Seizure Intensity Research Articles

Assessment of the potential protective effectsof culture filtrate ofTrichoderma harzianum to ameliorate the damagedhistoarchitecture of brain in epileptic rats.

The simultaneous hyperexcitability of the neural network is the most well-known manifestation of epilepsy that causes recurrent seizures. The current study was aimed to examine any potential safety benefits of the culture filtrate of Trichoderma harzianum (ThCF) to ameliorate damaged histoarchitecture of the brain in epileptic rats by assessing seizure intensity scale and behavioral impairments and follow up the spontaneous motor seizures during status epilepticus phases in rats. Twenty-four rats were divided into four groups; control (C), epileptic (EP) valproic acid-treated epileptic (EP-VPA), and epileptic treated with T. harzianum cultured filtrate (ThCF). In addition to a seizure intensity score and behavioral tests, routine H&E and Golgi-Copsch histopathology, were used to examine the cell somas, dendrites, axons, and neural spines. ThCF treatment increased activity and recorded movements during grooming, rearing, and ambulation frequency. Brain tissues of epileptic rats exhibited detached meninges, hypercellularity, mild edema in the cortex and markedly degenerated neurons, degenerated glial cells, and microcyst formation in the hippocampus. Moreover, brains of EP-ThCF were noticed with average blood vessels, and increased dendritogenesis. The current data revealed some of negative effects of epileptogenesis brought on by seizure intensity score and retarded histopathological alterations in the hippocampus. Therefore, the study is forecasting to identify novel active components from the metabolites of T. harzianum with a crucial therapeutic role in various disorders.

Effects of acute administration of 4-allyl-2,6-dimethoxyphenol in mouse models of seizures

Epilepsy, a chronic neurological disorder characterized by recurrent unprovoked seizures, presents a substantial challenge in approximately one-third of cases exhibiting resistance to conventional pharmacological treatments. This study investigated the effect of 4-allyl-2,6-dimethoxyphenol, a phenolic compound derived from various natural sources, in different models of induced seizures and its impact on animal electroencephalographic (EEG) recordings. Adult male Swiss albino mice were pre-treated (i.p.) with a dose curve of 4-allyl-2,6-dimethoxyphenol (50, 100, or 200 mg/kg), its vehicle (Tween), or standard antiepileptic drug (Diazepam; or Phenytoin). Subsequently, the mice were subjected to different seizure-inducing models – pentylenetetrazole (PTZ), 3-mercaptopropionic acid (3-MPA), pilocarpine (PILO), or maximal electroshock seizure (MES). EEG analysis was performed on other animals surgically implanted with electrodes to evaluate brain activity. Significant results revealed that animals treated with 4-allyl-2,6-dimethoxyphenol exhibited increased latency to the first myoclonic jerk in the PTZ and PILO models; prolonged latency to the first tonic-clonic seizure in the PTZ, 3-MPA, and PILO models; reduced total duration of tonic-clonic seizures in the PTZ and PILO models; decreased intensity of convulsive seizures in the PTZ and 3-MPA models; and diminished mortality in the 3-MPA, PILO, and MES models. EEG analysis indicated an increase in the percentage of total power attributed to beta waves following 4-allyl-2,6-dimethoxyphenol administration. Notably, the substance protected from behavioral and electrographic seizures in the PTZ model, preventing increases in the average amplitude of recording signals while also inducing an increase in the participation of theta and gamma waves. These findings suggest promising outcomes for the tested phenolic compound across diverse pre-clinical seizure models, highlighting the need for further comprehensive studies to elucidate its underlying mechanisms and validate its clinical relevance in epilepsy management.

Formulation, Optimization and In-Vivo Characterization of Thermosensitive In-Situ Nasal Gel Loaded with Bacoside a for Treatment of Epilepsy.

