Reduction In Seizure Duration Research Articles

Brief apnea with hypoventilation reduces seizure duration and shifts seizure location for several hours in a model of severe traumatic brain injury.

Seizures can be difficult to control in infants and toddlers. Seizures with periods of apnea and hypoventilation are common following severe traumatic brain injury (TBI). We previously observed that brief apnea with hypoventilation (A&H) in our severe TBI model acutely interrupted seizures. The current study is designed to determine the effect of A&H on subsequent seizures and whether A&H has potential therapeutic implications. Piglets (1 week or 1 month old) received multifactorial injuries: cortical impact, mass effect, subdural hematoma, subarachnoid hemorrhage, and seizures induced with kainic acid. A&H (1 min apnea, 10 min hypoventilation) was induced either before or after seizure induction, or control piglets received subdural/subarachnoid hematoma and seizure without A&H. In an intensive care unit, piglets were sedated, intubated, and mechanically ventilated, and epidural electroencephalogram was recorded for an average of 18 h after seizure induction. In our severe TBI model, A&H after seizure reduced ipsilateral seizure burden by 80% compared to the same injuries without A&H. In the A&H before seizure induction group, more piglets had exclusively contralateral seizures, although most piglets in all groups had seizures that shifted location throughout the several hours of seizure. After 8-10 h, seizures transitioned to interictal epileptiform discharges regardless of A&H or timing of A&H. Even brief A&H may alter traumatic seizures. In our preclinical model, we will address the possibility of hypercapnia with normoxia, with controlled intracranial pressure, as a therapeutic option for children with status epilepticus after hemorrhagic TBI.

Early treatment with rifaximin during epileptogenesis reverses gut alterations and reduces seizure duration in a mouse model of acquired epilepsy

The gut microbiota is altered in epilepsy and is emerging as a potential target for new therapies. We studied the effects of rifaximin, a gastrointestinal tract-specific antibiotic, on seizures and neuropathology and on alterations in the gut and its microbiota in a mouse model of temporal lobe epilepsy (TLE).Epilepsy was induced by intra-amygdala kainate injection causing status epilepticus (SE) in C57Bl6 adult male mice. Sham mice were injected with vehicle. Two cohorts of SE mice were fed a rifaximin-supplemented diet for 21 days, starting either at 24 h post-SE (early disease stage) or at day 51 post-SE (chronic disease stage). Corresponding groups of SE mice (one each disease stage) were fed a standard (control) diet. Cortical ECoG recording was done at each disease stage (24/7) for 21 days in all SE mice to measure the number and duration of spontaneous seizures during either rifaximin treatment or control diet. Then, epileptic mice ± rifaximin and respective sham mice were sacrificed and brain, gut and feces collected. Biospecimens were used for: (i) quantitative histological analysis of the gut structural and cellular components; (ii) markers of gut inflammation and intestinal barrier integrity by RTqPCR; (iii) 16S rRNA metagenomics analysis in feces. Hippocampal neuronal cell loss was assessed in epileptic mice killed in the early disease phase.Rifaximin administered for 21 days post-SE (early disease stage) reduced seizure duration (p < 0.01) and prevented hilar mossy cells loss in the hippocampus compared to epileptic mice fed a control diet. Epileptic mice fed a control diet showed a reduction of both villus height and villus height/crypt depth ratio (p < 0.01) and a decreased number of goblet cells (p < 0.01) in the duodenum, as well as increased macrophage (Iba1)-immunostaining in the jejunum (p < 0.05), compared to respective sham mice.Rifaximin’s effect on seizures was associated with a reversal of gut structural and cellular changes, except for goblet cells which remained reduced. Seizure duration in epileptic mice was negatively correlated with the number of mossy cells (p < 0.01) and with villus height/crypt depth ratio (p < 0.05).Rifaximin-treated epileptic mice also showed increased tight junctions (occludin and ZO-1, p < 0.01) and decreased TNF mRNA expression (p < 0.01) in the duodenum compared to epileptic mice fed a control diet.Rifaximin administered for 21 days in chronic epileptic mice (chronic disease stage) did not change the number or duration of seizures compared to epileptic mice fed a control diet. Chronic epileptic mice fed a control diet showed an increased crypt depth (p < 0.05) and reduced villus height/crypt depth ratio (p < 0.01) compared to respective sham mice. Rifaximin treatment did not affect these intestinal changes.At both disease stages, rifaximin modified α- and β-diversity in epileptic and sham mice compared to respective mice fed a control diet. The microbiota composition in epileptic mice, as well as the effects of rifaximin at the phylum, family and genus levels, depended on the stage of the disease. During the early disease phase, the abundance of specific taxa was positively correlated with seizure duration in epileptic mice.In conclusion, gut-related alterations reflecting a dysfunctional state, occur during epilepsy development in a TLE mouse model. A short-term treatment with rifaximin during the early phase of the disease, reduced seizure duration and neuropathology, and reversed some intestinal changes, strengthening the therapeutic effects of gut-based therapies in epilepsy.

