Model Of Temporal Lobe Epilepsy Research Articles

Pharmacological impact on the expression of microglial and astroglial proteins involved in the regulation of epileptogenesis as a possible new strategy for epilepsy therapy

Pharmacological impact on the expression of microglial and astroglial proteins involved in the regulation of epileptogenesis as a possible new strategy for epilepsy therapy

The effect of cardarine on the behavior of rats in a lithium-pylocarpine model of temporal lobe epilepsy

Epilepsy is a serious neuropsychiatric disorder characterized by the occurrence of spontaneous recurrent seizures and linked cognitive, psychoemotional, and social impairments. Objective research showed that up to 30% of epilepsy patients do not respond to current therapeutic interventions, necessitating the development of novel treatment options. In recent years, researchers actively studied the neuroprotective properties of peroxisome proliferator-activated receptor agonists (PPAR α, β/δ, γ). As nuclear transcription factors involved in inflammatory signaling pathways, PPARs play a role in the pathogenesis of neuropsychiatric disorders, such as epilepsy. Various nervous pathology models were used for the investigations. The neuroprotective properties of PPAR γ agonists were reported in epilepsy models, whereas sufficient investigation into PPAR β/δ agonists’ effects is lacking. The aim of this study was to evaluate the effectiveness of the PPAR β/δ receptor agonist cardarine in alleviating behavioral disruptions observed in rats exhibiting temporal lobe epilepsy in response to the lithium-pilocarpine model. The lithium-pilocarpine model is considered one of the most effective experimental models for studying temporal lobe epilepsy in humans. Administration of pilocarpine in animals results in acute seizures, followed by a latent period devoid of seizures. Subsequently, spontaneous recurrent seizures appear, marking the chronic phase of the model. Epilepsy was induced in male Wistar rats that were 7 weeks old, through the administration of pilocarpine, 24 hours after being injected with LiCl (127 mg/kg). The peripheral effects of pilocarpine were negated through the use of methyl bromide-scopolamine (1 mg/kg, administered intraperitoneally 1 hour before pilocarpine). Pilocarpine was administered in fractional doses of 10 mg/kg, every half hour, until the seizures reached at least stage 4 on the Racine scale, with a dose range of 20–40 mg/kg. Following pilocarpine administration, Cardarine was administered intraperitoneally at a dose of 2.5 mg/kg daily for a period of 7 days, with the initial injection taking place 24 hours post-administration. Behavioral tests were conducted during the chronic phase of the model, 2-2.5 months after pilocarpine injection, using several tests, including the Open Field (to measure exploratory behavior, motor activity, and anxiety levels), the Intruder-Resident test (to measure communicative behavior), the Y-maze test (to measure working memory), and the Morris Water Maze (to measure spatial memory in the short and long term). Untreated experimental animals with temporal lobe epilepsy exhibited heightened vertical and horizontal motor activity, increased anxiety in the Open Field test, reduced communicative activity in the Intruder-Resident test, and impaired memory in the Y-maze test and the Morris Water Maze. Cardarine reduced alterations in vertical movement (time of climbing) and anxiety levels (number of grooming behaviors) in the Open Field, hindered short-term memory in the Y-maze, and restrained communicative conduct in the Intruder-Resident test. However, the medication did not impact the rats’ survival rate, body weight changes, overall activity (distance traveled in the Open Field), and damage to learning and long-term memory in the Morris Water Maze. Thus, administration of cardarine partially neutralized behavioral disorders developing in rats in the lithium-pylocarpine model of temporal lobe epilepsy.

Effect of pioglitazone on the behavior and expression of genes involved in the regulation of epileptogenesis in a lithium-pylocarpine model of temporal lobe epilepsy in rats

