Therapeutic Interventions For Epilepsy Research Articles

Treatment effects in epilepsy: a mathematical framework for understanding response over time.

Epilepsy is a neurological disorder characterized by recurrent seizures, affecting over 65 million people worldwide. Treatment typically commences with the use of anti-seizure medications, including both mono- and poly-therapy. Should these fail, more invasive therapies such as surgery, electrical stimulation and focal drug delivery are often considered in an attempt to render the person seizure free. Although a significant portion ultimately benefit from these treatment options, treatment responses often fluctuate over time. The physiological mechanisms underlying these temporal variations are poorly understood, making prognosis a significant challenge when treating epilepsy. Here we use a dynamic network model of seizure transition to understand how seizure propensity may vary over time as a consequence of changes in excitability. Through computer simulations, we explore the relationship between the impact of treatment on dynamic network properties and their vulnerability over time that permit a return to states of high seizure propensity. For small networks we show vulnerability can be fully characterised by the size of the first transitive component (FTC). For larger networks, we find measures of network efficiency, incoherence and heterogeneity (degree variance) correlate with robustness of networks to increasing excitability. These results provide a set of potential prognostic markers for therapeutic interventions in epilepsy. Such markers could be used to support the development of personalized treatment strategies, ultimately contributing to understanding of long-term seizure freedom.

The ketogenic diet increases Neuregulin 1 expression via elevating histone acetylation and its anti-seizure effect requires ErbB4 kinase activity

BackgroundThe ketogenic diet (KD)has been considered an effective treatment for epilepsy, whereas its underlying mechanisms remain obscure. We have previously reported that the KD feeding increased Neuregulin 1 (NRG1) expression in the hippocampus; disruption of NRG1 signaling by genetically deleting its receptor-ErbB4 abolished KD’s effects on inhibitory synaptic activity and seizures. However, it is still unclear about the mechanisms underlying the effect of KD on NRG1 expression and whether the effects of KD require ErbB4 kinase activity.MethodsThe effects of the KD on NRG1 expression were assessed via western blotting and real-time PCR. Acetylation level at the Nrg1 promoter locus was examined using the chromatin immunoprecipitation technique. Kainic acid (KA)-induced acute seizure model was utilized to examine the effects of KD and histone deacetylase inhibitor-TSA on seizures. Synaptic activities in the hippocampus were recorded with the technique of electrophysiology. The obligatory role of ErbB4 kinase activity in KD’s effects on seizures and inhibitory synaptic activity was evaluated by using ErbB kinase antagonist and transgenic mouse-T796G.ResultsWe report that KD specifically increases Type I NRG1 expression in the hippocampus. Using the chromatin immunoprecipitation technique, we observe increased acetylated-histone occupancy at the Nrg1 promoter locus of KD-fed mice. Treatment of TSA dramatically elevates NRG1 expression and diminishes the difference between the effects of the control diet (CD) and KD. These data indicate that KD increases NRG1 expression via up-regulating histone acetylation. Moreover, both pharmacological and genetic inhibitions of ErbB4 kinase activity significantly block the KD’s effects on inhibitory synaptic activity and seizure, suggesting an essential role of ErbB4 kinase activity.ConclusionThese results strengthen our understanding of the role of NRG1/ErbB4 signaling in KD and shed light on novel therapeutic interventions for epilepsy.

Insights into Potential Targets for Therapeutic Intervention in Epilepsy.

Epilepsy is a chronic brain disease that affects approximately 65 million people worldwide. However, despite the continuous development of antiepileptic drugs, over 30% patients with epilepsy progress to drug-resistant epilepsy. For this reason, it is a high priority objective in preclinical research to find novel therapeutic targets and to develop effective drugs that prevent or reverse the molecular mechanisms underlying epilepsy progression. Among these potential therapeutic targets, we highlight currently available information involving signaling pathways (Wnt/β-catenin, Mammalian Target of Rapamycin (mTOR) signaling and zinc signaling), enzymes (carbonic anhydrase), proteins (erythropoietin, copine 6 and complement system), channels (Transient Receptor Potential Vanilloid Type 1 (TRPV1) channel) and receptors (galanin and melatonin receptors). All of them have demonstrated a certain degree of efficacy not only in controlling seizures but also in displaying neuroprotective activity and in modifying the progression of epilepsy. Although some research with these specific targets has been done in relation with epilepsy, they have not been fully explored as potential therapeutic targets that could help address the unsolved issue of drug-resistant epilepsy and develop new antiseizure therapies for the treatment of epilepsy.