Evaluation of Anti-epileptic Activity of Leaves of Leucas Cephalotes

Epilepsy is a neurological disorder characterized by recurrent seizures, affecting millions of people worldwide. Despite advancements in therapeutic interventions, there remains a need for novel and effective treatments with fewer side effects. This study aimed to evaluate the anti-epileptic potential of Leucas cephalotes leaves through experimental models. The leaves of Leucas cephalotes were collected, dried, and subjected to extraction using suitable solvents. The obtained extract was then evaluated for acute toxicity using standard guidelines. Subsequently, anti-epileptic activity was assessed using chemically induced seizure models in rodents. Behavioral observations, seizure latency, duration, and severity were recorded to determine the extract's efficacy. Preliminary phytochemical analysis of the extract revealed the presence of alkaloids, flavonoids, terpenoids, and phenolic compounds, which are known for their neurological effects. Acute toxicity testing indicated the safety of the extract at tested doses. In seizure models, the extract demonstrated a significant increase in seizure latency, reduction in seizure duration, and alleviation of seizure severity compared to control groups. These findings suggest that the leaves of Leucas cephalotes possess anti-epileptic properties, possibly attributed to the presence of bioactive compounds. Further studies are warranted to elucidate the underlying mechanisms and optimize dosage regimens for clinical application. Leucas cephalotes could emerge as a promising natural source for developing anti-epileptic agents with improved safety profiles.

Arisaema Cum Bile possesses significantly antiepileptic effects through regulation of PI3K/Akt/Nrf2 signaling pathways

This paper intended to study the mechanism and active ingredients of ACB anti-epilepsy. The antiepileptic activity of ACB validated in PTZ kindled rats, ACB could increase the seizure latency and reduce seizure duration, attenuate spatial learning and memory deficits, improve hippocampus neuronal damage and regulate unbalanced neurotransmitters. Furthermore, network pharmacology and molecular docking analysis predicted four potential active compounds, in addition, PI3K/Akt signal pathway may be the main signal pathway of ACB anti-epilepsy. In vitro, ACB greatly increased the vitality and reduced apoptosis of PC12 cells exposed to H2O2. Additionally, ACB elevated Bcl-2 and downregulated C-caspase-3 and Bax proteins expression. Importantly, ACB improved the phosphorylation of PI3K and Akt in H2O2-stimulated PC12 cells, and stimulated the nuclear transfer of Nrf2. These findings indicated that ACB has effective on antiepileptic by activating of the PI3K/Akt/Nrf2 pathway to reduce oxidative stress and neuronal cell apoptosis.

