Prevention Of Epilepsy Research Articles

The gut microbiome in epilepsy

The close relationship between epilepsy and autoimmune diseases and the fact that the cause of epilepsy is idiopathic in 60% of cases suggest that intestinal microbiota may play a role in the etiology of epilepsy. In this study, we analyzed and compared the intestinal microbiota composition of patients with idiopathic focal epilepsy (n = 30) and healthy volunteer group (n = 10) by 16s ribosomal DNA sequencing. Proteobacteria phylum was found to be higher in patients with epilepsy (25.4%) than in healthy volunteers group (1.5%). The genera of Campylobacter, Delftia, Haemophilus, Lautropia, Neisseria among Proteobacteria phylum were found to be statistically significantly higher in patients with epilepsy than in healthy volunteers (p < 0.05). Fusobacteria phylum was detected in 10.6% of the patients with epilepsy but not in the healthy volunteer group. The genus of the Fusobacteria phylum was found as Leptotrichia and Fusobacterium. In our study, taxonomic drift and significant differences in the intestinal microbiota of patients with epilepsy according to healthy volunteer group showed that autoimmune mechanisms and inflammation may have a role in the etiology of epilepsy. Our data should be supported by other studies as to the role of the intestinal microbiome in the prevention and treatment of epilepsy.

Proof-of-concept that network pharmacology is effective to modify development of acquired temporal lobe epilepsy

Epilepsy is a complex network phenomenon that, as yet, cannot be prevented or cured. We recently proposed network-based approaches to prevent epileptogenesis. For proof of concept we combined two drugs (levetiracetam and topiramate) for which in silico analysis of drug-protein interaction networks indicated a synergistic effect on a large functional network of epilepsy-relevant proteins. Using the intrahippocampal kainate mouse model of temporal lobe epilepsy, the drug combination was administered during the latent period before onset of spontaneous recurrent seizures (SRS). When SRS were periodically recorded by video-EEG monitoring after termination of treatment, a significant decrease in incidence and frequency of SRS was determined, indicating antiepileptogenic efficacy. Such efficacy was not observed following single drug treatment. Furthermore, a combination of levetiracetam and phenobarbital, for which in silico analysis of drug-protein interaction networks did not indicate any significant drug-drug interaction, was not effective to modify development of epilepsy. Surprisingly, the promising antiepileptogenic effect of the levetiracetam/topiramate combination was obtained in the absence of any significant neuroprotective or anti-inflammatory effects as indicated by multimodal brain imaging and histopathology. High throughput RNA-sequencing (RNA-seq) of the ipsilateral hippocampus of mice treated with the levetiracetam/topiramate combination showed that several genes that have been linked previously to epileptogenesis, were significantly differentially expressed, providing interesting entry points for future mechanistic studies. Overall, we have discovered a novel combination treatment with promise for prevention of epilepsy.

Electroencephalographic biomarkers of epilepsy development in patients with acute brain injury: a matched, parallel cohort study.

ObjectiveThis study was designed to investigate if highly epileptic electroencephalogram (EEG) findings in patients with acute brain injury increase the long‐term risk of epilepsy development.MethodsAdults patients, lacking epilepsy history, with electrographic seizures or lateralized periodic discharges (LPDs) (cases) were identified and matched based on age, mental status, and etiology with the ones lacking any epileptiform activity (controls) on continuous EEG (cEEG) during hospitalization. The primary outcome of clinical seizures after hospital discharge and their antiepileptic drug (AED) status was determined using a telephonic interview. Logistic regression models using generalized estimating equations to account for the matched nature of the data were performed.ResultsA total of 70 cases [16 (22.9%) “LPDs only,” 34 (48.6%) “electrographic seizure only,” and 20 (28.6%) “both”] and controls were enrolled. A total of 22 (31.4%) cases developed epilepsy after a mean follow‐up duration of 20.6 ± 5.0 months compared to three (4.3%) controls. After adjusting for cEEG indication and follow‐up duration, the odds of cases developing epilepsy were almost 15 times higher compared to the controls (OR = 14.8, 95% CI = 2.4–92.3, P = 0.004). This elevated risk was despite a 10 times higher likelihood of cases to be taking AEDs at the last follow‐up (OR = 10.34, 95% CI = 3.7–29, P < 0.001).InterpretationHighly epileptic EEG findings in patients with acute brain injury may serve as prognostic biomarkers of epilepsy development. Although prospective studies are required to confirm our findings, it seems that with epilepsy developing in almost one‐third cases in less than 2‐year follow‐up period, such patients may potentially be ideal candidates for epilepsy prevention clinical trials.