The intranasal route has demonstrated superior systemic bioavailability due to its extensive surface area, the porous nature of the endothelial membrane, substantial blood flow, and circumvention of first-pass metabolism. In traditional medicinal practices, Bacopa monnieri, also known as Brahmi, is known for its benefits in enhancing cognitive functions and potential effects in epilepsy. This study aimed to develop and optimize a thermosensitive in-situ nasal gel for delivering Bacoside A, the principal active compound extracted from Bacopa monnieri. The formulation incorporated Poloxamer 407 as a thermogelling agent and HPMC K4M as the Mucoadhesive polymer. A 32-factorial design approach was employed for Optimization. Among the formulations. F7 exhibited the most efficient Ex-vivo permeation through the nasal mucosa, achieving 94.69 ± 2.54% permeation, and underwent a sol-gel transition at approximately 30.48°C. The study's factorial design revealed that gelling temperature and mucoadhesive strength were critical factors influencing performance. The potential of in-situ nasal Gel (Optimized Batch-F7) for the treatment of epilepsy was demonstrated in an in-vivo investigation using a PTZ-induced convulsion model. This formulation decreased both the occurrence and intensity of seizures. The optimized formulation F7 showcases significant promise as an effective nasal delivery system for Bacoside A, offering enhanced bioavailability and potentially increased efficacy in epilepsy treatment.

Effect of vagus nerve stimulation on emergency department utilization in children with drug-resistant epilepsy: a retrospective cohort study.

Epilepsy affects approximately 470,000 children in the United States. The estimated median incidence is 50.4 cases per 100,000 persons per year. There are approximately 3.1 million seizure-related emergency department (ED) visits per year among children. Vagus nerve stimulation (VNS) is a treatment option for drug-resistant epilepsy (DRE). While its primary goal is to decrease seizure burden, VNS may decrease seizure intensity and improve quality of life. The authors assessed whether VNS decreased the number of seizure-related ED visits in a cohort of children with DRE. The authors performed a retrospective chart review of pediatric patients (aged 0-21 years) who underwent implantation of a vagus nerve stimulator between January 2009 and January 2020 at the University of Pittsburgh Medical Center Children's Hospital of Pittsburgh. They used paired t-tests to assess differences in the number of ED visits 2 years before versus 2 years after VNS device implantation. Univariable linear regression analyses were used to test associations of preoperative characteristics with change in the number of ED visits following vagus nerve stimulator insertion. This study included 240 patients. Compared with patients without seizure-related ED visits before VNS, patients with ≥ 1 ED visits were younger in age at first VNS surgery (9.5 vs 10.8 years), had a shorter epilepsy duration before VNS surgery (5.8 vs 7.4 years), had a later year of device implantation (2014 vs 2012), and on average took more antiseizure medications (ASMs; 2.4 vs 2.1). There was no significant difference between the total number of seizure-related ED visits pre- versus post-VNS surgery (1.72 vs 1.59, p = 0.50), and no difference in status epilepticus-related visits (0.59 vs 0.46, p = 0.17). Univariable linear regression analyses revealed a mean change in ED visits of +0.3 for each year prior to 2022 and -0.5 for each additional ASM that patients took before vagus nerve stimulator insertion. This single-institution analysis demonstrated no significant change in the number of seizure-related ED visits within 2 years following VNS device implantation. Earlier VNS surgery was associated with more seizure-related ED visits after device insertion, suggesting that medical management and center experience may play a role in decreasing seizure-related ED visits. A greater number of ASMs was associated with fewer seizure-related ED visits after VNS device insertion, suggesting the role of medical management, patient baseline seizure threshold, and caregiver comfort with at-home seizure management.

Visual detection of seizures in mice using supervised machine learning.

Seizures are caused by abnormally synchronous brain activity that can result in changes in muscle tone, such as twitching, stiffness, limpness, or rhythmic jerking. These behavioral manifestations are clear on visual inspection and the most widely used seizure scoring systems in preclinical models, such as the Racine scale in rodents, use these behavioral patterns in semiquantitative seizure intensity scores. However, visual inspection is time-consuming, low-throughput, and partially subjective, and there is a need for rigorously quantitative approaches that are scalable. In this study, we used supervised machine learning approaches to develop automated classifiers to predict seizure severity directly from noninvasive video data. Using the PTZ-induced seizure model in mice, we trained video-only classifiers to predict ictal events, combined these events to predict an univariate seizure intensity for a recording session, as well as time-varying seizure intensity scores. Our results show, for the first time, that seizure events and overall intensity can be rigorously quantified directly from overhead video of mice in a standard open field using supervised approaches. These results enable high-throughput, noninvasive, and standardized seizure scoring for downstream applications such as neurogenetics and therapeutic discovery.