Evaluation of the ameliorative effects of oral administration of metformin on epileptogenesis in the temporal lobe epilepsy model in rats

AimsUnderstanding the underlying molecular mechanisms involved in epileptogenesis is necessary to target the best therapeutic interventions in epilepsy. Recently, it has been postulated that metformin, an old antidiabetic oral drug, has anti-seizure properties mostly due to its antioxidant activities. This study was designed to evaluate the ameliorative effects of metformin on the progression of epilepsy in the temporal lobe epilepsy model in rats. Main methodsTemporal lobe Epilepsy was induced by intracerebroventricular microinjection of kainic acid. Metformin was orally administered for two weeks before induction of epilepsy. Anti-epileptogenic activity of metformin was evaluated by intracranial electroencepholography (IEEG) recording to detect spontaneous seizures, mossy fiber sprouting by Timm staining, neurogenesis by BrdU staining. Key findingsOral administration of metformin prior to kainite-induced status epilepticus blocked the variant characterizations of epileptogenesis like neuronal cell death, aberrant neurogenesis, mossy fiber sprouting, and spontaneous seizures. SignificanceThese findings indicate that metformin has potential anti-epileptogenic properties in temporal lobe epilepsy.

The novel GLP-1/GIP dual receptor agonist DA3-CH is neuroprotective in the pilocarpine-induced epileptogenesis rat model

AimsGlia-mediated neuro-inflammation and oxidative stress-induced neuronal apoptosis can contribute to epileptogenesis. We have demonstrated previously that mimetics of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and dual-GLP-1/GIP receptor agonists protect the brain from inflammation, oxidative stress, apoptosis and neuronal loss in animal models of central nervous system diseases. MethodsThis study investigated for the first time whether the novel dual GLP-1/GIP receptor agonist DA3-CH has neuroprotective effects in the pilocarpine-induced status epilepticus (SE) rat model and the studies the underlying mechanisms. DA3-CH was administered once daily at 10 nmol/kg ip. following SE induction. The effect of DA3-CH was evaluated by immunohistochemistry and western blot at 12 h, 1 d, 3 d, 7 d after kindling. ResultsOur findings show that DA3-CH reduced the chronic inflammation response (astrogliosis and microgliosis), and the associated release of the pro-inflammatory cytokines interleukin-1β (IL-β) and tumor necrosis factor-α (TNF-α) in the hippocampal CA1 area. Furthermore, DA3-CH reduced the expression of the mitochondrial pro-apoptotic protein Bax, while increasing the expression of the anti-apoptotic protein Bcl-2. Neuronal numbers in the CA1 area were much reduced by pilocarpine treatment, and DA3-CH protected neurons from neurotoxicity. ConclusionThese results demonstrated that DA3-CH could mitigate pilocarpine-induced neuro-inflammation, mitochondrial apoptosis and neuronal loss. The findings encourage the development of dual agonists as novel therapeutic interventions for epilepsy.

Role of JNK isoforms in the kainic acid experimental model of epilepsy and neurodegeneration.

Chemoconvulsants that induce status epilepticus in rodents have been widely used over the past decades due to their capacity to reproduce with high similarity neuropathological and electroencephalographic features observed in patients with temporal lobe epilepsy (TLE). Kainic acid is one of the most used chemoconvulsants in experimental models. KA administration mainly induces neuronal loss in the hippocampus. We focused the present review inthe c-Jun N-terminal kinase-signaling pathway (JNK), since it has been shown to play a key role in the process of neuronal death following KA activation. Among the three isoforms of JNK (JNK1, JNK2, JNK3), JNK3 is widely localized in the majority of areas of the hippocampus, whereas JNK1 levels are located exclusively in the CA3 and CA4 areas and in dentate gyrus. Disruption of the gene encoding JNK3 in mice renders neuroprotection to KA, since these animals showed a reduction in seizure activity and a diminution in hippocampal neuronal apoptosis. In light of this, JNK3 could be a promising subcellular target for future therapeutic interventions in epilepsy.

An Update on Promising Diagnostic and Therapeutic Interventions in Epilepsy

There have been many developments in the management of patients with epilepsy ranging from diagnostic modalities to pharmacological and non-pharmacological interventions. This review discusses several advances which the authors believe will have a significant impact on how such patients will be managed in the coming years. Electroencephalography [EEG] remains the main diagnostic tool in the evaluation of patients with seizure disorders. The novel discovery of high frequency EEG oscillations introduces new concepts of epileptogenicity. Also, techniques that couple EEG with imaging data will be discussed. The early intervention to abort seizures using a method that is easily administered by paramedic staff in the field has been shown to result in more rapid seizure cessation we elaborate on the pre-hospital management. Epilepsy surgery which has revolutionized the treatment of medically refractory patients is invasive and often resective in nature. We discuss the emerging science of neurostimulation as an alternative and potentially similarly efficacious technique.

