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1.
The sequelae of traumatic brain injury, including posttraumatic epilepsy, represent a major societal problem. Significant resources are required to develop a better understanding of the underlying pathophysiologic mechanisms as targets for potential prophylactic therapies. Posttraumatic epilepsy undoubtedly involves numerous pathogenic factors that develop more or less in parallel. We have highlighted two potential "prime movers": disinhibition and development of new functional excitatory connectivity, which occur in a number of animal models and some forms of epilepsy in humans. Previous experiments have shown that tetrodotoxin (TTX) applied to injured cortex during a critical period early after lesion placement can prevent epileptogenesis in the partial cortical ("undercut") model of posttraumatic epilepsy. Here we show that such treatment markedly attenuates histologic indices of axonal and terminal sprouting and presumably associated aberrant excitatory connectivity. A second finding in the undercut model is a decrease in spontaneous inhibitory events. Current experiments show that this is accompanied by regressive alterations in fast-spiking γ-aminobutyric acid (GABA)ergic interneurons, including shrinkage of dendrites, marked decreases in axonal length, structural changes in inhibitory boutons, and loss of inhibitory synapses on pyramidal cells. Other data support the hypothesis that these anatomic abnormalities may result from loss of trophic support normally provided to interneurons by brain-derived neurotrophic factor (BDNF).
Approaches that prevent these two pathophysiologic mechanisms may offer avenues for prophylaxis for posttraumatic epilepsy. However, major issues such as the role of these processes in functional recovery from injury and the timing of the critical period(s) for application of potential therapies in humans need to be resolved.  相似文献   

2.
Postlesional Epilepsy: The Ultimate Brain Plasticity   总被引:11,自引:1,他引:10  
Summary: Lesions that occur either during fetal development or after postnatal brain trauma often result in seizures that are difficult to treat. We used two animal models to examine epileptogenic mechanisms associated with lesions that occur either during cortical development or in young adults. Results from these experiments suggest that there are three general ways that injury may induce hyperexcitability. Direct injury to cortical pyramidal neurons causes changes in membrane ion channels that make these cells more responsive to excitatory inputs, including increases in input resistance and a reduction in calcium-activated potassium conductances that regulate the rate of action potential discharge. The connectivity of cortical circuits is also altered after injury, as shown by axonal sprouting within pyramidal cell intracortical arbors. Enhanced excitatory connections may increase recurrent excitatory loops within the epileptogenic zone. Hyperinnervation attributable to reorganization of thalamocortical, callosal, and intracortical circuitry, and failure to prune immature connections, may be prominent when lesions affect the developing neocortex. Finally, focal injury can produce widespread changes in γ-aminobutyric acid and glutamate receptors, particularly in the developing brain. All of these factors may contribute to epileptogenesis.  相似文献   

3.
Summary:  Knowledge of the processes by which epilepsy is generated (epileptogenesis) is incomplete and has been a topic of major research efforts. Animal models can inform us about these processes. We focus on the distinguishing features of epileptogenesis in the developing brain and model prolonged febrile seizures (FS) that are associated with human temporal lobe epilepsy. In the animal model of FS, epileptogenesis occurs in ∼35% of rats. Unlike the majority of acquired epileptogeneses in adults, this process early in life (in the febrile seizures model as well as in several others) does not require "damage" (cell death). Rather, epileptogenesis early in life involves molecular mechanisms including seizure-evoked, long-lasting alterations of the expression of receptors and ion channels. Whereas transient changes in gene expression programs are common after early-life seizures, enduring effects, such as found after experimental FS, are associated with epileptogenesis. The ability of FS to generate long-lasting molecular changes and epilepsy suggests that mechanisms, including cytokine activation that are intrinsic to FS generation, may play a role also in the epileptogenic consequences of these seizures.  相似文献   

4.
Wong M 《Epilepsia》2008,49(1):8-21
Malformations of cortical development (MCDs) are increasingly recognized as causes of medically intractable epilepsy. In order to develop more effective, rational therapies for refractory epilepsy related to MCDs, it is important to achieve a better understanding of the underlying mechanisms of epileptogenesis, but this is complicated by the wide variety of different radiographic, histopathological, and molecular features of these disorders. A subset of MCDs share a number of characteristic cellular and molecular abnormalities due to early defects in neuronal and glial proliferation and differentiation and have a particularly high incidence of epilepsy, suggesting that this category of MCDs with abnormal glioneuronal proliferation may also share a common set of primary mechanisms of epileptogenesis. This review critically analyzes both clinical and basic science evidence for overlapping mechanisms of epileptogenesis in this group of disorders, focusing on tuberous sclerosis complex, focal cortical dysplasia with balloon cells, and gangliogliomas. Specifically, the role of lesional versus perilesional regions, circuit versus cellular/molecular defects, and nonneuronal factors, such as astrocytes, in contributing to epileptogenesis in these MCDs is examined. An improved understanding of these various factors involved in epileptogenesis has direct clinical implications for optimizing current treatments or developing novel therapeutic approaches for epilepsy in these disorders.  相似文献   