Epilepsy is a chronic neurological disorder characterized by spontaneous recurrent seizures and various psychoemotional and cognitive impairments [1]. Roughly 30% of patients experience pharmacoresistant epilepsy, and current antiepileptic medications do not prevent the progression of brain epilepsy, necessitating the exploration of novel therapeutics. Recently, the potential involvement of peroxisome proliferator-activated receptors (PPARs) in the development of epilepsy has been examined. PPARs (α, β/δ, γ) are nuclear transcription factors affecting many intracellular cascades, both in the periphery and in the brain. Their agonists were proposed to restrict neuroinflammation, a crucial factor contributing to the pathogenesis of various neuropsychiatric disorders, such as epilepsy [2]. The aim of this study was to investigate the impact of the PPARγ receptor agonist pioglitazone on the regulation of neuroinflammation and epileptogenesis-associated genes, as well as the expression of disorders in research and social behavior in a lithium-pilocarpine model of epilepsy. The lithium-pilocarpine model of temporal lobe epilepsy consists of three phases: 1) induction of an acute epileptic status by administering pilocarpine, 2) a latent period lacking seizures, and 3) a chronic period characterized by spontaneous recurrent seizures. The experiments were conducted on male Wistar rats. At seven to eight weeks of age, the research subjects were administered a LiCl solution (w/w, 127 mg/kg). After 24 hours, they were given methylscopolamine (w/w, 1 mg/kg), followed by pilocarpine (w/w, 20–30 mg/kg, 10 mg/kg until convulsions were pronounced) 30 minutes later. Pilocarpine was not administered to the control rats. Pioglitazone was administered using a biphasic course. The first injection was given at a dose of 7 mg/kg, 75 minutes after pilocarpine-induced status epilepticus. Subsequently, the rats were given a dosage of 1 mg/kg, once daily at 24-hour intervals, for a period of 7 days. The open field test and the foreign object test were performed on days 7 and 8 after pilocarpine administration, respectively. The brain was sampled for further biochemical analysis 12 hours after behavioral testing. The temporal cortex underwent analysis using real-time RT-PCR for the expression of Nlrp3, Aif1, Tnfa, Gfap, Il1b, Il1rn, Bdnf, S100a10, Fgf2, and Tgfb1 genes. The research reveals a surge in the expression of pro-inflammatory proteins and activation markers of glial cell in temporal cortex caused by a lithium-pilocarpine model of epilepsy. This leads to impaired social behavior and hyperactivity in the open field. Pioglitazone successfully decreases the severity of the pilocarpine-induced behavioral disruptions. The PPARg agonist does not have a noteworthy impact on the expression of proinflammatory factors and glia activation markers Aif1 and Gfap. However, it was found to enhance the gene expression of neuroprotective proteins S100A10 and TGFB1 and decrease the expression of growth factors Fgf2 and Bdnf, which worsen epileptogenesis. Overall, these findings suggest that activation of PPARg might provide a protective role in the development of epileptic processes in the brain. Therefore, pioglitazone could be regarded as a possible therapeutic agent for treating epilepsy.

Temporal relationship between levetiracetam nonadherence and breakthrough seizures in a preclinical model of temporal lobe epilepsy.

Poor medication adherence remains a concern for individuals managing their epilepsy with antiseizure medicines (ASMs); however, ethical concerns around withholding medication make it impossible to study the causal relationship between missed doses and seizures in patients. Previous preclinical studies from our group suggest that mechanistically distinct ASMs have varying degrees of forgiveness when a dose is missed. However, with only a few ASMs studied in the context of nonadherence, we sought to expand on previous work to understand the relationship between levetiracetam (LEV) nonadherence and breakthrough seizures. Chronic oral dosing was initiated in rats with established epilepsy via our automated medication-in-food delivery system coupled to 24/7 video-electroencephalographic recording. Baseline seizure burden was established for 4 weeks before enrolling subjects into a 4-week treatment period with LEV in a 100% fully adherent (75 mg/kg four times daily) or 50% variably adherent paradigm. The temporal relationship between missed doses and breakthrough seizures was correlated with LEV plasma and brain concentrations in separate cohorts of animals. Full adherence to LEV significantly improved seizure control by 50% in half of the animals. Poor adherence worsened seizure frequency by 85%, with most rats having more severe seizures that formed in clusters following missed doses. LEV concentrations remained below therapeutic levels (<10 μg/mL) in nonadherent animals, with brain and plasma levels directly correlating with the degree of adherence in a 24-h period. Missed doses of LEV immediately increased the risk of breakthrough seizures; however, this risk was significantly reduced with improved adherence in a 24-h period. These findings enhance our understanding of ASM nonadherence in preclinical models, highlighting that the timing of missed doses and their impact on seizures may vary between different ASMs. Notably, LEV demonstrates a robust pharmacokinetic reliance on missed doses leading to breakthrough seizures.