Seizure severity and duration in the cortical stimulation model of experimental epilepsy in rats: A longitudinal study

The aim of this study was to determine the current intensities necessary to elicit three levels of varying EEG and behavioural phenomena with electrical stimulation, and also to determine the consistency of the EEG and behavioural components of the triggered seizures over time. Electrical stimulation of the primary motor/somatosensory cortex was performed in 16 adult rats with multichannel microwire electrode arrays. Stimulation was delivered at a frequency of 60 Hz (1 ms pulse width), for 2 s duration, as biphasic rectangular pulses over four of the eight available electrode pairs. Current intensity thresholds for interruption of normal behaviour, epileptiform afterdischarge (EAD) longer than 5 s and motor seizures with Racine severity greater than 3 were not correlated to time post-surgery. The Racine threshold was shown to be negatively correlated to the EAD duration and Racine severity of seizures elicited in the following sessions. Seizures were reliably generated in rats through cortical stimulation with microwire electrode arrays and these seizures were not shown to be subject to any kindling type effects up to 53 days post-implantation. Both the electrographic duration and behavioural severity of stimulated seizures remained, on average, constant during this experimental period. Approximately one-third of stimulations did not cause observable motor seizures and of those that did result in seizures, forelimb clonus was the most common manifestation and the mean EAD duration was 18.5 s. No damage beyond that caused by surgical implantation of electrodes was observed in the histological analyses of stimulated and non-stimulated tissue. The consistency, duration and severity of seizures within this timeframe make this cortical stimulation model suitable for investigations into novel therapeutic interventions for epilepsy that require a known seizure focus.

Association study of idiopathic primary generalized epilepsy (IGE)

s 429 with a 25year history of anticonvulsant drug-resistant complex partial seizures. Computer analysis of captured images revealed over 100 differentially regulated genes, some involved in neurotransmitter release, plasticity and signalling mechanisms. Other candidate genes were novel. Secondary validation with selected candidate clones re-gridded was undertaken by hybridizing newly constructed probes derived from further RNA samples from the same epileptic patient and control. This technology is an effective approach to analysing gene expression changes and may yield new targets from therapeutic intervention in epilepsy. Association study of idiopathic primary generalized epilepsy (IGE) A. Makoff*+, B. Chioza’i, N. Currant, F! Ashersod & L. Nashefsl *Department of Psychological Medicine, institute of Psychiatry, London, UK; t Department of Neuroscience, institute of Psychiatry, London, UK; $ Social Genetic & Developmental Psychiatry Research Centre, Institute of Psychiatry, London, UK; 5 Kent and Canterbury Hospital, Canterbury IKings College Hospital, London, UK Twin studies have demonstrated concordance rates of up to 95% for idiopathic generalized epilepsy (IGE) in monozygotic twin pairs. There are a few rare mendelian forms of IGE, but most show a complex pattern of inheritance. The relative risk for IGE among first-degree relatives is in the range 5-10 suggesting that association studies will be required to detect the expected small gene effects. We have collected an initial sample of 100 probands with IGE and 100 ethnically matched controls. Our initial studies have focused on the metabotropic glutamate receptor type 7 (mGluR7) and the (r4 nicotinic acetylcholine receptor subunit (nAchRo4). Mouse knockouts of mGluR7 result in an epileptic phenotype. Studies of a biallelic polymorphisms in mGluR7 are in progress. Mutations within nAchRo4 have been shown to cause the rare dendelian epilepsy autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). An association study with a mixture of different IGE syndromes provides some evidence for association to nAchrcr4. The gene for nAchRo4 lies only 50 Kb from a voltage-sensitive potassium channel gene (KCNQ2) in which mutations cause one type of another mendelian epilepsy, benign familial neonatal convulsions (BFNC). We are currently utilizing polymorphisms in the nAchRa4 gene and KCNQ2 in our sample. Functional and structural findings in epilepsy demonstrated with diffusion weighted imaging U.C. Wieshamnn, MR. Symms & S.D. Shorvon Epilepsy Research Group, institute of Neurology, Queen Square, London, UK Diffusion weighted imaging (DWI) is a magnetic resonance imaging technique which is sensitive to molecular motion of water. Transient or permanent changes of the microstructural organization of tissue, for example, widening or shrinkage of the extracellular space cause diffusion changes which can be detected by DWI. We used DWI to investigate patients with epilepsy. In a patient with focal status we detected transient diffusion changes which were likely to reflect neuronal dysfunction. During the interictal stage we found an increased diffusion in structural lesions associated with epilepsy. These included hippocampal sclerosis, tumours and most forms of brain damage. These changes were associated with a reduced anisotropy of water diffusion which is likely to reflect a breakdown of the structural organization. A reduction of anisotropy was the predominant finding in cortical dysgenesis. In conclusion, DWI can show changes of water diffusion in focal status epilepticus. In addition, DWI provides information about the microstructure in lesions which may help to understand the pathophysiology of seizures.