Study of Anticonvulsant effect of Simvastatin in Maximal Electroshock and Pentylenetetrazole Induced Seizure Model In Albino Mice

Epilepsy is a common neurological condition affecting people of all ages and both sexes. Most of the currently used antiepileptic drugs have neurotoxic and teratogenic effects. There are scanty reports of anticonvulsant activity with statins. The present study was undertaken to evaluate the anticonvulsant effect of simvastatin using MES and PTZ models in mice and compare it with the standard drugs phenytoin and diazepam respectively.64 albino mice of either sex weighing 25-35g were divided into 8 groups of 8 mice each – 4 group each for MES and PTZ model. In MES model, seizures were induced via trans auricular electrodes with a current of 80mA for 0.2 second. Each mouse was pretreated with drugs 30 minutes before in both models. The different groups 1 to 4 were administered polyethylene glycol (0.5ml/Kg), phenytoin (20mg/kg), simvastatin (10mg/Kg) and simvastatin (20mg/Kg) respectively. In PTZ model, seizures were induced by giving PTZ 80mg/Kg. The different groups 5 to 8 were administered polyethylene glycol (0.5ml/Kg), diazepam (2mg/kg), simvastatin (10mg/Kg) and simvastatin (20mg/Kg) respectively. Statistical analysis was doneby ANOVA followed by Tukey’s post hoc analysis for group wise comparison. Results indicated that the anticonvulsant effect of simvastatin (10 and 20mg/Kg) was comparable to phenytoin in the MES model. In the PTZ model, simvastatin (10mg/Kg) produced a reduction in seizure duration but did not provide seizure protection as compared to that of the diazepam. The present study demonstrated the anticonvulsant effect of simvastatin. Further studies may explore the potential of this as an add-on drug in patients with dyslipidemia and epilepsy.

Evaluation of the Effect of Pheophytin A on Electroshock- Induced Seizures in Experimental Animals

Abstract: Background: An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Approximately, 5–10% of the people have at least one kind of seizure, with more chance of occurrence in early childhood and late adulthood. There are many drugs used in seizures such as phenytoin and valproate sodium, so the main objective of current study was evaluated the efficacy of Pheophytin A compared to Valproate sodium on electroshock-induced seizures in experimental mice. Materials and Methods: The total number of 18 mice were used after divided into 3 groups in which each group was 6 mice. The first group, which is control, was received injection with distilled water. The second group was standard reference which received valproate sodium at dose of 300 mg/kg. The third group was test group which received 20 mg /kg of pheophytin A. Maximum electrical shocker was used to induce seizures. Results: The present study showed that pheophytin-A group had significantly reduced duration of seizures after 30 min of injection as compared to valproate sodium group. Valproate sodium produced more reduction in duration of seizures than pheophytin-A. Conclusion: The Pheophytin A showed antiseizure effect using maximal electrical shocker, so that it may be used in the future for treatment of seizures after further investigations. Keywords: Seizures, Pheophytin A, Valproate sodium, Maximal electroshock seizure, In vivo.

LINCs Are Vulnerable to Epileptic Insult and Fail to Provide Seizure Control via On-Demand Activation.

Temporal lobe epilepsy (TLE) is notoriously pharmacoresistant, and identifying novel therapeutic targets for controlling seizures is crucial. Long-range inhibitory neuronal nitric oxide synthase-expressing cells (LINCs), a population of hippocampal neurons, were recently identified as a unique source of widespread inhibition in CA1, able to elicit both GABAA-mediated and GABAB-mediated postsynaptic inhibition. We therefore hypothesized that LINCs could be an effective target for seizure control. LINCs were optogenetically activated for on-demand seizure intervention in the intrahippocampal kainate (KA) mouse model of chronic TLE. Unexpectedly, LINC activation at 1 month post-KA did not substantially reduce seizure duration in either male or female mice. We tested two different sets of stimulation parameters, both previously found to be effective with on-demand optogenetic approaches, but neither was successful. Quantification of LINCs following intervention revealed a substantial reduction of LINC numbers compared with saline-injected controls. We also observed a decreased number of LINCs when the site of initial insult (i.e., KA injection) was moved to the amygdala [basolateral amygdala (BLA)-KA], and correspondingly, no effect of light delivery on BLA-KA seizures. This indicates that LINCs may be a vulnerable population in TLE, regardless of the site of initial insult. To determine whether long-term circuitry changes could influence outcomes, we continued testing once a month for up to 6 months post-KA. However, at no time point did LINC activation provide meaningful seizure suppression. Altogether, our results suggest that LINCs are not a promising target for seizure inhibition in TLE.