The use of ibuprofen as an anti-seizure medication: a systematic review

Summary Background Epileptic seizure is a transient period of signs and symptoms resulting from the abnormal excessive and synchronous neuronal activity in the brain, resulting in brain damage. To prevent complications, the antiseizure medication is needed. Several agents have a potency of anti-seizure effect, including ibuprofen. Unfortunately, there are few studies regarding the anti-seizure effect of ibuprofen. Aim To determine the anti-seizure effect of ibuprofen to reduce the symptoms of epileptic seizures. Materials and Methods A systematic review using the databases ScienceDirect, SpringerLink, Nature, and Pubmed. The article was obtained using the keywords “ibuprofen” and (“epilepsy” or “anticonvulsant” or “antiseizure” or “epileptic” or “neuroinflammation”) in the period 2012 to 2022 and screened with inclusion and exclusion criteria. Out of the 1376 articles screened, there are three studies included in this review. The SYRCLE Risk of Bias Tool was used to assess the risk of bias, and the data was synthesised using SWiM guidelines. Results Ibuprofen affects seizures by reducing the number, grade, and duration of seizure intensity in the PTZ-induced rats. Despite the risk of bias assessment revealing some potential bias in the studies, our study shows that ibuprofen has potency as an additional agent for epileptic seizures among febrile convulsive patients. Conclusion In animal models of seizures, ibuprofen has an antiseizure effect by reducing the number, grade, and duration of seizures.

Piroxicam reduced the intensity of epileptic seizures in a kindling seizure model

ABSTRACT Introduction: The close relationship between inflammatory processes and epileptic seizures is already known, although the exact pathophysiological mechanism is unclear. In this study, the anticonvulsant capacity of piroxicam, an anti-inflammatory drug, was evaluated. A rat pentylenetetrazole kindling model was used. Methods: Male Wistar rats, 8–9 weeks old, received piroxicam (0.15 and 0.30 mg/kg), diazepam (2 mg/kg) or saline for 14 days, and PTZ, on alternate days. Intraperitoneal was chosen as the route of administration. The intensity of epileptic seizures was assessed using a modified Racine scale. The open field test and object recognition analysis were performed at the beginning of the study to ensure the safety of the drugs used. At the end of the protocol, the animals were euthanized to measure the levels of inflammatory (TNF-a and IL-6) and anti-inflammatory (IL-10) cytokines in the cortex, hippocampus, and serum. Results:There were no changes in the open field test and object recognition analysis. Piroxicam was found to decrease Racine scale scores at both concentrations. The reported values for IL-6 levels remained steady in all structures, whereas the TNF-alpha level in the cortex was higher in animals treated with piroxicam than in the saline and diazepam subjects. Finally, animals treated with the anti-inflammatory drug presented reduced IL-10 levels in the cortex and hippocampus. onclusions: Using inflammation as a guiding principle, the anticonvulsant effect of PIRO could be associated with the hippocampal circuits, since this structure showed no increase in inflammatory cytokines.

Wireless EEG Recording of Audiogenic Seizure Activity in Freely Moving Krushinsky-Molodkina Rats.

This study investigates audiogenic epilepsy in Krushinsky-Molodkina (KM) rats, questioning the efficacy of conventional EEG techniques in capturing seizures during animal restraint. Using a wireless EEG system that allows unrestricted movement, our aim was to gather ecologically valid data. Nine male KM rats, prone to audiogenic seizures, received implants of wireless EEG transmitters that target specific seizure-related brain regions. These regions included the inferior colliculus (IC), pontine reticular nucleus, oral part (PnO), ventrolateral periaqueductal gray (VLPAG), dorsal area of the secondary auditory cortex (AuD), and motor cortex (M1), facilitating seizure observation without movement constraints. Our findings indicate that targeted neural intervention via electrode implantation significantly reduced convulsive seizures in approximately half of the subjects, suggesting therapeutic potential. Furthermore, the amplitude of brain activity in the IC, PnO, and AuD upon audiogenic stimulus onset significantly influenced seizure severity and nature, highlighting these areas as pivotal for epileptic propagation. Severe cases exhibited dual waves of seizure generalization, indicative of intricate neural network interactions. Distinctive interplay between specific brain regions, disrupted during convulsive activity, suggests neural circuit reconfiguration in response to escalating seizure intensity. These discoveries challenge conventional methodologies, opening avenues for novel approaches in epilepsy research and therapeutic interventions.

