 1H-MRS spectra showed a progressive increase in mIns and GSH levels after SE, which was maintained in epileptic rats Lac signal transiently increased during epileptogenesis being undetectable in chronic epileptic tissue NAA levels were chronically reduced from day 2 post-SE Immunohistochemistry confirmed the activation of microglia and astrocytes and the progressive neuronal cell loss GSH levels during epileptogenesis showed a negative correlation with the frequency of spontaneous seizures, whereas S100β levels in epileptic tissue were positively correlated with this outcome measure A negative correlation was also found between GSH or mIns levels during epileptogenesis and the extent of neurodegeneration in hippocampus of epileptic rats
Significance: 1H-MRS is a valuable in vivo technique for determining the extent and temporal profile of glia activation after an epileptogenic injury S100β levels measured in the epileptic tissue may represent a biomarker of seizure frequency, whereas GSH levels during epileptogenesis could serve as a predictive marker of seizure frequency Both mIns and GSH levels measured before the onset of spontaneous seizures predict the extent of neuronal cell loss in epileptic tissue These findings highlight the potential of serial 1H-MRS analysis for searching epilepsy biomarkers for prognostic, diagnostic, or therapeutic purposes
74 citations
TL;DR: These experimental data show that early intervention of SE has an effect on long-term functional outcome, and emphasise the need to use additional outcome measures, such as markers of normal development or cognitive performance, when the benefits of neuroprotection achieved by the use of neuroprotective AEDs are assessed.
Abstract: Antiepileptic drugs (AEDs) are designed to prevent and suppress seizure activity. Their effects on calcium influx and molecular cascades contributing to necrotic and apoptotic neuronal death, however, suggests that they have functions other than just suppression of excitability. The neuroprotective effects of 20 AEDs currently in use or being investigated in Phase II - III clinical trials for treatment of epilepsy are reviewed. Data analyses is complicated by several factors. Firstly, the available data on the neuroprotective effects of different AEDs varies largely. Secondly, most of the evidence demonstrating neuroprotective effects comes from stroke models and it is uncertain whether these data can be extrapolated to other conditions, such as status epilepticus (SE) or traumatic brain injury. Thirdly, data obtained in adult animals cannot be extrapolated to young animals without caution. For example, AEDs protecting adult brain from stroke or SE-induced injury can cause apoptosis in immature brain. Finally, data comparison is complicated by the variability in study designs and methodologies between studies. With these caveats in mind, an analysis of the available data suggests that AEDs with different mechanisms of action can have mild-to-moderate neuroprotective effects. It is difficult, however, to associate the neuroprotective effects with a favourable functional outcome. For example, it is difficult to conclude that administration of AEDs during the latency phase would have an effect on the molecular cascades underlying epileptogenesis. The few favourable data demonstrating a decrease in the incidence of epilepsy after SE are probably related to the administration of AEDs during SE, which resulted in modification/alleviation of the insult itself and consequently, reduced its epileptogenecity. These experimental data, however, are clinically important because they show that early intervention of SE has an effect on long-term functional outcome. These observations emphasise the need to use additional outcome measures, such as markers of normal development or cognitive performance, when the benefits of neuroprotection achieved by the use of neuroprotective AEDs are assessed.
74 citations
TL;DR: The critical role of brain-resident immune mediators is highlighted and the proposed possible immune mechanisms that underlie epileptogenesis are proposed, including the interleukin-1 receptor/toll-like receptor signaling cascade, the pathways activated by damage-associated molecular patterns, and the cyclooxygenase-2/prostaglandin pathway.
Abstract: Epilepsy is a chronic brain disorder that affects one percent of the human population worldwide. Immune responses are implicated in seizure induction and the development of epilepsy. Pre-clinical and clinical evidence have accumulated to suggest a positive feedback cycle between brain inflammation and epileptogenesis. Prolonged or recurrent seizures and brain injuries lead to upregulation of proinflammatory cytokines and activated immune responses to further increase seizure susceptibility, promote neuronal excitability, and induce blood-brain barrier (BBB) breakdown. This review focuses on the potential role of innate and adaptive immune responses in the pathogenesis of epilepsy. Both human studies and animal models that help delineate the contributions of brain inflammation in epileptogenesis will be discussed. We highlight the critical role of brain-resident immune mediators and emphasize the contribution of brain-infiltrating peripheral leukocytes. Additionally, we propose possible immune mechanisms that underlie epileptogenesis. Several proinflammatory pathways are discussed, including the interleukin-1 receptor/ toll-like receptor signaling cascade, the pathways activated by danger-associated molecular patterns, and the cyclooxygenase-2 / prostaglandin pathway. Finally, development of better therapies that target the key constituents and processes identified in these mechanisms are considered, for instance, engineering antagonizing agents that effectively block these pathways in an antigen-specific manner.
74 citations
TL;DR: This article describes the recent advances in epileptogenesis and novel therapeutic approaches for the prevention of epilepsy, with a special emphasis on the pharmacological basis of disease-modification of epilepsyptogenesis for curing epilepsy.
74 citations