Therapeutical impacts of transcranial direct current stimulation on drug-resistant epilepsy in pediatric patients: A double-blind parallel-group randomized clinical trial

BackgroundDrug-resistant epilepsy is a challenging problem in pediatrics. Transcranial direct current stimulation (TDCS) is a non-invasive neurostimulation technique suggested as a promising method for treating epilepsy. This study aims to evaluate the efficacy of TDCS in focal epilepsy in children with drug-resistant epilepsy. MethodWe conducted a randomized sham-controlled study with 18 subjects between 6 and 16 years of age, divided equally into two groups. TDCS was performed in 20-minute daily stimulation protocol for five days for both groups. The current intensity was one mA for the first three days, increasing to 1.5 mA on day four and 2 mA on the last day of stimulation. EEG was done before and after the intervention. ResultsThere was a significant reduction in seizure duration in the case group compared with the sham group. Conclusionfive consecutive days of performing TDCS significantly reduced seizure duration in children with focal Drug-resistant epilepsy. However,further studies in this field are necessary to test the effectiveness and set up a coherent and comprehensive protocol.

Development of charybdotoxin Q18F variant as a selective peptide blocker of neuronal BK(α + β4) channel for the treatment of epileptic seizures.

Epilepsy is the results from the imbalance between inhibition and excitation in neural circuits, which is mainly treated by some chemical drugs with side effects. Gain-of-function of BK channels or knockout of its β4 subunit associates with spontaneous epilepsy. Currently, few reports were published about the efficacy of BK(α + β4) channel modulators in epilepsy prevention. Charybdotoxin is a non-specific inhibitor of BK and other K+ channels. Here, by nuclear magnetic resonance (NMR) and other biochemical techniques, we found that charybdotoxin might interact with the extracellular loop of human β4 subunit (i.e., hβ4-loop) of BK(α + β4) channel at a molar ratio 4:1 (hβ4-loop vs. charybdotoxin). Charybdotoxin enhanced its ability to prevent K+ current of BK(α + β4 H101Y) channel. The charybdotoxin Q18F variant selectively reduced the neuronal spiking frequency and increased interspike intervals of BK(α + β4) channel by π-π stacking interactions between its residue Phe18 and residue His101 of hβ4-loop. Moreover, intrahippocampal infusion of charybdotoxin Q18F variant significantly increased latency time of seizure, reduced seizure duration and seizure numbers on pentylenetetrazole-induced pre-sensitized rats, inhibited hippocampal hyperexcitability and c-Fos expression, and displayed neuroprotective effects on hippocampal neurons. These results implied that charybdotoxin Q18F variant could be potentially used for intractable epilepsy treatment by therapeutically targeting BK(α + β4) channel.

Anticonvulsant appraisal of benzylideneacetophenone analogues in Swiss mice

Background: Diketones and α,β-unsaturated ketone are useful intermediates for the synthesis of antiepileptic moieties. Epilepsy is a neurological disorder that affects about fififty million people worldwide. The aim of the study was to assess benzylideneacetophenone analogues for their potential antiepileptic effects in mice. Methods: The compounds used in the pharmacological assay which include; 4-Dimethylaminochalcone (A), 1(4-Nitrophenyl) – 3 (ϒ -benzopyranoyl)-2-propen – 1-one (B), 1(4' –Nitrophenyl) – 3 (1,3-benzodioxolyl) 2 – propen – 1 – one (C), 1-Phenyl-3- (benzodioxolyl) – 2 –propen – 1-one (D), 4-Chlorochalcone (E), 4'-Nitro-4-dimethylaminochalcone (F) 4'-Nitro-4-methoxychalcone (G), were assayed using three models; Strychnine, Pentylenetetrazole (PTZ) and Maximal Electroshock (MES). The samples were given at 500, 1000 and 1500 mg/kg while standard&nbsp;drug diazepam and distilled water were given at 5 mg and 10 ml/kg intraperitoneal respectively.&nbsp;Convulsion inducing agents (Strychnine 2 mg/kg and PTZ, 100 mg/kg) were administered intraperitoneal 1hour after the administration of test samples while MES model electroconvulsive&nbsp;shock was applied using electroconvulsive machine.&nbsp; Results: The samples (A-G) showed significant (P&lt;0.03, 0.003, 0.0007 and 0.0001) effect in delaying onset of seizure compared to control in strychnine model, while in PTZ model samples (A-F) evaluated at 500,1000 and 1500 mg/kg are equipotent at all the doses by signifificantly (P&lt;0.0001) and sample G (P&lt;0.0007) reduced the onset of seizure compared to control. However in MES model samples (A-F and G) evaluated at 500, 1000 and 1500 mg/kg are equipotent at all the doses by significantly (P&lt;0.0001; 0.0007), reduced the duration of seizure compared to control respectively.&nbsp; Conclusion: Benzylideneacetophenone analogues showed various effects in control of seizure in all the models used.This effect is due to delayed onset and reduction of seizure duration. The samples could act by stimulating the glycine, Gamma Aminobutyric acid (GABA) receptor, inhibition of&nbsp;GABAAminotransferase and prolong inactivation of sodium ion channel.