Challenges and opportunities in the prevention and treatment of epilepsy in Africa: Perspectives from across the continent

Challenges and opportunities in the prevention and treatment of epilepsy in Africa: Perspectives from across the continent

Prevention of Epilepsy by Reducing Neonatal Encephalopathy

Prevention of Epilepsy by Reducing Neonatal Encephalopathy

Seizure detection watch improves quality of life for adolescents and their families

This article reports the findings from a pilot study conducted to explore the impact of using a wearable seizure detection device on quality of life for 10 adolescents with epilepsy and their parents. Quality of life in Epilepsy for Adolescent (QOLIE AD-48) and the Parent Response to Child Illness (PRCI) Scale were compared at study onset and 6 months after using the SmartWatch seizure detection device. At the conclusion of the study, a qualitative interview explored the adolescent's and parent's experiences with using the device. In this sample, the wearable seizure detection device was well accepted as a means to increase seizure safety for both adolescents and their caregivers. In addition, adolescents and parents felt more secure with the adolescent increasing independent activities when wearing the watch. Barriers to use included technical difficulties, such as false alarms, and the burden of adding another aspect to their epilepsy care. While these data cannot be generalized to all populations, findings suggest that further research with wearable seizure detection devices is warranted. Considering current sudden unexplained death from epilepsy (SUDEP) prevention guidelines that encourage seizure monitoring, especially during sleep, the wearable seizure detection device may provide adequate seizure monitoring without the negative consequences to the adolescent's developing autonomy.

Identification of Susceptibility Variants to BECTS in Chinese Han Population

Benign Childhood Epilepsy with Centro-temporal Spikes (BECTS) is the most common form of idiopathic epilepsy in children. To explore the genetic susceptibility loci in children with BECTS, we conducted 2stage genome-wide association study (GWAS) in over 1,800 Chinese Han patients with BECTS, and 7,090 healthy controls. We combined the datasets of the two stages by meta-analysis to identify the SNPs associated to BECTS. Significant common variant heritability of BECTS was observed. Heritability in the combined phase 1 and 2 datasets was > 10% even for assumed prevalence as low as 0.00025 on the liability scale. Twelve loci achieved suggestive evidence of association (5x10-8 < P < 10-5). In addition, the intersection between the GWAS findings and gene expression in brain tissue was analyzed by Summary-data-based Mendelian Randomization (SMR). We found association of t3603436 transcripts in CHRNA5 gene with SNP rs1948, which is suggestively associated with BECTS (Peqtl = 2.10x10-12, Psmr = 7.9x10-5), suggesting that rs1948 is significantly associated with BECTS through effects on expression of CHRNA5 in brain tissue. These findings suggest involvements of KALRN and CHRNA5-A3-B4 cluster in BECTS, give new directions to biological understanding of pediatric epilepsy, and opens avenues for investigation of prognostic factors and possible prevention of epilepsy in children. Funding: The study was funded by the National Key R&D Program of China (No. 2016YFC1000707), the National Natural Science Foundation of China (No. 81771389 and No. 81471329), and China Ministry of Science and technology (973 Program of China 2014CB541800). The study was also funded by Australian Research Council grant LPl10200926, and by the Queensland Premier’s Fellowship for Science (awarded to MAB, 2013). MAB was funded by Electronic copy available at: https://ssrn.com/abstract=3384897 a National Health and Medical Research Council Senior Principal Research Fellowship (APP1024879). Declaration of Interest: The authors have no conflict of interest. Ethical Approval: Written informed consent was obtained from all the parents or guardians, and the study was approved by the relevant ethics committees of the hospitals and institutions involved.