Utilizing GO/PEDOT:PSS/PtNPs-enhanced high-stability microelectrode arrays for investigating epilepsy-induced striatal electrophysiology alterations.

The striatum plays a crucial role in studying epilepsy, as it is involved in seizure generation and modulation of brain activity. To explore the complex interplay between the striatum and epilepsy, we engineered advanced microelectrode arrays (MEAs) specifically designed for precise monitoring of striatal electrophysiological activities in rats. These observations were made during and following seizure induction, particularly three and 7days post-initial modeling. The modification of graphene oxide (GO)/poly (3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS)/platinu-m nanoparticles (PtNPs) demonstrated a marked reduction in impedance (10.5 ± 1.1kΩ), and maintained exceptional stability, with impedance levels remaining consistently low (23kΩ) even 14days post-implantation. As seizure intensity escalated, we observed a corresponding increase in neuronal firing rates and local field potential power, with a notable shift towards higher frequency peaks and augmented inter-channel correlation. Significantly, during the grand mal seizures, theta and alpha bands became the dominant frequencies in the local field potential. Compared to the normal group, the spike firing rates on day 3 and 7 post-modeling were significantly higher, accompanied by a decreased firing interval. Power in both delta and theta bands exhibited an increasing trend, correlating with the duration of epilepsy. These findings offer valuable insights into the dynamic processes of striatal neural activity during the initial and latent phases of temporal lobe epilepsy and contribute to our understanding of the neural mechanisms underpinning epilepsy.

Nicotinamide mononucleotide alleviates seizures via modulating SIRT1-PGC-1α mediated mitochondrial fusion and fission.

Both human and animal experiments have demonstrated that energy metabolism dysfunction in neurons after seizures is associated with an imbalance in mitochondrial fusion/fission dynamics. Effective neuronal mitochondrial dynamics regulation strategies remain elusive. Nicotinamide mononucleotide (NMN) can ameliorate mitochondrial functional and oxidative stress in age-related diseases. But whether NMN improves mitochondrial energy metabolism to exert anti-epileptic effects is unclear. This study aims to clarify if NMN can protect neurons from pentylenetetrazole (PTZ) or Mg2+ -free-induced mitochondrial disorder and apoptosis via animal and cell models. We established a continuous 30-day PTZ (37 mg/kg) intraperitoneal injection-induced epileptic mouse model and a cell model induced by Mg2+ -free solution incubation to explore the neuroprotective effects of NMN. We found that NMN treatment significantly reduced the seizure intensity of PTZ-induced epileptic mice, improved their learning and memory ability, and enhanced their motor activity and exploration desire. At the same time, invitro and invivo experiments showed that NMN can inhibit neuronal apoptosis and improve the mitochondrial energy metabolism function of neurons. In addition, NMN down-regulated the expression of mitochondrial fission proteins (Drp1 and Fis1) and promoted the expression of mitochondrial fusion proteins (Mfn1 and Mfn2) by activating the SIRT1-PGC-1α pathway, thereby inhibiting PTZ or Mg2+ -free extracellular solution-induced mitochondrial dysfunction, cell apoptosis, and oxidative stress. However, combined intervention of SIRT1 inhibitor, Selisistat, and PGC-1α inhibitor, SR-18292, eliminated the regulatory effect of NMN pre-treatment on mitochondrial fusion and fission proteins and apoptosis-related proteins. Therefore, NMN intervention may be a new potential treatment for cognitive impairment and behavioral disorders induced by epilepsy, and targeting the SIRT1-PGC-1α pathway may be a promising therapeutic strategy for seizures.

