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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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Journal ArticleDOI
TL;DR: The ionic currents that underlie the mechanisms of epileptogenesis have been systematically characterised in different experimental preparations and better understanding of the role of these epileptogenic mechanisms will promote new advances in the development of selective and targeted antiepileptic drugs.
Abstract: Summary The ionic currents that underlie the mechanisms of epileptogenesis have been systematically characterised in different experimental preparations. The recent elucidation of the molecular structures of most membrane channels and receptors has enabled structure–function analyses in both physiological and pathophysiological conditions. The neurophysiological and biomolecular features of epileptogenic mechanisms that putatively account for human epilepsies are summarised in this review. Particular emphasis is given to epilepsies that are associated with genetically determined alterations of ligand-gated and voltage-gated ion channels. Changes in ionic currents that flow through sodium, potassium, and calcium channels can lead to different types of epilepsies. Inherited or acquired changes that alter the function of receptors for acetylcholine, glutamate, and γ-aminobutryic acid are also involved. A better understanding of the role of these epileptogenic mechanisms will promote new advances in the development of selective and targeted antiepileptic drugs.

118 citations

Journal ArticleDOI
TL;DR: Mitochondrial dysfunction has gained considerable interest as a potential cause of epileptic seizures and therapy-resistant forms of severe epilepsy because mitochondria are intimately involved in pathways leading to the neuronal cell death characteristic for the areas of epileptogenesis.
Abstract: Mitochondrial dysfunction has gained considerable interest as a potential cause of epileptic seizures and therapy-resistant forms of severe epilepsy. Impairment of mitochondrial function has recently been observed in the seizure focus of human and experimental epilepsy. Additionally, a broad variety of mutation of mitochondrial DNA leading to the inhibition of mitochondrial respiratory chain or directly of mitochondrial adenosine triphosphate synthesis in epileptogenic areas of the human brain has been associated with epileptic phenotypes. Since mitochondrial oxidative phosphorylation provides the major source of adenosine triphosphate in neurons, and mitochondria participate in cellular Ca2+ homeostasis they can modulate neuronal excitability and synaptic transmission. Furthermore, mitochondria are intimately involved in pathways leading to the neuronal cell death characteristic for the areas of epileptogenesis.

118 citations

Journal ArticleDOI
TL;DR: Evidence is provided that ectopically overexpressed galanin can be released and dampen the development of epilepsy by means of receptor-mediated action, at least partly by reducing glutamate release from mossy fibers.
Abstract: The neuropeptide galanin has been shown to suppress epileptic seizures. In cortical and hippocampal areas, galanin is normally mainly expressed in noradrenergic afferents. We have generated a mouse overexpressing galanin in neurons under the platelet-derived growth factor B promoter. RIA and HPLC analysis revealed up to 8-fold higher levels of galanin in transgenic as compared with wild-type mice. Ectopic galanin overexpression was detected especially in dentate granule cells and hippocampal and cortical pyramidal neurons. Galanin-overexpressing mice showed retardation of seizure generalization during hippocampal kindling, a model for human complex partial epilepsy. The high levels of galanin in mossy fibers found in the transgenic mice were further increased after seizures. Frequency facilitation of field excitatory postsynaptic potentials, a form of short-term synaptic plasticity assessed in hippocampal slices, was reduced in mossy fiber-CA3 cell synapses of galanin-overexpressing mice, indicating suppressed glutamate release. This effect was reversed by application of the putative galanin receptor antagonist M35. These data provide evidence that ectopically overexpressed galanin can be released and dampen the development of epilepsy by means of receptor-mediated action, at least partly by reducing glutamate release from mossy fibers.

117 citations

Journal ArticleDOI
Peter B. Crino1
TL;DR: Although it is widely believed that structural alterations induced by hyperactivated mTOR signaling are critical for epileptogenesis, newer evidence suggests that mTOR activation on its own may enhance neuronal excitability.
Abstract: Over the past decade enhanced activation of the mammalian target of rapamycin (mTOR)-signaling cascade has been identified in focal malformations of cortical development (MCD) subtypes, which have been collectively referred to as "mTORopathies." Mutations in mTOR regulatory genes (e.g., TSC1, TSC2, AKT3, DEPDC5) have been associated with several focal MCD highly associated with epilepsy such as tuberous sclerosis complex (TSC), hemimegalencephaly (HME; brain malformation associated with dramatic enlargement of one brain hemisphere), and cortical dysplasia. mTOR plays important roles in the regulation of cell division, growth, and survival, and, thus, aberrant activation of the cascade during cortical development can cause dramatic alterations in cell size, cortical lamination, and axon and dendrite outgrowth often observed in focal MCD. Although it is widely believed that structural alterations induced by hyperactivated mTOR signaling are critical for epileptogenesis, newer evidence suggests that mTOR activation on its own may enhance neuronal excitability. Clinical trials with mTOR inhibitors have shown efficacy in the treatment of seizures associated with focal MCD.

117 citations

Journal ArticleDOI
TL;DR: A mechanism for Gower's dictum that "seizures beget seizures" is suggested and the importance of the interneurons of the dentate gyrus in epileptogenesis is highlighted.
Abstract: Recent evidence suggests that hippocampal damage can be both the result of seizure activity and the cause of further chronic epilepsy. A review of current models of status epilepticus-induced brain damage reveals that excitotoxic mechanisms probably mediate the lesions in most brain regions. NMDA receptors appear to play a dominant role, although non-NMDA glutamate receptors are important in several specific neuronal populations. In the immature brain, a number of unique metabolic features determine a different set of vulnerabilities, resulting in a brain which is more resistant than the adult's to certain mechanisms of brain damage, but quite vulnerable to others. The inhibition of growth by severe seizure activity has implications for the developing brain that have not yet been fully explored. The mechanisms by which seizure-induced hippocampal lesions cause chronic epilepsy have been explored in several recent animal models. A rearrangement of hippocampal circuits may result from death of selected populations of inhibitory neurons, or from misdirected regeneration by excitatory neurons. It could lead to chronic epilepsy through loss of normal inhibition, through sprouting of new excitatory connections, through conservation of excitatory connections which in a healthy brain would be pruned during development, or through facilitation of kindling by one of these mechanisms. These recent results are beginning to reconcile the pathology seen in human hippocampi ablated for intractable epilepsy with that observed in experimental animals, and offer the promise of even greater advances in the future. They suggest a mechanism for Gower's dictum that "seizures beget seizures" and highlight the importance of the interneurons of the dentate gyrus in epileptogenesis.

117 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
2023181
2022348
2021245
2020219
2019210
2018209