Economic Burden of Epilepsy in Rural Ituri, Democratic Republic of Congo

BackgroundEpilepsy is still very prevalent in Sub-Saharan Africa, particularly in remote, poverty-confronted onchocerciasis-endemic villages. It constitutes a significant burden for the families and communities. However, the financial costs of managing persons with epilepsy (PWE) have not been assessed in these settings. Proper cost analyses will facilitate future health interventions. MethodsIn November 2017, persons with epilepsy (PWE) and their caretakers were recruited at health centres of the Logo health zone in the Democratic Republic of Congo. A pre-tested questionnaire was administered to collect information on both direct and indirect costs of epilepsy, as well as household income of participants. FindingsThe weighted mean cost of epilepsy was 241.2 USD per PWE per year (50.2% direct cost, 49.8% indirect cost). Epilepsy-related expenses represented 46.5% of the mean household income. Traditional medicine accounted for 68.2% of the direct cost. An estimated cumulative cost of 1929.6 USD attributable to epilepsy had been incurred by the populations of the Logo health zone for each PWE in the community. InterpretationAlmost half of the household revenue was spent on epilepsy care. Expenses on traditional medicine must be discouraged via education and regular provision of affordable anti-epileptic drugs. Prevention of onchocerciasis-associated epilepsy using optimal control measures will avert additional epilepsy-related costs on the community. Early diagnosis and proper management of epilepsy would be economically beneficial in the study villages.

Transient use of a systemic adenosine kinase inhibitor attenuates epilepsy development in mice.

Over one-third of all patients with epilepsy are refractory to treatment and there is an urgent need to develop new drugs that can prevent the development and progression of epilepsy. Epileptogenesis is characterized by distinct histopathologic and biochemical changes, which include astrogliosis and increased expression of the adenosine-metabolizing enzyme adenosine kinase (ADK; EC 2.7.1.20). Increased expression of ADK contributes to epileptogenesis and is therefore a target for therapeutic intervention. We tested the prediction that the transient use of an ADK inhibitor administered during the latent phase of epileptogenesis can mitigate the development of epilepsy. We used the intrahippocampal kainic acid (KA) mouse model of temporal lobe epilepsy, which is characterized by ipsilateral hippocampal sclerosis with granule cell dispersion and the development of recurrent hippocampal paroxysmal discharges (HPDs). KA-injected mice were treated with the ADK inhibitor 5-iodotubercidin (5-ITU, 1.6mg/kg, b.i.d., i.p.) during the latent phase of epileptogenesis from day 3-8 after injury; the period when gradual increases in hippocampal ADK expression begin to manifest. HPDs were assessed at 6 and 9weeks after KA administration followed by epilepsy histopathology including assessment of granule cell dispersion, astrogliosis, and ADK expression. 5-ITU significantly reduced the percent time in seizures by at least 80% in 56% of mice at 6weeks post-KA. This reduction in seizure activity was maintained in 40% of 5-ITU-treated mice at 9weeks. 5-ITU also suppressed granule cell dispersion and prevented maladaptive ADK increases in these protected mice. Our results show that the transient use of a small-molecule ADK inhibitor, given during the early stages of epileptogenesis, has antiepileptogenic disease-modifying properties, which provides the rationale for further investigation into the development of a novel class of antiepileptogenic ADK inhibitors with increased efficacy for epilepsy prevention.

Analysis on the Main Obstacle Factors of Preventing and Controlling Epilepsy in Chongqing Community

Objective: Epilepsy is a serious disease in China, and its community prevention and control is a great challenge, but few studies have focused on depicting these difficulties from a broader perspective. The purpose of this study was to identify barriers to prevention and control of epilepsy in the community from the perspective of medical institution managers, health care providers, and epilepsy patients. Methods: A total of 6 heads of CHS centers, 16 specialists, and 270 epilepsy patients were selected through purposeful sampling, and the qualitative data from the interviews were analyzed using a thematic framework. Results: The main obstacles to the prevention and control of epilepsy in community were the lack of community self-service ability, imperfect inter-agency sharing mechanism, poor disease-related cognition and insufficient cognition of community health service of patients. Conclusion: It is suggested that the existing platform should be used to promote and guarantee the community service ability, optimize the community health management service, adjust the medical insurance compensation method, correctly publicize the first consultation at the grass-roots level, and strengthen health education, so as to improve the community prevention and control planning of epilepsy.

Are Seizure Detection Devices Ready for Prime Time?