Comparative characteristics of healthy pregnant women and non-healthy pregnant women

We carried out a systematic search by using a literature about the issue of our interest in the PubMed and Scopus search databases. We systematically searched the literature published from December 1, 2019 to July 30, 2021 across multiple databases including PubMed, Web of Science, Google Scholar and the WHO COVID-19 database using the following keywords: “COVID-19” and “pregnancy”. Filter by date: March 1, 2020-until March 1, 2021. We have made a review of the literature on the issue of our interest in the PubMed and Scopus search databases. Based on our understanding, we want to present a small literary review. Changes in the cardiorespiratory and immune systems during pregnancy increase woman's susceptibility to severe infection and hypoxic compromise, but at the same time they may also delay diagnosis and source control in those who have only mild upper respiratory symptoms such as sore throat and nasal congestion; the latter are observed in 5% of patients with COVID-19. With gestational rhinitis, it should also be noted that in pregnant women the content of estrogen, β-estradiol increases, which increases the reactivity of the immune system. Therefore, the intensity of seizures during gestation can increase significantly. However, a high con-centration of estrogen disrupts vascular motility, causing vasomotor rhinitis during pregnancy, usually affects a fifth of healthy women in late pregnancy and leads to severe nasal congestion and rhinorrhea; these signs can mask the symptoms of COVID-19, leading to uncontrolled viral shedding and trans-mission. Dyspnea occurs in 18% of patients with COVID-19.

Quercetin Exerts Anticonvulsant Effect through Mitigation of Neuroinflammatory Response in Pentylenetetrazole-induced Seizure in Mice.

Epilepsy is a chronic disease of the brain characterized by seizures. The currently available anticonvulsants only treat symptoms with serious adverse drug reactions. Therefore, there is need for new therapeutic intervention that will prevent epileptogenesis with greater therapeutic success. Quercetin (QT) is a flavonoid with known neuroprotective and anti-inflammatory properties. The study aimed to investigate its effects against pentylenetetrazole (PTZ)-induced seizures. Animals were divided into four groups (n = 10). Group 1(control) only received vehicle (10 mL/kg), group 2 received vehicle, groups 3 and 4 received QT 12.5 mg/kg and 25 mg/kg respectively. Sixty minutes after treatments, animals in groups 2 to 4 were injected with sub-convulsive dose of pentylenetetrazole (35 mg/kg, i.p.) on every alternate day (48±2h) for 21 days. The mice were observed for 30 minutes after each PTZ injection for seizure activity. Brain samples were collected for biochemical assays. Administration of PTZ caused significant increase in the intensity of seizures, neuronal degeneration and level of proinflammatory cytokines in animals compared to control. These behavioural alterations were attenuated significantly by QT (12.5 and 25 mg/kg). The PTZ-induced increase in IL-12, TNF-α and IFN-ɣ were significantly reduced by pre-treatment with the QT (12.5 and 25 mg/kg, p.o). Quercetin also reduced neuronal loss compared to control. Quercetin attenuates seizures in kindled mice and reduces neuroinflammation and neurodegeneration. This neuroprotective effect may be attributed to its ability to inhibit inflammatory mediators in the brain.

Female sex steroids and epilepsy: Part 1. A review of reciprocal changes in reproductive systems, cycles, and seizures.

Seizures, antiseizure medications, and the reproductive systems are reciprocally entwined. In Section2 of this review, we outline how seizures may affect the hypothalamic-pituitary-gonadal axis, thereby altering sex steroids, and changes in sex steroids across the menstrual cycle and changes in pharmacokinetics during pregnancy may alter seizure susceptibility. The literature indicates that females with epilepsy experience increased rates of menstrual disturbances and reproductive endocrine disorders. The latter include polycystic ovary syndrome, especially for females on valproate. Studies of fertility have yielded mixed results. We aim to summarize and attempt to detangle the existing knowledge on these reciprocal interactions. The menstrual cycle causes changes in seizure intensity and frequency for many females. When this occurs perimenstrually, during ovulation, or in association with an inadequate luteal phase, it is termed catamenial epilepsy. There is a clear biophysiological rationale for how the key female reproductive neurosteroids interact with the brain to alter the seizure threshold, and Section3 outlines this important relationship. Critically, what remains unknown is the specific pathophysiology of catamenial epilepsy that describes why not all females are affected. There is a need for mechanism-focused investigations in humans to uncover the complexity of the relationship between reproductive hormones, menstrual cycles, and the brain.