Preclinical efficacy of cannabidiol for the treatment of early-life seizures.

The treatment of epilepsy during early life poses unique challenges-first-line therapies leave many individuals with poorly controlled seizures. In response to the pharmaco-resistance of current first-line anti-seizure drugs (ASDs) during early life, new therapies have emerged. One such therapy is cannabidiol (CBD). While well studied in adult models of epilepsy, it is poorly studied in immature animals. Here we assessed the efficacy of CBD in immature rodent models of the epilepsies. Pups were pre-treated with CBD (1, 10, 50, 100, 200mg/kg) and assessed for anticonvulsant efficacy using two well-established anti-seizure screening models: the pentylenetetrazole (PTZ) and maximal electroshock (MES) models. We assessed drug efficacy in postnatal day (P)7 and P21 rats. In the PTZ model, CBD delayed seizure onset in adolescent but not neonatal rats. By contrast, higher doses of CBD reduced seizure duration in both neonatal and adolescent rats in the MES model. The effects of CBD in both models were modest but consistent. Efficacy of CBD increased in older as compared to younger animals, producing an age-, model-, and dose-dependent suppression of seizures. These data suggest neonatal seizures (modeled by P7 treatment) may be less responsive to CBD. They also suggest preferential efficacy against tonic seizures as compared to partial motor seizures.

Seratrodast, a thromboxane A2 receptor antagonist, inhibits neuronal ferroptosis by promoting GPX4 expression and suppressing JNK phosphorylation

More than 30 % of individuals with epilepsy are refractory to currently available drugs, highlighting the urgent need to develop novel candidate drugs. Accumulating evidence implicates the key role of ferroptosis in the pathophysiology of epileptic seizuresand its potential as a new drug target. Drug repurposing is a promising strategy for the rapid generation of new candidate drugs from the market drugs with new therapeutic indications, such as the best-selling drug thalidomide. Herein, we reported the discovery of Seratrodast, a market drug of thromboxane A2 receptor antagonist as a new ferroptosis inhibitor (IC50: 4.5 μmol·L-1). Seratrodast could reduce lipid ROS production, regulate the system xc-/glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis, and inhibit JNK phosphorylation and p53 expression. In addition, Seratrodast elevated GPX4 expression and decreased JNK phosphorylation in pentylenetetrazole-induced seizures in mice. Seratrodast increased the latency of seizures and reduced seizure duration in pentylenetetrazole-induced seizures. Our results suggest Seratrodast might be either a ferroptosis inhibitor or a novel lead compound for further optimization of novel drug discovery.