Cannabidiol Modifies the Glutamate Over-Release in Brain Tissue of Patients and Rats with Epilepsy: A Pilot Study.

Drug-resistant epilepsy (DRE) is associated with high extracellular levels of glutamate. Studies support the idea that cannabidiol (CBD) decreases glutamate over-release. This study focused on investigating whether CBD reduces the evoked glutamate release in cortical synaptic terminals obtained from patients with DRE as well as in a preclinical model of epilepsy. Synaptic terminals (synaptosomes) were obtained from the epileptic neocortex of patients with drug-resistant temporal lobe epilepsy (DR-TLE, n = 10) or drug-resistant extratemporal lobe epilepsy (DR-ETLE, n = 10) submitted to epilepsy surgery. Synaptosomes highly purified by Percoll-sucrose density gradient were characterized by confocal microscopy and Western blot. Synaptosomes were used to estimate the high KCl (33 mM)-evoked glutamate release in the presence of CBD at different concentrations. Our results revealed responsive tissue obtained from seven patients with DR-TLE and seven patients with DR-ETLE. Responsive tissue showed lower glutamate release (p < 0.05) when incubated with CBD at low concentrations (less than 100 µM) but not at higher concentrations. Tissue that was non-responsive to CBD (DR-TLE, n = 3 and DR-ELTE, n = 3) showed high glutamate release despite CBD exposure at different concentrations. Simultaneously, a block of the human epileptic neocortex was used to determine its viability through whole-cell and extracellular electrophysiological recordings. The electrophysiological evaluations supported that the responsive and non-responsive human epileptic neocortices used in the present study exhibited proper neuronal viability and stability to acquire electrophysiological responses. We also investigated whether the subchronic administration of CBD could reduce glutamate over-release in a preclinical model of temporal lobe epilepsy. Administration of CBD (200 mg/kg, p.o. every 24 h for 7 days) to rats with lithium-pilocarpine-evoked spontaneous recurrent seizures reduced glutamate over-release in the hippocampus. The present study revealed that acute exposure to low concentrations of CBD can reduce the glutamate over-release in synaptic terminals obtained from some patients with DRE. This effect is also evident when applied subchronically in rats with spontaneous recurrent seizures. An important finding was the identification of a group of patients that were non-responsive to CBD effects. Future studies are essential to identify biomarkers of responsiveness to CBD to control DRE.

Challenges in reproducing the standard lithium Pilocarpine model of temporal lobe epilepsy in wistar rats: troubleshooting strategies

Introduction: Animal model of temporal lobe epilepsy (TLE) provide an essential platform to study the disease pathophysiology, and disease modifying management protocols. Lithium –pilocarpine model is one of the most favored model. Many practical difficulties have been encountered while creating this model in this study as well as by other authors. We have systematically attempted to compile all issues and their possible solutions in establishment of Li-Pi model of status epilepticus in wistar rats, to provide a dependable protocol with improved seizure induction rates and lower mortality rates. Materials and Methods: Young small size male wistar rats (100-150gm) were injected with lithium chloride (LiCl) (127 mg/kg, i.p.), followed by methyl scopolamine (1mg/kg, i.p.) after 18-22 hrs. Precisely after 30 minutes, dose of pilocarpine (i.p.) was administered. Post seizures, diazepam (10 mg/kg) was injected to reduce seizures severity and to increase survival rate and rats were fed glucose (10% of body weight) through oral gavage. Model creation was validated by histological examination of hippocampus. The rats which did not develop seizures, were reutilized for the model generation after drug wash-out period of 48 hours. Results: Initial model creation was unsuccessfully attempted in 75 rats. Standard described protocol of three incremental doses of pilocarpine (10mg/kg, maximum of 30mg/kg) did not elicit epilepsy. Loading dose of 30mg/kg pilocarpine caused stage 1 epilepsy in 60% rats; second dose of pilocarpine (30mg/kg), caused stage 2 epilepsy in 70% rats. Successful TLE model creation was seen in 33 out of 57 rats, using proposed modification in which 2 incremental doses of pilocarpine (30mg/kg each) were followed by 3 doses of 10mg/kg each; 6 rats died. Conclusions: The study provides a detailed procedure for lithium pilocarpine model creation and various pitfalls encountered. Modified pilocarpine dosage led to improved seizure induction rates (58%) and lower mortality rates (10%). Keywords: Epilepsy animal model; Status epilepticus; lithium-pilocarpine; Animal mortality