Characteristics of murine phenotypes with signs of epilepsy obtained through ENU mutagenesis

Epilepsy is a chronic neurological disorder marked by recurring seizures and associated dysfunctions of motor, sensory, autonomic, and mental functions resulting from excessive electrical activity of neurons. Identification and characterization of the mutations that cause this pathology are essential for understanding the mechanisms that control epileptogenesis. The aim of the study is to characterize the S8-3 mutant mice strain, which shows induced epileptiform activity in response to audiogenic stimulation. Mutant strains of mice were acquired through induced chemical mutagenesis using N-ethyl-N-nitrosourea (ENU). Twenty-nine male mice were administered three rounds of ENU injections at a dose of 90 mg/kg during the study. On day 21 after birth (P21), identification and selection of mouse mutants with an elevated inclination towards epileptic seizures were conducted using the Krushinsky scale, which considered the intensity of audiogenic seizures. Strains with a recessive mutation were created by selecting animals that exhibited the aberrant phenotype for the second time. The abnormal phenotype was confirmed in the G5 generation, and basic behavioral phenotyping was performed to characterize the resulting epileptic lines. Correct grammar, spelling, and punctuation. This included assessing memory, learning ability, motor reactions, and emotional status. In vitro experiments assessed spontaneous calcium activity with primary neuronal cultures of the cerebral cortex isolated from newborn mice. The Ca2+ indicator used was Oregon Green 488 BAPTA-1 AM. Upon screening 60 strains of mice for sensitivity to audiogenic stimulation, 12 strains exhibiting epileptiform activity were observed. Subsequently, the S8-3 group was selected for further research, as its offspring (G3) showed a higher frequency of the aberrant phenotype in comparison to the other groups. Results from behavioral studies comparing S5-1 mice to the control hybrid animal group displayed a higher intensity of the acoustic startle response. The open field tests revealed that the motor activity of S8-3 strain mice was higher than that of the control group, based on the average distance traveled, and their anxiety level was lower, as indicated by fewer rears, urinary points, and boluses. When assessing cognitive functions through the CPAR test, mutant individuals exhibited high learning ability. In vitro experiments showed an increase in the frequency of spontaneous calcium events in primary cell cultures of the cerebral cortex isolated from S8-3 mice.

Long-term treatment with ganaxolone for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: Two-year open-label extension follow-up.

In the placebo-controlled, double-blind phase of the Marigold study (NCT03572933), ganaxolone significantly reduced major motor seizure frequency (MMSF) in patients with cyclin-dependent kinase-like 5 deficiency disorder (CDD). We report 2-year safety and clinical outcomes data from the open-label extension (OLE) phase of Marigold. Patients with CDD who completed the double-blind phase were eligible to continue in the OLE. Efficacy assessments included MMSF reduction from prerandomization baseline, responder rates, and Clinical Global Impression-Improvement scores, including assessment of seizure intensity and duration (CGI-CSID). Safety assessments included treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. Of 101 patients who enrolled in Marigold, 88 (87.1%) entered the OLE (median age = 5 years, 79.5% female). Median 28-day MMSF at baseline was 50.6. At 2 years in the OLE (months 22-24), MMSF was reduced by a median of 48.2% (n = 50); when missing data were imputed, median reduction in MMSF was 43.8% using a mixed effects model and 27.4% using a last observation carried forward model. During months 22-24, 23 of 50 (46.0%) patients experienced reductions in MMSF of ≥50%; 12 of 50 (24.0%) patients experienced MMSF reductions of ≥75%. During months 22-24, 40 of 49 (81.6%) patients were rated by caregivers as having improvement in seizure-related outcomes based on CGI-CSID scores. Thirty-seven patients discontinued ganaxolone due to lack of efficacy (n = 13), withdrawal by caregiver (n = 12), adverse event (n = 10), physician decision (n = 1), or death (n = 1; unrelated to study drug). The most common treatment-related TEAEs were somnolence (17.0%), seizure (11.4%), and decreased appetite (5.7%). Patients reported serious TEAEs (n = 28, 31.8%); those reported in ≥3% of patients were seizure (n = 6), pneumonia (n = 5), acute respiratory failure (n = 3), aspiration pneumonia (n = 3), and dehydration (n = 3). Sustained reductions in MMSF at 2 years in the OLE support the efficacy of ganaxolone in seizures associated with CDD. Safety findings in the OLE were consistent with the double-blind phase.