Standards for testing and clinical validation of seizure detection Beniczky S, Ryvlin P. Epilepsia. 2018;59(S1):9-13. doi:10.1111/epi.14049To increase the quality of studies on seizure detection devices, we propose standards for testing and clinical validation of such devices. We identified 4 key features that are important for studies on seizure detection devices: subjects, recordings, data analysis and alarms, and reference standard. For each of these features, we list the specific aspects that need to be addressed in the studies, and depending on these, studies are classified into 5 phases (0-4). We propose a set of outcome measures that need to be reported, and we propose standards for reporting the results. These standards will help in designing and reporting studies on seizure detection devices, they will give readers clear information on the level of evidence provided by the studies, and they will help regulatory bodies in assessing the quality of the validation studies. These standards are flexible, allowing classification of the studies into one of the 5 phases. We propose actions that can facilitate development of novel methods and devices. User-based evaluation of applicability and usability of a wearable accelerometer device for detecting bilateral tonic-clonic seizures: a field study Meritam P, Ryvlin P, Beniczky S. Epilepsia. 2018;59(S1):48-52. doi:10.1111/epi.14051Clinical validation studies of seizure detection devices conducted in epilepsy monitoring units (EMUs) can be biased by the artificial environment. We report a field (phase 4) study of a wearable accelerometer device (Epi-Care) that has previously been validated in EMUs for detecting bilateral tonic–clonic seizures (BTCS). Seventy-one patients using the device (or their caregivers) completed the modified Post-Study System Usability Questionnaire. Median time patients had been using the device was 15 months (range = 24 days to 6 years). In 10% of cases, patients stopped using the device due to reasons related to the device. The median sensitivity (90%) and false alarm rate (0.1/day) were similar to what had been determined in EMUs. Patients and caregivers were overall satisfied with the device (median = 5.5 on the 7-point Likert scale), considered the technical aspects satisfactory, and considered the device comfortable and efficient. Adverse effects occurred in 11% but were only mild: skin irritation at the wrist and interference with home electronic appliances. In 55%, the device influenced the number of seizures logged into the seizure diary, and in 40%, it contributed to fewer seizure-related injuries. This field study demonstrates the applicability and usability of the wearable accelerometer device for detecting BTCS. Wearable devices for sudden unexpected death in epilepsy prevention Ryvlin P, Ciumas C, Wisniewski I, Beniczky S. Epilepsia. 2018;59(S1):61-66. doi:10.1111/epi.14054Sudden unexpected death in epilepsy (SUDEP) is most often associated with the occurrence of generalized tonic–clonic seizures (GTCS), a seizure type that can now be detected with high sensitivity and specificity by wearable or bed devices. The recent development in such devices and their performance offer multiple opportunities to tackle SUDEP and its prevention. Reliable GTCS detection might help physicians optimize antiepileptic treatment, which could in turn reduce the risk of SUDEP. Generalized tonic–clonic seizures–triggered alarms can lead to immediate intervention by caregivers that are also likely to decrease the odd of SUDEP. The biosignals used to detect GTCS might provide novel SUDEP biomarkers, in particular, by informing on several important characteristics of the ictal and postictal periods (type of GTCS, duration of tonic phase, rotation in the prone position, presence and duration of postictal immobility and bradycardia, rise in electrodermal activity). Other biosensors not yet used for detecting GTCS might provide complementary information, such as the presence and intensity of ictal/postictal hypoxemia. The above biomarkers, if strongly predictive, could help identify patients at very high risk of SUDEP, enabling better assessment of individual risk, as well as selection of appropriate patients for clinical studies aiming at preventing SUDEP. The same biosignals could also be used as ancillary biomarkers to test the impact of various interventions before moving to highly challenging randomized controlled trials with SUDEP as a primary outcome.

Prevention of epilepsy in humans - truth or myth? The experience from Sturge-Weber syndrome and Tuberous Sclerosis Complex.

Epilepsy is a chronic neurological disease, usually decreasing the quality of life and often resulting in other comorbidities e.g. cognitive impairment in children. Despite the recent discovery of new antiepileptic drugs, roughly one in three patients suffers from drug-resistant seizures. Therefore, the prevention of epilepsy is becoming one of the most important challenges in medicine. Is it, however, in fact possible to prevent epilepsy? We present the results of preventive antiepileptic treatment in children with Sturge-Weber syndrome and Tuberous Sclerosis Complex as examples of the possible prevention of epilepsy and epilepsy-associated cognitive impairment in children.

Protective effects of the ROCK inhibitor fasudil against cognitive dysfunction following status epilepticus in male rats.

