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We used the method of rapid hippocampal kindling to assess the potential antiepileptogenic efficacy of a number of anticonvulsant medications. This method afforded a higher throughput than methods based on traditional kindling or post–status epilepticus models of epileptogenesis. This “compressed epileptogenesis” model also permitted the study of age‐dependent pharmacologic targets, and distinguished...
Neurotrophic factors are involved in the survival of neurons as well as in the proliferation and differentiation of neuronal precursors. Therefore, modulating their levels in lesion areas may exert favorable effects on seizure‐induced damage. However, it is unclear if damage limitation or repair may prevent epileptogenesis; it is also uncertain which neurotrophic factor should be administered for...
One of the major challenges in developing novel therapeutics for human epileptic disorders comes from the wide range of brain abnormalities capable of producing epilepsy. In children and adults that undergo epilepsy surgery for treatment of refractory seizures, these abnormalities range from developmental defects to injuries, infections, tumors, and ischemia. Given the many molecular mechanisms likely...
Neurosteroids such as allopregnanolone (THP) act as positive allosteric modulators of γ‐aminobutyric acid (GABA)A receptors and have exerted anticonvulsant properties. However, their role in the regulation of epileptogenesis is unclear. It has been shown that circulating levels of THP fluctuate during development and seizure episodes. Furthermore, both chronic administration of THP and its withdrawal...
Brain derived neurotrophic factor (BDNF) regulates diverse neuronal functions and plasticity, and its expression is increased by seizures. Here we review the evidence that actions of BDNF at TrkB receptors contribute to temporal lobe epilepsy. In addition, regulation of BDNF by steroid hormones might explain syndromes such as catamenial epilepsy. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition...
Epilepsy often results from a brain insult. Herein, I describe the complex time‐dependent alterations in glutamatergic and γ‐aminobutyric acid (GABA)ergic circuitry triggered by the initial insult. I will relate these modifications to the occurrence of the first spontaneous seizure, the development of epileptogenic networks, and associated cognitive deficits. For an expanded treatment of this topic...
Posttraumatic epilepsy (PTE) is defined as a recurrent seizure disorder due to injury to the brain following head trauma. Traumatic brain injury (TBI) accounts for 20% of symptomatic epilepsy in the general population and 5% of all epilepsy. Prevention or suppression of the development of PTE is a major unmet challenge in medicine. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition...
Neonatal hypoxic/ischemic encephalopathy is the most common cause of neonatal seizures, and these seizures are refractory to conventional antiseizure drugs and can lead to later life epilepsy and congitive deficits. Data from human tissue studies as well as rodent models suggest unique age‐specific mechanisms underlying these neonatal seizure and their consequences, and are leading to a number of...
Aberrant sprouting of granule cell axons is a common feature in temporal lobe epilepsy. An increasingly detailed picture of granule cell circuit changes has emerged, but the cause–effect relationship between mossy fiber sprouting and epileptogenesis remains unclear. Recent progress in suppressing mossy fiber sprouting might help address its functional consequences. For an expanded treatment of this...
Myoclonin1/EFHC1 mutations cause 9% of juvenile myoclonic epilepsy (JME) by impairing apoptosis in neurons/synapses where R type voltage dependent calcium channel function is altered, imbuing susceptibility to myoclonic and grand mal seizures. By disrupting mitotic spindle assembly and radial migration of neuroblasts, mutations could produce abnormal intracortical architecture upon which epileptogenesis...
Although multiple genes drive epileptogenesis, uncovering the mechanisms controlling expression of GABAA receptors (GABAARs), the brain’s major inhibitory receptors, may have far‐reaching therapeutic implications. In this review, we describe how seizure‐induced changes in GABAARs result from brain‐derived neurotrophic factor (BDNF)‐induced changes in Janus kinase/Signal Transducer and Activators of...
Hyperpolarization‐activated, cyclic nucleotide‐gated (HCN) channels are voltage‐gated ion channels that influence neuronal excitability in brain regions implicated in both focal and generalized epilepsies. Dysregulation of HCN channel function occurs in many animal models of epilepsy; understanding HCN channel regulation may lead to novel therapies for the prevention and treatment of human epilepsy...
In 1969, H.H. Jasper, A.A. Ward, and A. Pope and the Public Health Service Advisory Committee on the Epilepsies of the National Institutes of Health (NIH) published the first edition on Basic Mechanisms of the Epilepsies (BME). Since then, basic and clinical researchers in epilepsy have gathered together each decade to assess where epilepsy research has been, what it has accomplished, and where it...
Voltage‐gated Na+ (NaV) channels are key mediators of neuronal function and essential for neuronal excitability. Their abnormal activity is implicated in the generation of seizures, both in acquired and genetic epilepsy. Several of the most widely used antiepileptic drugs inhibit NaV activity by binding to a common receptor site. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition...
Most current treatments for epilepsy are symptomatic therapies that suppress seizures but do not affect the underlying course or prognosis of epilepsy. The need for disease‐modifying or “antiepileptogenic” treatments for epilepsy is widely recognized, but no such preventive therapies have yet been established for clinical use. A rational strategy for preventing epilepsy is to target primary signaling...
Purpose: Chronic epilepsy frequently develops after brain injury, but prediction of which individual patient will develop spontaneous recurrent seizures (i.e., epilepsy) is not currently possible. Here, we use continuous radiotelemetric electroencephalography (EEG) and video monitoring along with automated computer detection of EEG spikes and seizures to test the hypothesis that EEG spikes precede...
Purpose: Epilepsy is a heterogeneous syndrome characterized by recurrent, spontaneous seizures; continuous medication is, therefore, necessary, even after the seizures have long been suppressed with antiepileptic drug (AED) treatments. The most disturbing issue is the inability of AEDs to provide a persistent cure, because these compounds generally suppress the occurrence of epileptic seizures without...
We have previously shown that selective activation of group I metabotropic glutamate receptors (mGluRs) results in long‐lasting enhancement of synchronized network activity in the hippocampal slice. Data herein suggest that activation of group I mGluRs need not result in this potentially epileptogenic effect. (1S,3R)‐1‐Aminocyclopentane‐1,3‐dicarboxylic acid (ACPD), a nonselective mGluR agonist, elicits...
Purpose: Despite intensive studies, our understanding of the cellular and molecular mechanisms underlying epileptogenesis remains largely unsatisfactory. Our defective knowledge derives in part from the lack of adequate experimental models of the distinct phases that characterize the epileptic event, that is, initiation, propagation, and cessation. The aim of our study is the development of a new...
Purpose: Hippocampal sclerosis, characterized by prominent neuronal loss and reactive gliosis, is the most common pathology in human temporal lobe epilepsy (TLE). Although prolonged febrile convulsion (FC) is a risk factor of TLE, it is not clear whether FC provokes hippocampal sclerosis and subsequent TLE. Given that underlying brain lesions, such as cortical dysplasia (CD), in the immature brain...
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