Adrenergic mechanisms of absence status epilepticus.

Absence status epilepticus is a prolonged, generalized absence seizure that lasts more than half an hour. The mechanisms underlying the absence of status epilepticus are still not entirely understood. In this study, the study concentrates on alpha2-adrenergic mechanisms of absence status using the WAG/Rij rat model. In this model, a prolonged spike-wave activity was associated with a specific behavioral state in transition between sedation («alpha2-wakefulness»)-resembled absence status in human patients. Pharmacological activation of alpha2-adrenoreceptors may target the locus coeruleus (presynaptic alpha2-adrenoreceptors) and the thalamic part of the seizure-generating thalamocortical system (postsynaptic alpha2B-adrenoreceptors). The duration of EEG-behavioral correlates of absence status was not dose-dependent and was predetermined by the intensity of absence seizures at baseline. This model could help scientists better understand the underlying causes of absence status and develop more effective and personalized treatments for each individual.

Anti-inflammatory effects of icariin in the acute and chronic phases of the mouse pilocarpine model of epilepsy

Neuroinflammation mediated by microglia made a significant contribution in the pathophysiology of epilepsy. Icariin (ICA), a bioactive ingredient isolated from Epimedium, has been shown to present both antioxidant and anti-inflammatory properties. This study was to explore the potential therapeutic effects of icariin on mouse pilocarpine model of epilepsy and its underlying mechanisms in vivo and in vitro. To this end, we firstly measured the serum concentrations of the proinflammatory cytokines IL-1β and IL-6 from patients with temporal lobe epilepsy and found that patients with a higher seizure frequency showed correspondingly higher inflammatory reaction. Mouse pharmacokinetic study, transmembrane transportation assay, and cell viability assay collectively demonstrated that ICA was able to cross the blood-brain barrier and has good biocompatibility. The acute and chronic epilepsy models were next established in a pilocarpine mouse model of acquired epilepsy. Icariin has been identified that it could cross the blood-brain barrier and enter the hippocampus to exhibit therapeutic effects. ICA treatment dramatically promoted microglial polarization to the M2 phenotype in epilepsy mice both in the acute and chronic phases. Reduced release of M1-associated proinflammatory factors, such as IL-1β and IL-6, corroborates the altered glial cell polarization. Furthermore, ICA alleviated seizure intensity and mortality in acute phase epileptic mice. Models in the chronic group also showed improved general condition, cognition ability, and memory function after ICA treatment. Taken together, our research strongly suggested that icariin has the potential to treat epilepsy via inhibiting neuroinflammation by promoting microglial polarization to the M2 phenotype.

Effects of N-acetylcysteine and acetyl-L-carnitine on acute PTZ-induced seizures in larval and adult zebrafish.