Acute hippocampal volume loss and metabolic neuronal dysfunction post pilocarpine induced status epilepticus in a rodent model of temporal lobe epilepsy

Acute hippocampal volume loss and metabolic neuronal dysfunction post pilocarpine induced status epilepticus in a rodent model of temporal lobe epilepsy

Visually or auditorily induced seizures involve the activation of nonhippocampal brain areas and hippocampal removal does not alleviate seizures in a mouse model of temporal lobe epilepsy.

Several studies have attributed epileptic activities in temporal lobe epilepsy (TLE) to the hippocampus; however, the participation of nonhippocampal neuronal networks in the development of TLE is often neglected. Here, we sought to understand how these nonhippocampal networks are involved in the pathology that is associated with TLE disease. A kainic acid (KA) model of temporal lobe epilepsy was induced by injecting KA into dorsal hippocampus of C57BL/6J mice. Network activation after spontaneous seizure was assessed using c-Fos expression. Protocols to induce seizure using visual or auditory stimulation were developed, and seizure onset zone (SOZ) and frequency of epileptic spikes were evaluated using electrophysiology. The hippocampus was removed to assess seizure recurrence in the absence of hippocampus. Our results showed that cortical and hippocampal epileptic networks are activated during spontaneous seizures. Perturbation of these networks using visual or auditory stimulation readily precipitates seizures in TLE mice; the frequency of the light-induced or noise-induced seizures depends on the induction modality adopted during the induction period. Localization of SOZ revealed the existence of cortical and hippocampal SOZ in light-induced and noise-induced seizures, and the development of local and remote epileptic spikes in TLE occurs during the early stage of the disease. Importantly, we further discovered that removal of the hippocampi does not stop seizure activities in TLE mice, revealing that seizures in TLE mice can occur independent of the hippocampus. This study has shown that the network pathology that evolves in TLE is not localized to the hippocampus; rather, remote brain areas are also recruited. The occurrence of light-induced or noise-induced seizures and epileptic discharges in epileptic mice is a consequence of the activation of nonhippocampal brain areas. This work therefore demonstrates the fundamental role of nonhippocampal epileptic networks in generating epileptic activities with or without the hippocampus in TLE disease.

Low glycemic index diet restrains epileptogenesis in a gender-specific fashion

Dietary restriction, such as low glycemic index diet (LGID), have been successfully used to treat drug-resistant epilepsy. However, if such diet could also counteract antiepileptogenesis is still unclear. Here, we investigated whether the administration of LGID during the latent pre-epileptic period, prevents or delays the appearance of the overt epileptic phenotype. To this aim, we used the Synapsin II knockout (SynIIKO) mouse, a model of temporal lobe epilepsy in which seizures manifest 2–3 months after birth, offering a temporal window in which LGID may affect epileptogenesis. Pregnant SynIIKO mice were fed with either LGID or standard diet during gestation and lactation. Both diets were maintained in weaned mice up to 5 months of age. LGID delayed the seizure onset and induced a reduction of seizures severity only in female SynIIKO mice. In parallel with the epileptic phenotype, high-density multielectrode array recordings revealed a reduction of frequency, amplitude, duration, velocity of propagation and spread of interictal events by LGID in the hippocampus of SynIIKO females, but not mutant males, confirming the gender-specific effect. ELISA-based analysis revealed that LGID increased cortico-hippocampal allopregnanolone (ALLO) levels only in females, while it was unable to affect ALLO plasma concentrations in either sex. The results indicate that the gender-specific interference of LGID with the epileptogenic process can be ascribed to a gender-specific increase in cortical ALLO, a neurosteroid known to strengthen GABAergic transmission. The study highlights the possibility of developing a personalized gender-based therapy for temporal lobe epilepsy.

