We searched all PubMed articles published up to September, 2010, with terms “epileptogenesis” and “antiepileptogenesis”. For transcriptomics in epileptogenesis, we did searches using the following terms: “microarrays and epileptogenesis”, “transcriptome and epileptogenesis”, “microarrays and traumatic brain injury”, and “transcriptome and traumatic brain injury”. Articles describing alterations in gene expression at timepoints longer than 4 days post-insult were selected. For epigenetics,
ReviewMechanisms of epileptogenesis and potential treatment targets
Introduction
Epilepsy is one of the world's oldest recognised disorders, first described by Hippocrates in the 5th century BC.1 At present, around 50 million people worldwide have active epilepsy with continuing seizures that need treatment, and 30% of patients are drug refractory.2 Nearly 90% of epilepsy cases are in low-income countries, and in India, for example, the total cost for an estimated 5 million cases of epilepsy has been shown to be equivalent to 0·5% of the gross national product.2 Europe has been estimated to have 6 million patients with active epilepsy, and the annual European health costs associated with epilepsy are over €20 billion.3 In addition to the cost, the social burden associated with the disease and the two-to-three-times increased risk of death mean that there is an urgent need to find ways to prevent the disease in individuals at risk.
Currently, the most efficient ways to prevent epileptogenesis are genetic counselling or prevention of primary epileptogenic injury, for example, by wearing a helmet while riding a bike. In 2011, the prevention of epilepsy in patients at risk after acquired injury remains an unmet medical need worldwide. However, there have been recent developments in the modelling of epileptogenesis after genetic or acquired conditions in mice and rats, which increase the clinical relevance of these models. By use of these animal models, large-scale molecular profiling studies have provided clues to the mechanisms that can contribute to formation of seizure-generating (ictogenic) neuronal circuits. Finally, several laboratories have made attempts to target these mechanisms in clinically relevant experimental study designs, and some of these have shown favourable antiepileptogenic effects. We review and discuss these studies to identify unsolved problems needing attention before the current proof-of-principle studies are taken to preclinical antiepileptogenesis trials or even to the clinic.
Section snippets
Definitions
The term epileptogenesis is most often associated with the development of symptomatic (acquired) epilepsy that presents with an identifiable structural lesion in the brain.4 Some studies suggest that epileptogenesis also occurs in genetic epilepsies, in which it is regulated, for example, by developmental programming of gene expression leading to abnormal circuitry during maturation.5
Currently, the terms epileptogenesis or latency period are used synonymously as operational terms to refer to a
Identification of molecular mechanisms
If we consider epileptogenesis to be the result of circuitry reorganisation that can occur either at the synaptic or network level, a critical question is: what molecular pathways are involved in epileptogenic plasticity and how can we identify them? Because they are likely to be multiple and diverse, what reasoning should be used to select the candidate mechanism to be tested in vivo in proof-of-principle experiments?
AEDs as antiepileptogenic treatments
The first antiepileptogenesis trial in human beings was done more than 60 years ago.95 It attempted to prevent epileptogenesis after TBI using phenytoin. Several other AEDs, including phenobarbital, carbamazepine, and valproate in monotherapy or polytherapy, as well as non-AEDs such as magnesium sulphate and glucocorticoids, have been tested since then. These studies have failed to provide evidence that the use of AEDs (or other compounds) during epileptogenesis would have favourable
Proconvulsants
Many preclinical and clinical studies have shown that drugs designed to prevent epileptic seizures and suppress neuronal activity (ie, AEDs) do not prevent acquired epileptogenesis.96, 98 Recent data have provided surprising evidence that the administration of the proconvulsant drugs atipamezole or rimonabant could have favourable effects on antiepileptogenesis after epileptogenic brain insults, including SE and TBI.56, 57
We induced SE with electrical stimulation of the amygdala and 1 week
Differences across conditions and patients
As mentioned earlier, there are some similarly regulated genes in different conditions (eg, SE and TBI) during epileptogenesis. However, even considering the bias related to the use of different array platforms or other methodological issues, most analyses of epileptogenesis in rodents suggest differences in the pattern of molecular changes as well as in the time course and severity of the cellular alterations between conditions, such as electrically or chemically induced SE or TBI.102 Even the
Conclusions
The molecular and cellular data on processes that underlie epileptogenesis suggest a wide spectrum of treatment targets. Therefore, is it even realistic to believe that the modulation of one target pathway would be antiepileptogenic, unless treating specific syndromes such as tuberous sclerosis? Should we focus on target selectivity versus pathophysiological process selectivity in multifactorial disorders like post-SE or post-TBI epileptogenesis? Do “omics” provide a category of biological
Search strategy and selection criteria
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