5.
The last decade has seen a considerable increase in promising new drugs to treat epilepsy, yet the outcome, measured as percentage of patients becoming seizure free, has changed very little. The last decade has also seen a vast increase in the understanding of cellular mechanisms which may contribute to epileptogenesis and the development of pharmacoresistance, yet the mechanisms underlying both phenomena in human epilepsy are poorly understood. Investigations of human epileptogenic tissue from epilepsy surgery must provide clues towards the pivotal mechanisms, considering the plethora of electrophysiological, molecular biological and immunohistochemical tools available. We investigate resected tissue from epilepsy surgery on a regular basis, focussing on aspects likely to contribute to hyperexcitability: 1) alterations in intrinsic properties governing the integration of synaptic signals in dendrites of human neocortical neurones, 2) changes in the composition of individual synaptic potentials which may increase responses at the cellular or network level and 3) processes which contribute to frequency limitations of synaptic responses, failures of which may lead to repetitive synaptic activity. Comparison of tissues from different patients with standardised protocols should reveal whether certain mechanisms are affected in distinct pathological groups or whether some mechanisms are common denominators of epilepsy across the various pathologies. Here we briefly review some of the current projects. The data from 155 resections reveal three key changes: 1) GABAA responses are in some neurones excitatory rather than inhibitory, probably due to impaired chloride transport, 2) GABAB receptor-mediated events are reduced, allowing for higher frequencies of synaptic activity and 3) HCN currents are reduced, which augments the spread of synaptic and intrinsic responses along cortical dendrites. These findings obtained in variable proportions of the neurones are more than sufficient to account for the severity of the pharmacoresistant epilepsy these patients suffered. Each mechanism in isolation cause epilepsy in knockout mice.  相似文献   

6.
Animal seizure models, in vitro preparations of cell cultures and tissue slices, and an unravelling of some of the basic mechanisms underlying epileptogenesis and epilepsy have furthered the understanding of mechanisms of action of antiepileptic drugs at the cellular and subcellular levels. Nevertheless, the mechanism of action of most antiepileptic drugs in clinical use is incompletely understood. Multiple physiologic mechanisms are altered by antiepileptic drugs. Some of these drugs, such as phenytoin and carbamazepine, decrease sustained repetitive firing and post-tetanic potentiation through their blocking effects on the sodium channel. Benzodiazepines and barbiturates enhance GABA-mediated inhibition. Many antiepileptic drugs inhibit calcium influx and calcium-mediated secondary effects at supratherapeutic concentrations. Newer drugs that inhibit excitatory receptors or enhance various forms of inhibition are presently under investigation.  相似文献   

7.
The cellular, molecular, and metabolic mechanisms that underlie the development of mesial temporal lobe epilepsy are incompletely understood. Here we review the role of astrocytes in epilepsy development (a.k.a. epileptogenesis), particularly astrocyte pathologies related to: aquaporin 4, the inwardly rectifying potassium channel Kir4.1, monocarboxylate transporters MCT1 and MCT2, excitatory amino acid transporters EAAT1 and EAAT2, and glutamine synthetase. We propose that inhibition, dysfunction or loss of astrocytic glutamine synthetase is an important causative factor for some epilepsies, particularly mesial temporal lobe epilepsy and glioblastoma-associated epilepsy. We postulate that the regulatory mechanisms of glutamine synthetase as well as the downstream effects of glutamine synthetase dysfunction, represent attractive, new targets for antiepileptogenic interventions. Currently, no antiepileptogenic therapies are available for human use. The discovery of such interventions is important as it will fundamentally change the way we approach epilepsy by preventing the disease from ever becoming manifest after an epileptogenic insult to the brain.  相似文献   

8.
Epilepsy is one of the most common neurological disorders. Although many factors contribute to epileptogenesis, seizure generation is mostly linked to hyperexcitability due to alterations in excitatory/inhibitory (E/I) balance. The common hypothesis is that reduced inhibition, increased excitation, or both contribute to the etiology of epilepsy. Increasing evidence shows that this view is oversimplistic, and that increased inhibition through depolarizing γ-aminobutyric acid (GABA) similarly contributes to epileptogenisis. In early development, GABA signaling is depolarizing, inducing outward Cl currents due to high intracellular Cl concentrations. During maturation, the mechanisms of GABA action shift from depolarizing to hyperpolarizing, a critical event during brain development. Altered timing of this shift is associated with both neurodevelopmental disorders and epilepsy. Here, we consider the different ways that depolarizing GABA contributes to altered E/I balance and epileptogenesis, and discuss that alterations in depolarizing GABA could be a common denominator underlying seizure generation in neurodevelopmental disorders and epilepsies.  相似文献   

9.
Because epilepsy often occurs during development, understanding the mechanisms by which this process takes place (epileptogenesis) is important. In addition, the age-specificity of seizures and epilepsies of the neonatal, infancy, and childhood periods suggests that the processes and mechanisms that culminate in epilepsy might be age specific as well. Here we provide an updated review of recent and existing literature and discuss evidence that neuronal loss may occur during epileptogenesis in the developing brain, but is not required for the epileptogenic process. We speculate about the mechanisms for the resilience of neurons in immature limbic structures to epileptogenic insults, and propose that the type, duration and severity of these insults influence the phenomenology of the resulting spontaneous seizures.  相似文献   

10.
Yuan Y 《Neurotoxicology》2012,33(1):119-126
Epilepsy or seizure disorder is one of the most common neurological diseases in humans. Although genetic mutations in ion channels and receptors and some other risk factors such as brain injury are linked to epileptogenesis, the underlying cause for the majority of epilepsy cases remains unknown. Gene-environment interactions are thought to play a critical role in the etiology of epilepsy. Exposure to environmental chemicals is an important risk factor. Methylmercury (MeHg) is a prominent environmental neurotoxicant, which targets primarily the central nervous system (CNS). Patients or animals with acute or chronic MeHg poisoning often display epileptic seizures or show increased susceptibility to seizures, suggesting that MeHg exposure may be associated with epileptogenesis. This mini-review highlights the effects of MeHg exposure, especially developmental exposure, on the susceptibility of humans and animals to seizures, and discusses the potential role of low level MeHg exposure in epileptogenesis. This review also proposes that a preferential effect of MeHg on the inhibitory GABAergic system, leading to disinhibition of excitatory glutamatergic function, may be one of the potential mechanisms underlying MeHg-induced changes in seizure susceptibility.  相似文献   

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