The Anticonvulsant Activity of Thiamine, Vitamin D3, and Melatonin Combination on Pentylenetetrazole-induced Seizures in Mice

Objective:Epilepsy is a neurological disorder associated with the elevation of oxidative stress levels and alteration in vitamins and endogenous antioxidant levels. The current study was designed to evaluate the effects of Vit D3, thiamine, melatonin, and their combination on pentylenetetrazol (PTZ)-induced tonic-clonic seizures in mice along with measuring the alteration in oxidative stress markers.Methods:Male mice were randomly divided into seven groups; group I received normal saline (0.5 ml, i.p.) on the 15th day, group II received PTZ (60 mg/kg, i.p) on the 15th day, groups III-VI received diazepam (4 mg/kg), Vit D3 (6000 IU/kg, p.o.), thiamine (200 mg/kg, p.o.), and melatonin (20 mg/kg, p.o.), respectively, before PTZ (60 mg/kg, i.p.) injection on the 15th day, and group VII received the combination of Vit D3, thiamine, and melatonin, before PTZ injection on the 15th day. After PTZ injection, the seizure latency and duration were measured. The malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were evaluated in mice brains.Results:In the treatment group, the seizure latency was greater and the seizure duration was lower than in the PTZ group. These agents decreased the MDA level and increased SOD activity compared to the PTZ group. The combination of these agents was more effective than each alone to increase seizure latency and reduce seizure duration.Conclusion:The combination of Vit D3, thiamine, and melatonin could improve PTZ-induced seizures more effectively than each one alone; this may be mediated by inhibiting oxidative stress and regulating various mechanisms involved in seizures.

Putrescine Intensifies Glu/GABA Exchange Mechanism and Promotes Early Termination of Seizures.

Endogenous anticonvulsant mechanisms represent a reliable and currently underdeveloped strategy against recurrent seizures and may recall novel original therapeutics. Here, we investigated whether the intensification of the astroglial Glu-GABA exchange mechanism by application of the GABA precursor putrescine (PUT) may be effective against convulsive and non-convulsive seizures. We explored the potential of PUT to inhibit spontaneous spike-and-wave discharges (SWDs) in WAG/Rij rats, a genetic model of absence epilepsy. Significant shortening of SWDs in response to intraperitoneally applied PUT has been observed, which could be antagonized by blocking GAT-2/3-mediated astrocytic GABA release with the specific inhibitor SNAP-5114. Direct application of exogenous GABA also reduced SWD duration, suggesting that PUT-triggered astroglial GABA release through GAT-2/3 may be a critical step in limiting seizure duration. PUT application also dose-dependently shortened seizure-like events (SLEs) in the low-[Mg2+] in vitro model of temporal lobe epilepsy. SNAP-5114 reversed the antiepileptic effect of PUT in the in vitro model as well, further confirming that PUT reduces seizure duration by triggering glial GABA release. In accordance, we observed that PUT specifically reduces the frequency of excitatory synaptic potentials, suggesting that it specifically acts at excitatory synapses. We also identified that PUT specifically eliminated the tonic depolarization-induced desynchronization of SLEs. Since PUT is an important source of glial GABA and we previously showed significant GABA release, it is suggested that the astroglial Glu-GABA exchange mechanism plays a key role in limiting ictal discharges, potentially opening up novel pathways to control seizure propagation and generalization.

Multiple mechanisms shape the relationship between pathway and duration of focal seizures.

A seizure’s electrographic dynamics are characterized by its spatiotemporal evolution, also termed dynamical ‘pathway’, and the time it takes to complete that pathway, which results in the seizure’s duration. Both seizure pathways and durations have been shown to vary within the same patient. However, it is unclear whether seizures following the same pathway will have the same duration or if these features can vary independently. We compared within-subject variability in these seizure features using (i) epilepsy monitoring unit intracranial EEG (iEEG) recordings of 31 patients (mean: 6.7 days, 16.5 seizures/subject), (ii) NeuroVista chronic iEEG recordings of 10 patients (mean: 521.2 days, 252.6 seizures/subject) and (iii) chronic iEEG recordings of three dogs with focal-onset seizures (mean: 324.4 days, 62.3 seizures/subject). While the strength of the relationship between seizure pathways and durations was highly subject-specific, in most subjects, changes in seizure pathways were only weakly to moderately associated with differences in seizure durations. The relationship between seizure pathways and durations was strengthened by seizures that were ‘truncated’ versions, both in pathway and duration, of other seizures. However, the relationship was weakened by seizures that had a common pathway, but different durations (‘elasticity’), or had similar durations, but followed different pathways (‘semblance’). Even in subjects with distinct populations of short and long seizures, seizure durations were not a reliable indicator of different seizure pathways. These findings suggest that seizure pathways and durations are modulated by multiple different mechanisms. Uncovering such mechanisms may reveal novel therapeutic targets for reducing seizure duration and severity.