Despite remarkable advances in epilepsy research, prevention and reversal of cognitive deficits following epilepsy remain a challenge. It was reported that the Rho kinase (ROCK) inhibitor fasudil hydrochloride (FH) could improve cognitive deficits in animal models of Alzheimer's disease (AD). Thus, the aim of the present study was to determine whether FH-mediated inhibition of the effects of ROCK signaling could improve cognitive deficits in male rats (postnatal 21-day old) following status epilepticus (SE) induced by lithium-pilocarpin, the therapeutic window of opportunity and to elucidate the underlying mechanisms. Western blotting analysis showed upregulation of phosphorylated RhoA (p-RhoA) expression, and indicated activation of Rho/ROCK signaling after SE. The Morris water maze (MWM) test was used to analyze learning-memory ability. HE staining, immunofluorescence staining with antineuronal nuclei (NeuN) and anti-neurofilament proteins 200 kD (NF200), transmission electron microscopy, and quantitative analysis of NeuN and synaptophysin by western blotting were performed to observe alterations in neurons, axons, and synapses in the hippocampi. Electroencephalogram (EEG) monitoring was used to record electrophysiological activities after SE. Our results indicated that treatment with FH at the first day following SE or 5 days later both could ameliorate cognitive dysfunction by reducing neuron, axon, and synapse damage, and mitigating EEG discharges, suggesting various roles for the Rho/ROCK signaling pathway in the pathological processes of brain damages following SE induced by lithium-pilocarpine. The Rho/ROCK signaling pathway is, therefore, a potential therapeutic target for the prevention or reversal of epilepsy induced brain damages.

A Retrospective Analysis of the Clinical Features of Inpatients With Epilepsy in the Ganzi Tibetan Autonomous Prefecture.

Background: There is limited detailed clinical information for patients with epilepsy in Tibet. This study sought to provide data about the clinical features of epilepsy in the Ganzi Tibetan Autonomous Prefecture to improve strategies for epilepsy prevention and management in this region.Methods: We reviewed the clinical record of patients with epilepsy in the Neurology Department, Ganzi Tibetan Autonomous Prefecture People's Hospital and compared the clinical features and compared it with control, from West China Hospital in Chengdu.Results: This retrospective study included 165 patients with epilepsy admitted between January 2015 and February 2018. Majority of patients (97%) in this study had active epilepsy; 28.5% had generalized onset seizures and 68.5% had focal onset seizures. Fifty-four patients had received anti-epileptic drug (AED) treatment prior to hospitalization, however, 38 (70.4%) patients took the medication irregularly. The leading etiology of this cohort was head trauma (20.6%), followed by stroke (10.9%), neurocysticercosis (7.9%), brain hydatidosis (6.7%) and tuberculous infection (5.5%). Compared with in-patients in Chengdu, epilepsy in Ganzi was more frequently caused by infection (OR = 4.216, 95% CI, 2.124–8.367), including neurocysticercosis (OR = 29.301, 95% CI, 1.727–497.167) and brain hydatidosis (OR = 24.637, 95% CI, 1.439–421.670).Conclusions: These data suggest that the control of cerebral infections, especially parasite infection, is essential for the prevention of epilepsy in the Ganzi Tibetan Autonomous Prefecture. Education of local primary doctors and patients about the literacy of epilepsy will enable better management of epilepsy in this population.

Transgenic overexpression of furin increases epileptic susceptibility

The proprotein convertase Furin plays crucial roles in the pathology of many diseases. However, the specific role of furin in epilepsy remains unclear. In our study, furin protein was increased in the temporal neocortex of epileptic patients and in the hippocampus and cortex of epileptic mice. The furin transgenic (TG) mice showed increased susceptibility to epilepsy and heightened epileptic activity compared with wild-type (WT) mice. Conversely, lentivirus-mediated knockdown of furin restrained epileptic activity. Using whole-cell patch clamp, furin knockdown and overexpression influenced neuronal inhibitory by regulating postsynaptic gamma-aminobutyric acid A receptor (GABAAR)-mediated synaptic transmission. Importantly, furin influenced the expression of GABAAR β2/3 membrane and total protein in epileptic mice by changing transcription level of GABAAR β2/3, not the protein degradation. These results reveal that furin may regulate GABAAR-mediated inhibitory synaptic transmission by altering the transcription of GABAAR β2/3 subunits in epilepsy; this finding could provide new insight into epilepsy prevention and treatment.