A simple, automated method of seizure detection in mouse models of temporal lobe epilepsy

The lack of preventive and disease modifying therapies for temporal lobe epilepsy (TLE) is a major unmet medical need. Search for such therapies utilize mouse models and require detection of seizures in electroencephalography (EEG) recordings. The labor-intensive nature of reviewing EEGs spanning many weeks underscores the need for a method of automated detection. Here we report a simple automated method of detecting seizures in long term EEG recordings from electrodes implanted in the hippocampus in animal models of TLE. We utilize a 2-pronged approach that relies on the increase in power within the gamma band range (20–50hz) during the seizure followed by suppression of activity following the seizure (post-ictal suppression [PIS]). We demonstrate the utility of this method for detecting seizures in hippocampal and amygdala EEG recordings from multiple models of TLE.

Repurposing dimethyl fumarate as an antiepileptogenic and disease-modifying treatment for drug-resistant epilepsy

BackgroundEpilepsy affects over 65 million people worldwide and significantly burdens patients, caregivers, and society. Drug-resistant epilepsy occurs in approximately 30% of patients and growing evidence indicates that oxidative stress contributes to the development of such epilepsies. Activation of the Nrf2 pathway, which is involved in cellular defense, offers a potential strategy for reducing oxidative stress and epilepsy treatment. Dimethyl fumarate (DMF), an Nrf2 activator, exhibits antioxidant and anti-inflammatory effects and is used to treat multiple sclerosis.MethodsThe expression of Nrf2 and its related genes in vehicle or DMF treated rats were determined via RT-PCR and Western blot analysis. Neuronal cell death was evaluated by immunohistochemical staining. The effects of DMF in preventing the onset of epilepsy and modifying the disease were investigated in the kainic acid-induced status epilepticus model of temporal lobe epilepsy in rats.The open field, elevated plus maze and T-Maze spontaneous alteration tests were used for behavioral assessments.ResultsWe demonstrate that administration of DMF following status epilepticus increased Nrf2 activity, attenuated status epilepticus-induced neuronal cell death, and decreased seizure frequency and the total number of seizures compared to vehicle-treated animals. Moreover, DMF treatment reversed epilepsy-induced behavioral deficits in the treated rats.Moreover, DMF treatment even when initiated well after the diagnosis of epilepsy, reduced symptomatic seizures long after the drug was eliminated from the body.ConclusionsTaken together, these findings suggest that DMF, through the activation of Nrf2, has the potential to serve as a therapeutic target for preventing epileptogenesis and modifying epilepsy.

Increased expression of galanin and its receptors in the dorsal hippocampus during epileptogenesis in a rat model of pilocarpine-induced temporal lobe epilepsy

Increased expression of galanin and its receptors in the dorsal hippocampus during epileptogenesis in a rat model of pilocarpine-induced temporal lobe epilepsy

Differential patterns of very high-frequency oscillations in two seizure types of the pilocarpine-induced TLE model

AimsVery high-frequency oscillations (VHFOs, >500 Hz) are considered a highly sensitive biomarker of seizures. We hypothesized that VHFOs may exhibit specificity towards hypersynchronous (HYP) seizures and low-voltage fast (LVF) seizures in temporal lobe epilepsy (TLE). MethodsLocal field potentials were recorded from the hippocampal network in TLE mice induced by pilocarpine. Subsequently, we analyzed the VHFO features, including their temporal-frequency characteristics and VHFO/theta coupling, during three states: baseline, preictal, and postictal for both HYP- and LVF-seizure groups. ResultsSignificant changes in most of the VHFO features were observed during the preictal state in both seizure groups. In the postictal state, VHFO features in the HYP-seizure group exhibited inverse alterations and appeared to align with those observed during baseline conditions. However, such phenomena were not observed after TLE seizures in the LVF-seizure group. ConclusionOur findings highlight distinct patterns of VHFO feature changes across different states of HYP seizures and LVF seizures. These results suggest that VHFOs could serve as indicative biomarkers for seizure alterations specifically associated with HYP-seizure states