Thiopentone sodium versus propofol for anaesthesia in modified electro-convulsive therapy (ECT)

&#x0D; Objectives: To compare the effects of thiopentone sodium and propofol as an intravenous anaesthetic agent in modified ECT. Methods: 100 patients of ASA I &amp; II grade were randomly assigned in to two groups. Both groups were premedicated in ususal manner. Patients in Group A were induced with inj. thiopentone sodium 3-5mg/kg and in Group B inj. Propofol 1.5-2mg/kg. Then, Inj. Succinyl choline 0.5-1mg/kg was given. Patients were ventilated with 100% oxygen with bain circuit and mask. Shock was given after putting bite block. Patients were again ventilated till spontaneous respiration after seizures. Results: Propofol is better induction agent as compared to thiopentone sodium in terms of faster induction, better haemodynaemic stability, no significant effect on seizure duration, early recovery without any side effects. Conclusion: Propofol in the dosage of 1.5-2 mg/kg body weight intravenously can be safely used for modified ECT in ASA grade I and II pateints. Fast, smooth induction, better hemodynamics, early smooth recovery, antiemetic property and uncompromised therapeutic outcome makes propofol as an agent of choice for day care procedure. Though there is reduced seizure duration with Propofol as compared to thiopentone, there is no effect on outcome of the therapy or effectiveness of ECT.

440 Modulating decreases in Superior Colliculus activity through optogenetic activation attenuates seizures in the WAG/Rij genetic model of Absence Epilepsy

OBJECTIVES/GOALS: While anti-seizure medications are effective, nearly one third of patients have seizures that go untreated. Prior studies using evoked seizure models have shown that activation of the Superior Colliculus (SC) display anti-seizure effects. Here we monitored and modulated the DLSC to suppress spontaneous seizures in a genetic model of epilepsy. METHODS/STUDY POPULATION: WAG/Rij rats (4 months old) were employed as study subjects. Animals were surgically prepared for virus injection (ChR2 excitatory opsin, or control vector), fiber optic implantation and cortical EEG for optogenetic studies. For In vivo electrophysiology, animals were implanted with a 16 wire multi-electrode array into the DLSC. In optogenetic experiments, we compared the efficacy of continuous neuromodulation to that of on-demand neuromodulation (real time detection of seizures) paradigms on a within-subject basis. We compared three stimulation frequencies on a within-subject basis (5, 20, 100 Hz). We quantified the number and duration of each spike wave discharge (SWD) during each two-hour-long trial. Electrode array single units were sorted and analyzed for activity before, during and after seizures. RESULTS/ANTICIPATED RESULTS: In vivo electrophysiology found there to be a significant decrease in single unit activity leading up to the start of SWDs. Interestingly, on-demand neuromodulation was effective in both females and males – where the greatest reduction in seizure duration was under 100 Hz light delivery. As expected, male and female animals injected with a control vector did not show a reduction in seizures in response to light delivery. In the open-loop (continuous) stimulation paradigm, optogenetic activation of the DLSC was without effect on the number or duration of SWDs at any of the frequencies examined. DISCUSSION/SIGNIFICANCE: SC activity is significantly decreased prior to the start of seizures. Furthermore, activation of the SC displays anti-seizure effects in a model of spontaneous seizures. A striking difference between open and closed-loop neuromodulation approaches underscores the importance of stimulation paradigm in determining therapeutic effect.

Blockade of TASK-1 Channel Improves the Efficacy of Levetiracetam in Chronically Epileptic Rats.