Automated quantification of EEG spikes and spike clusters as a new read out in Theiler's virus mouse model of encephalitis-induced epilepsy

Intracerebral infection of C57BL/6 mice with Theiler's murine encephalomyelitis virus (TMEV) replicates many features of viral encephalitis-induced epilepsy in humans, including neuroinflammation, early (insult-associated) and late (spontaneous) seizures, neurodegeneration in the hippocampus, and cognitive and behavioral alterations. Thus, this model may be ideally suited to study mechanisms involved in encephalitis-induced epilepsy as potential targets for epilepsy prevention. However, spontaneous recurrent seizures (SRS) occur too infrequently to be useful as a biomarker of epilepsy, e.g., for drug studies. This prompted us to evaluate whether epileptiform spikes or spike clusters in the cortical electroencephalogram (EEG) may be a useful surrogate of epilepsy in this model. For this purpose, we developed an algorithm that allows efficient and large-scale EEG analysis of early and late seizures, spikes, and spike clusters in the EEG. While 77% of the infected mice exhibited early seizures, late seizures were only observed in 33% of the animals. The clinical characteristics of early and late seizures did not differ except that late generalized convulsive (stage 5) seizures were significantly longer than early stage 5 seizures. Furthermore, the frequency of SRS was much lower than the frequency of early seizures. Continuous (24/7) video-EEG monitoring over several months following infection indicated that the latent period to onset of SRS was 61 (range 16–91) days. Spike and spike clusters were significantly more frequent in infected mice with late seizures than in infected mice without seizures or in mock-infected sham controls. Based on the results of this study, increases in EEG spikes and spike clusters in groups of infected mice may be used as a new readout for studies on antiepileptogenic or disease-modifying drug effects in this model, because the significant increase in average spike counts in mice with late seizures obviously indicates a proepileptogenic alteration.

The Effect of Statins in Epilepsy: A Systematic Review.

Background and Objectives:Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, used for the management of hypercholesterolemia and related atherosclerotic diseases. Several studies have indicated the neuroprotective effects of statins on several neuropathological conditions. However, the role of these medications in epilepsy is still unclear. The purpose is to evaluate and summarize the level of evidence on the efficacy of statins in neuronal hyperexcitability and the neuroinflammatory processes of epilepsy.Methods:A systematic review was performed. Eligibility Criteria: This review involved studies conducted in humans and nonhuman experimental models, covering the use of an inhibitor of HMG-CoA reductase, alone or accompanied by another medication, in epilepsy. Information Sources: A systematic literature search was performed in PubMed, Embase, Ebsco Host, Scopus, Science Direct, Medline, and LILACS. Risk of Bias: It was evaluated with the Newcastle–Ottawa Scale and the experimental studies were evaluated using the GRADE tool.Results:Twenty articles of the 183 evaluated were included. Sixteen studies were conducted in animal models and four studies in humans. Most studies in mice reported a reduction in epileptiform activity and reduction in systemic inflammation with the treatment of statins, potentially influencing epilepsy control. Few studies in humans were performed in the geriatric population with variable results (neuroinflammation, seizure prevention, cell death, prevention of kindling, increase in convulsive threshold, increase in latency, decrease in frequency of crisis, and reduction in mortality) related to reduction in the rate of hospitalizations, mortality, and prevention of epilepsy. Studies in mice found a decrease in interleukin-1β (IL-1β), IL-6, and tumor necrosis factor alpha and an increase in IL-10 and endothelial nitric oxide synthase.Conclusions:The possible antiepileptic mechanism of statins may be related to the reduction in neuroinflammation mediated by a decrease in pro-inflammatory cytokines and action in the nitrergic system. Further studies evaluating the impact of statins on seizure control are necessary.

Echinacoside, an Active Constituent of Cistanche Herba, Exerts a Neuroprotective Effect in a Kainic Acid Rat Model by Inhibiting Inflammatory Processes and Activating the Akt/GSK3β Pathway.