Sudden unexpected death in ‘epilepsy’—a missed opportunity to diagnose a long QT syndrome

s 429 with a 25year history of anticonvulsant drug-resistant complex partial seizures. Computer analysis of captured images revealed over 100 differentially regulated genes, some involved in neurotransmitter release, plasticity and signalling mechanisms. Other candidate genes were novel. Secondary validation with selected candidate clones re-gridded was undertaken by hybridizing newly constructed probes derived from further RNA samples from the same epileptic patient and control. This technology is an effective approach to analysing gene expression changes and may yield new targets from therapeutic intervention in epilepsy. Association study of idiopathic primary generalized epilepsy (IGE) A. Makoff*+, B. Chioza’i, N. Currant, F! Ashersod & L. Nashefsl *Department of Psychological Medicine, institute of Psychiatry, London, UK; t Department of Neuroscience, institute of Psychiatry, London, UK; $ Social Genetic & Developmental Psychiatry Research Centre, Institute of Psychiatry, London, UK; 5 Kent and Canterbury Hospital, Canterbury IKings College Hospital, London, UK Twin studies have demonstrated concordance rates of up to 95% for idiopathic generalized epilepsy (IGE) in monozygotic twin pairs. There are a few rare mendelian forms of IGE, but most show a complex pattern of inheritance. The relative risk for IGE among first-degree relatives is in the range 5-10 suggesting that association studies will be required to detect the expected small gene effects. We have collected an initial sample of 100 probands with IGE and 100 ethnically matched controls. Our initial studies have focused on the metabotropic glutamate receptor type 7 (mGluR7) and the (r4 nicotinic acetylcholine receptor subunit (nAchRo4). Mouse knockouts of mGluR7 result in an epileptic phenotype. Studies of a biallelic polymorphisms in mGluR7 are in progress. Mutations within nAchRo4 have been shown to cause the rare dendelian epilepsy autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). An association study with a mixture of different IGE syndromes provides some evidence for association to nAchrcr4. The gene for nAchRo4 lies only 50 Kb from a voltage-sensitive potassium channel gene (KCNQ2) in which mutations cause one type of another mendelian epilepsy, benign familial neonatal convulsions (BFNC). We are currently utilizing polymorphisms in the nAchRa4 gene and KCNQ2 in our sample. Functional and structural findings in epilepsy demonstrated with diffusion weighted imaging U.C. Wieshamnn, MR. Symms & S.D. Shorvon Epilepsy Research Group, institute of Neurology, Queen Square, London, UK Diffusion weighted imaging (DWI) is a magnetic resonance imaging technique which is sensitive to molecular motion of water. Transient or permanent changes of the microstructural organization of tissue, for example, widening or shrinkage of the extracellular space cause diffusion changes which can be detected by DWI. We used DWI to investigate patients with epilepsy. In a patient with focal status we detected transient diffusion changes which were likely to reflect neuronal dysfunction. During the interictal stage we found an increased diffusion in structural lesions associated with epilepsy. These included hippocampal sclerosis, tumours and most forms of brain damage. These changes were associated with a reduced anisotropy of water diffusion which is likely to reflect a breakdown of the structural organization. A reduction of anisotropy was the predominant finding in cortical dysgenesis. In conclusion, DWI can show changes of water diffusion in focal status epilepticus. In addition, DWI provides information about the microstructure in lesions which may help to understand the pathophysiology of seizures.

Learning disability and epilepsy. I, towards common outcome measures

A major component of the population of people who have epilepsy are people with a learning disability. As a group, such individuals often have complex epilepsy which is refractory to treatment. Current available measures to assess the outcomes of therapeutic interventions in epilepsy are based on seizure frequency, seizure severity and quality-of-life measures, but have not been validated in people with a learning disability. Thus, we do not know if such measures of outcome serve the needs of this group. This review examines how able we are to assess the efficacy of our interventions to control epilepsy in people with learning disability. It is suggested that a standard data set is necessary as the basis of the assessment of any therapeutic intervention. Central components of this data set would encompass a definition of important characteristics of an individual, a description of their epilepsy and an assessment of the impact of their condition on both their own and their carer's health. The approach to obtaining this information should employ a methodology which can allow for environmental influences.

Potassium channel activators abolish excitotoxicity in cultured hippocampal pyramidal neurons

When hippocampal pyramidal neurons are grown in culture they develop excitatory synaptic contacts. If these cultures are perfused with Mg2(+)-free, glycine supplemented medium the neurons exhibit fluctuations in [Ca2+]i and associated cell death ('excitotoxicity'). These phenomena involve the activation of NMDA receptors. When cultures are treated with the K(+)-channel activators cromakalim and diazoxide both the [Ca2+]i fluctuations and the neuronal death are abolished. These effects are reversed by the sulfonylurea glyburide. It thus appears that K(+)-channel activators may be a novel therapeutic intervention in epilepsy and associated disorders.