The role of subicular VIP-expressing interneurons on seizure dynamics in the intrahippocampal kainic acid model of temporal lobe epilepsy

The subiculum, a key output region of the hippocampus, is increasingly recognized as playing a crucial role in seizure initiation and spread. The subiculum consists of glutamatergic pyramidal cells, which show alterations in intrinsic excitability in the course of epilepsy, and multiple types of GABAergic interneurons, which exhibit varying characteristics in epilepsy. In this study, we aimed to assess the role of the vasoactive intestinal peptide interneurons (VIP-INs) of the ventral subiculum in the pathophysiology of temporal lobe epilepsy. We observed that an anatomically restricted inhibition of VIP-INs of the ventral subiculum was sufficient to reduce seizures in the intrahippocampal kainic acid model of epilepsy, changing the circadian rhythm of seizures, emphasizing the critical role of this small cell population in modulating TLE. As we expected, permanent unilateral or bilateral silencing of VIP-INs of the ventral subiculum in non-epileptic animals did not induce seizures or epileptiform activity. Interestingly, transient activation of VIP-INs of the ventral subiculum was enough to increase the frequency of seizures in the acute seizure model. Our results offer new perspectives on the crucial involvement of VIP-INs of the ventral subiculum in the pathophysiology of TLE. Given the observed predominant disinhibitory role of the VIP-INs input in subicular microcircuits, modifications of this input could be considered in the development of therapeutic strategies to improve seizure control.

A Ketogenic Diet may Improve Cognitive Function in Rats with Temporal Lobe Epilepsy by Regulating Endoplasmic Reticulum Stress and Synaptic Plasticity.

A ketogenic diet (KD) is often used in the treatment of refractory epilepsy. Many studies have found that it also has a positive impact on cognitive comorbidities, but the specific mechanism remains unclear. In many disease models, endoplasmic reticulum stress (ERS) and synaptic plasticity is considered a new therapeutic target for improving cognitive impairment, and it has become a research focus in recent years. Recently, studies have found that a KD has a certain regulatory effect on both ERS and synaptic plasticity, but this result has not been confirmed in epilepsy. To investigate the effect of a KD on ERS and synaptic plasticity. In this study, a rat model of temporal lobe epilepsy (TLE) induced by lithium chloride-pilocarpine was used. After the model was successfully established, the rats in each group were fed a normal diet or a KD for 28 days, and the effect of a KD on the latency and seizure frequency of spontaneous recurrent seizures (SRSs) was observed via video monitoring. Subsequently, a Morris water maze was used to evaluate the spatial learning and memory abilities of the rats in each group; the ultrastructure of the ER and the synapses of the hippocampus were observed by transmission electron microscopy, and the dendritic spine density of the hippocampus was analysed by Golgi staining. Long-term potentiation (LTP) was used to detect the synaptic plasticity of the rats' hippocampi, and the expression of ERS-related proteins and synapse-related proteins was detected by Western blotting. A KD effectively reduced the frequency of SRSs in rats with TLE and improved their learning and memory impairment. Further investigations found that a KD inhibited the up-regulation of glucose-regulated protein 78, phospho-protein kinase-like ER kinase, phosphorylated α subunit of eukaryotic initiation factor 2, activating transcription factor 4 and C/EBP homologous protein expression in the hippocampi of rats with TLE and protected the ultrastructure of the neuronal ER, suggesting that a KD suppressed excessive ERS induced by epilepsy. Concurrently, we also found that a KD not only improved the synaptic ultrastructure and increased the density of dendritic spines in rats with TLE but also reversed the epilepsy-induced LTP deficit to some extent. More importantly, the expression of postsynaptic density protein 95, synaptotagmin-1 and synaptosomal-associated protein 25 in the hippocampi of rats with epilepsy was significantly increased after KD intervention. The study findings indicate that a KD improves learning and memory impairment in rats with epilepsy, possibly by regulating ERS and synaptic plasticity.

Antiepileptogenic Effects of Anakinra, Lamotrigine and Their Combination in a Lithium-Pilocarpine Model of Temporal Lobe Epilepsy in Rats.