Echinacoside is a major compound of Cistanche Herb and has glutamate release-inhibiting activity in the brain. Given the involvement of excitotoxicity caused by massive glutamate in the pathophysiology of epilepsy, we explored the antiepileptic effect of echinacoside on kainic acid-induced seizures in rats. The rats were intraperitoneally administrated echinacoside for 30 min prior to intraperitoneal injection with kainic acid. The results showed that kainic acid induced seizure-like behavioral patterns, increased glutamate concentrations, caused neuronal loss and microglial activation, and stimulated proinflammatory cytokine gene expression in the hippocampus. These kainic acid-induced alternations were found to be attenuated by echinacoside pretreatment. Furthermore, decreased Akt and glycogen synthase kinase 3β (GSK3β) phosphorylation as well as Bcl-2 expression in the hippocampus was reversed by the echinacoside pretreatment. These results demonstrate that echinacoside exert its antiepileptic and neuroprotective actions in a kainic acid rat model through suppressing inflammatory response and activating the Akt/GSK3β signaling. Therefore, the present study suggests that echinacoside is the potentially useful in the prevention of epilepsy.

ERG3 potassium channel-mediated suppression of neuronal intrinsic excitability and prevention of seizure generation in mice.

ERG3 channels have a high expression level in the central nervous system. Knockdown of ERG3 channels enhances neuronal intrinsic excitability (caused by decreased fast afterhyperpolarization, shortened delay time to the generation of an action potential and enhanced summation of somatic excitatory postsynaptic potentials) in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. The expression of ERG3 protein is reduced in human and mouse hippocampal epileptogenic foci. Knockdown of ERG3 channels in hippocampus enhanced seizure susceptibility, while mice treated with the ERG channel activator NS-1643 were less prone to epileptogenesis. The results provide strong evidence that ERG3 channels have a crucial role in the regulation of neuronal intrinsic excitability in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells and are critically involved in the onset and development of epilepsy. The input-output relationship of neuronal networks depends heavily on the intrinsic properties of their neuronal elements. Profound changes in intrinsic properties have been observed in various physiological and pathological processes, such as learning, memory and epilepsy. However, the cellular and molecular mechanisms underlying acquired changes in intrinsic excitability are still not fully understood. Here, we demonstrate that ERG3 channels are critically involved in the regulation of intrinsic excitability in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Knock-down of ERG3 channels significantly increases neuronal intrinsic excitability, which is mainly caused by decreased fast afterhyperpolarization, shortened delay time to the generation of an action potential and enhanced summation of somatic excitatory postsynaptic potentials. Interestingly, the expression level of ERG3 protein is significantly reduced in human and mouse brain tissues with temporal lobe epilepsy. Moreover, ERG3 channel knockdown in hippocampus significantly enhanced seizure susceptibility, while mice treated with the ERG channel activator NS-1643 were less prone to epileptogenesis. Taken together, our results suggest ERG3 channels play an important role in determining the excitability of hippocampal neurons and dysregulation of these channels may be involved in the generation of epilepsy. ERG3 channels may thus be a novel therapeutic target for the prevention of epilepsy.

Dietary intake of magnesium and the risk of epilepsy in middle-aged and older Finnish men: A 22-year follow-up study in a general population.

Magnesium may play an important role in the prevention or treatment of epilepsy. We aimed to examine the association between dietary intake of magnesium and the incidence of epilepsy in middle-aged Finnish men in a prospective setting. As a secondary analysis, we also considered a possible association between dietary intake of magnesium and inflammation in subjects with epilepsy. The study included 2442 men, ages 42 to 60 y, from the prospective Kuopio Ischaemic Heart Disease Risk Factor Study who were free of epilepsy at baseline between 1984 and 1989. Dietary intake of magnesium was assessed with a 4-d food record. The hospital discharge diagnosis of epilepsy was used as an outcome variable. During the average follow-up period of 22.4 y, 74 men (3%) developed epilepsy. Those who followed the recommended dietary intake (>350 mg/d) of magnesium had a lower risk of epilepsy (hazard ratio [HR]: 0.52; confidence interval [CI], 0.28-0.99; P = 0.045) after multivariate adjustments. However, the risk was not significant after adjustment for C-reactive protein (CRP). We also found that CRP concentration was directly associated with the risk of epilepsy (HR: 1.24; CI, 1.00-1.54; P = 0.048). This association was attenuated after adjustment for dietary intake of magnesium and no longer significantly associated with the risk of epilepsy (HR: 1.22; CI, 0.99-1.52; P = 0.07). A higher dietary intake of magnesium was associated with lower incident epilepsy, and this association was slightly mediated by CRP. Further studies are required to identify the potential mechanisms.