Epilepsy is a prevalent neurological disease, affecting approximately 1-2% of the global population. The hallmark of epilepsy is the occurrence of epileptic seizures, which are characterized by predictable behavioral changes reflecting the underlying neural mechanisms of the disease. Unfortunately, around 30% of patients do not respond to current pharmacological treatments. Consequently, exploring alternative therapeutic options for managing this condition is crucial. Two potential candidates for attenuating seizures are N-acetylcysteine (NAC) and Acetyl-L-carnitine (ALC), as they have shown promising neuroprotective effects through the modulation of glutamatergic neurotransmission. This study aimed to assess the effects of varying concentrations (0.1, 1.0, and 10mg/L) of NAC and ALC on acute PTZ-induced seizures in zebrafish in both adult and larval stages. The evaluation of behavioral parameters such as seizure intensity and latency to the crisis can provide insights into the efficacy of these substances. Our results indicate that both drugs at any of the tested concentrations were not able to reduce PTZ-induced epileptic seizures. On the other hand, the administration of diazepam demonstrated a notable reduction in seizure intensity and increased latencies to higher scores of epileptic seizures. Consequently, we conclude that, under the conditions employed in this study, NAC and ALC do not exhibit any significant effects on acute seizures in zebrafish.

(-)-α-bisabolol exerts neuroprotective effects against pentylenetetrazole-induced seizures in rats by targeting inflammation and oxidative stress

Epilepsy is the most common neurological disorder which is accompanied with behavioral and psychiatric alternations. Current evidences have shown that (-)-α-bisabolol (BSB) possess anti-inflammatory and antioxidative effects in several animal studies. Here, we conducted present study to evaluate its neuroprotective effects against pentylenetetrazole (PTZ)-induced seizures in rats. We used fifty male rats and they were randomly assigned into 5 groups control, BSB100, PTZ, BSB50 + PTZ, BSB100 + PTZ. The animals intraperitoneally received PTZ (45 mg/kg) for ten consecutive days to induce epilepsy model. BSB in doses of 50 and 100 mg/kg was administrated orally one hour before PTZ administration for ten days. The elevated plus maze (EPM) test was carried out to assess anxiety-like behavior. The seizure intensity was evaluated according to modifies Racine's convulsion scale (RCS). Y-maze and passive avoidance were utilized to assess working memory and aversive memory. The expression of pro-inflammatory cytokines and oxidative stress factors were measured using the enzyme-linked immunosorbent assay (ELISA). The neuronal cell loss in the hilar region was assessed using Nissl staining. Results showed that PTZ-treated rats had more seizure intensity, anxiety-like behavior, memory deficits, higher levels of TNF-α, IL-1β, and oxidative markers. Pre-treatment with BSB 100 significantly inhibited seizure intensity, anxiety-like behavior, and memory deficits; reduced levels of TNF-α, IL-1β, and MDA oxidative markers. Collectively, outcome of this work shows that BSB at the dose of 100 mg/kg may exert neuroprotective effects by mitigating seizures, oxidative stress, and neuroinflammation, and ameliorates memory and anxiety disorders in the PTZ-induced seizure rats.

Cenobamate in patients with highly refractory focal epilepsy: A retrospective real-world study

PurposeTo determine the effectiveness and safety outcomes of cenobamate in a cohort of patients with highly refractory focal epilepsy in routine clinical practice. MethodsObservational, retrospective, phase 4 study on subjects receiving cenobamate in three Spanish centers. The primary endpoint was the retention rate at the last follow-up. The main secondary endpoints were the 50%-responder and seizure-free rates at three months and the last follow-up. Other secondary endpoints were Global Clinical Impressions-Improvement (CGI-I) scores and treatment-emergent adverse events (TEAEs). ResultsFifty-one patients with highly refractory focal epilepsy with 24.7 years of disease evolution, ten previously tried ASM, and a 23.5% of previous epilepsy surgery were included. The retention rate at the last follow-up was 80.4%. The 50% responder rate in focal seizures at three months was 56.5% (median reduction per month 51%, 0–74.6; p < 0.0001) and in focal to bilateral tonic-clonic seizures was 63.6% (median reduction per month 89%, 0–100; p = 0.022). A total of 54.3% of subjects reported a reduction in the intensity of focal seizures, and 66% manifested clinically significant satisfaction. Cenobamate allowed a significant decrease in concomitant ASM, especially sodium channel blockers. TEAEs were reported in 43.1% of individuals, 85% of whom resolved or improved, with no new safety findings. ConclusionIn this analysis of patients with highly refractory focal epilepsy treated with cenobamate according to standard clinical practice, there was evidence of a high reduction in both seizure frequency and intensity, with a manageable safety profile.