Tandem of P domains in a weak inwardly rectifying K+ channel (TWIK)-related acid sensitive K+-1 channel (TASK-1) is an outwardly rectifying K+ channel that acts in response to extracellular pH. TASK-1 is upregulated in the astrocytes (particularly in the CA1 region) of the hippocampi of patients with temporal lobe epilepsy and chronically epilepsy rats. Since levetiracetam (LEV) is an effective inhibitor for carbonic anhydrase, which has a pivotal role in buffering of extracellular pH, it is likely that the anti-epileptic action of LEV may be relevant to TASK-1 inhibition, which remains to be elusive. In the present study, we found that LEV diminished the upregulated TASK-1 expression in the CA1 astrocytes of responders (whose seizure activities were responsive to LEV), but not non-responders (whose seizure activities were not controlled by LEV) in chronically epileptic rats. ML365 (a selective TASK-1 inhibitor) only reduced seizure duration in LEV non-responders, concomitant with astroglial TASK-1 downregulation. Furthermore, ML365 co-treatment with LEV decreased the duration, frequency and severity of spontaneous seizures in non-responders to LEV. To the best of our knowledge, our findings suggest, for the first time, that the up-regulation of TASK-1 expression in CA1 astrocytes may be involved in refractory seizures in response to LEV. This may be a potential target to improve responsiveness to LEV.

Activation of Calcium-Activated Chloride Channels Suppresses Inherited Seizure Susceptibility in Genetically Epilepsy-Prone Rats.

Inherited seizure susceptibility in genetically epilepsy-prone rats (GEPR-3s) is associated with increased voltage-gated calcium channel currents suggesting a massive calcium influx resulting in increased levels of intraneuronal calcium. Cytosolic calcium, in turn, activates many processes, including chloride channels, to restore normal membrane excitability and limit repetitive firing of the neurons. Here we used EACT and T16Ainh-A01, potent activator and inhibitor of calcium-activated channels transmembrane protein 16A (TMEM16A), respectively, to probe the role of these channels in the pathophysiology of acoustically evoked seizures in the GEPR-3s. We used adult male and female GEPR-3s. Acoustically evoked seizures consisted of wild running seizures (WRSs) that evolved into generalized tonic-clonic seizures (GTCSs) and eventually culminated into forelimb extension (partial tonic seizures). We found that acute EACT treatment at relatively higher tested doses significantly reduced the incidences of WRSs and GTCSs, and the seizure severity in male GEPR-3s. Furthermore, these antiseizure effects were associated with delayed seizure onset and reduced seizure duration. Interestingly, the inhibition of TMEM16A channels reversed EACT’s antiseizure effects on seizure latency and seizure duration. No notable antiseizure effects were observed in female GEPR-3s. Together, these findings suggest that activation of TMEM16A channels may represent a putative novel cellular mechanism for suppressing GTCSs.

Efficacy of Lacosamide Add-on Therapy on Refractory Focal Epilepsies in Children and Adolescents: An Open-Label Clinical Trial.

Epilepsy is a chronic neurological disorder that affects 0.5%-1% of children. 30%-40% of patients are resistant to current anti-epileptic drugs. Lacosamide (LCM) appeared to be effective, safe, and well tolerated in children and adolescents. This study was aimed to evaluate whether LCM could be an effective add-on therapy in children with refractory focal epilepsies. This study was conducted from April 2020 to April 2021 in Imam Hossein Children Hospital, Isfahan, Iran. We included 44 children aged 6 months to 16 years with refractory focal epilepsy (based on International League Against Epilepsy criteria). LCM was given in divided doses of 2 mg/kg/day, increasing by 2 mg/kg every week. The first follow-up visit was 6 weeks later, when all patients had reached the therapeutic dose. The average age of the patients was 89.9 months. 72.5% of children had focal motor seizures. Evaluation of percent change in seizure frequency and duration before and after treatment showed a 53.22% reduction in seizure frequency and 43.72% reduction in seizure duration after treatment. Our study group tolerated LCM well, with few side effects. Headache, dizziness, and nausea were common side effects. In line with other studies, none of the suspected risk factors could predict response to LCM treatment. LCM appears to be an effective, safe, and well-tolerated medication in children with uncontrolled drug-resistant focal epilepsy.