Temporal lobe epilepsy is a common, chronic disorder with spontaneous seizures that is often refractory to drug therapy. A potential cause of temporal lobe epilepsy is primary brain injury, making prevention of epileptogenesis after the initial event an optimal method of treatment. Despite this, no preventive therapy for epilepsy is currently available. The purpose of this study was to evaluate the effects of anakinra, lamotrigine, and their combination on epileptogenesis using the rat lithium-pilocarpine model of temporal lobe epilepsy. The study showed that there was no significant difference in the number and duration of seizures between treated and untreated animals. However, the severity of seizures was significantly reduced after treatment. Anakinra and lamotrigine, alone or in combination, significantly reduced neuronal loss in the CA1 hippocampus compared to the control group. However, the drugs administered alone were found to be more effective in preventing neuron loss in the hippocampal CA3 field compared to combination treatment. The treatment alleviated the impairments in activity level, exploratory behavior, and anxiety but had a relatively weak effect on TLE-induced impairments in social behavior and memory. The efficacy of the combination treatment did not differ from that of anakinra and lamotrigine monotherapy. These findings suggest that anakinra and lamotrigine, either alone or in combination, may be clinically useful in preventing the development of histopathological and behavioral abnormalities associated with epilepsy.

Phase II randomised placebo-controlled trial of sodium selenate as a disease-modifying treatment in chronic drug-resistant temporal lobe epilepsy: the SeLECT study protocol

IntroductionEpilepsy is one of the most common neurological conditions worldwide. Despite many antiseizure medications (ASMs) being available, up to one-third of patients do not achieve seizure control. Preclinical studies have...

Seizing hope: Advancing cell therapy for pharmaco-resistant epilepsy toward the clinic.

In this issue of Cell Stem Cell, Bershteyn etal.1 developed a human interneuron cell therapy that reduced spontaneous seizure activity in a mouse model of mesial temporal lobe epilepsy (MTLE). The data presented here support an ongoing phase 1/2 clinical trial for the treatment of pharmaco-resistant epilepsy in patients.

Dimethyl sulfoxide’s impact on epileptiform activity in a mouse model of chronic temporal lobe epilepsy

In the quest for novel treatments for patients with drug-resistant seizures, poor water solubility of potential drug candidates is a frequent obstacle. Literature indicated that the highly efficient solvent dimethyl sulfoxide (DMSO) may have a confounding influence in epilepsy research, reporting both pro- and antiepileptic effects. In this study, we aim to clarify the effects of DMSO on epileptiform activity in one of the most frequently studied models of chronic epilepsy, the intrahippocampal kainic acid (IHKA) mouse model, and in a model of acute seizures. We show that 100 % DMSO (in a volume of 1.5 µl/g corresponding to 1651 mg/kg) causes a significant short-term anti-seizure effect in epileptic IHKA mice of both sexes, but does not affect the threshold of acute seizures induced by pentylenetetrazol (PTZ). These findings highlight that the choice of solvent and appropriate vehicle control is crucial to minimize undesirable misleading effects and that drug candidates exclusively soluble in 100 % DMSO need to be modified for better solubility already at initial testing.

Ictogenesis proceeds through discrete phases in hippocampal CA1 seizures in mice

Epilepsy is characterized by spontaneous non-provoked seizures, yet the mechanisms that trigger a seizure and allow its evolution remain underexplored. To dissect out phases of ictogenesis, we evoked hypersynchronous activity with optogenetic stimulation. Focal optogenetic activation of putative excitatory neurons in the mouse hippocampal CA1 reliably evoked convulsive seizures in awake mice. A time-vs-time pulsogram plot characterized the evolution of the EEG pulse response from a light evoked response to induced seizure activity. Our results depict ictogenesis as a stepwise process comprised of three distinctive phases demarcated by two transition points. The induction phase undergoes the first transition to reverberant phase activity, followed by the second transition into the paroxysmal phase or a seizure. Non-seizure responses are confined to either induction or reverberant phases. The pulsogram was then constructed in seizures recorded from a murine model of temporal lobe epilepsy and it depicted a similar reverberance preceding spontaneous seizures. The discovery of these distinct phases of ictogenesis may offer means to abort a seizure before it develops.