The bidirectional role of music effect in epilepsy: Friend or foe?

Epilepsy is a prevalent neurological disease that impacts around 70 million individuals globally. Anti-seizure medications (ASMs) are the first choice for clinicians to control unprovoked epileptic seizures. Although more than 30 ASMs are available in the market, patients with epilepsy (PWEs) still show poor responses to adequate drug treatment. Meanwhile, long-term medications not only bring heavy financial burdens but also lead to undesirable side effects. Music, a ubiquitous art form throughout human history, has been confirmed as therapeutically effective in various neurological conditions, including epilepsy. This alternative therapy offers convenience and a relatively safe approach to alleviating epileptic symptoms. Paradoxically, besides anti-convulsant effect, some particular music would cause seizures inversely, indicating the pro-convulsant effect of it. Considering that investigating the impact of music on epilepsy emerges as a compelling subject. In this review, we tried to present the following sections of content on this topic. Initially, we overviewed the impact of music on the brain and the significant progress of music therapy in central neurological disorders. Afterward, we classified the anti-convulsant and pro-convulsant effects of music in epilepsy, relying on both clinical and laboratory evidences. Finally, possible mechanisms and neural basis of the music effect were concluded, and the translational potentials and some future outlooks about the music effect in epilepsy were proposed. PLAIN LANGUAGE SUMMARY: Epilepsy is an extremely severe neurological disorder. Although anti-seizure medications are preferred choice to control seizures, the efficacy is not satisfied due to the tolerance. Anecdotal music effect had been deemed functional diversity but not clarified on epilepsy, pro-convulsive, or anti-convulsive. Here, we reviewed this interesting but puzzling topic, as well as illustrating the potential mechanisms and its translational potential.

Results from a randomized controlled trial of zonisamide in the treatment of alcohol use disorder.

There is preliminary evidence that the anticonvulsant medication Zonisamide (ZON) may be an effective, well-tolerated treatment for alcohol use disorder (AUD). However, further evaluation of its efficacy for treating patients with AUD is needed, and much remains unknown about ZON's therapeutic mechanisms. The present study aimed to evaluate the efficacy and tolerability of ZON in a double-blind, placebo-controlled, randomized trial. Eighty-one adults (ages 21-65) diagnosed with AUD were randomly assigned to receive either ZON (at a target dose of 400 mg/d) or a pill placebo over 12 weeks, followed by a two-week taper. All participants also received a computerized alcohol reduction program, Take Control (TC). Primary drinking outcomes were average daily drinks, percentage drinking days, and percentage heavy drinking days. Further, we evaluated changes in AUD clinical severity and performance on neuropsychological measures. For both groups, drinking outcomes generally decreased, as did AUD clinical severity, though group differences were not statistically significant. Neuropsychological testing performance was similar for both groups at baseline; however, at post-treatment, participants in the ZON group demonstrated poorer working memory and lower performance on verbal fluency tests compared to the placebo group, and these differences were statistically significant with moderate-large effect sizes. One serious adverse event was reported among individuals receiving ZON. Study findings indicate that ZON combined with TC does not demonstrate superior effectiveness for reducing average daily drinks in this clinical sample with principal AUD compared to placebo and TC, and treatment with ZON may be associated with reduced neurocognitive performance over time.

Are circadian rhythms more favorable with lithium than with other mood stabilizers? An exploratory actigraphy study in euthymic bipolar disorder type 1.

BACKGROUND: Bipolar Disorder (BD) is associated with alterations of circadian rhythms of activity (CRA). Experimental research suggests that lithium (Li) modifies CRA, but this has been rarely explored in BD using actigraphy. METHODS: The sample comprised 88 euthymic BD-I cases with 3 weeks of actigraphy. We used a Principal Component Analysis (PCA) to generate CRA dimensions. We then used linear regression analyses to compare these dimensions between groups of individuals defined according to prescribed mood stabilizers: Li monotherapy ("Li" group, n = 28), anticonvulsant or atypical antipsychotic monotherapy ("AC or AAP" group, n = 27) or combined treatments ("Li+AC or Li+AAP" group, n = 33). Analyses were adjusted for potential confounders (gender, age, body mass index, depressive symptoms, co-prescribed benzodiazepines and antidepressants, smoking status and past alcohol use disorder). RESULTS: The PCA identified two dimensions: "robust CRA" (high amplitude and interdaily stability, with low intradaily variability) and "late chronotype". Univariate analyses showed higher scores for "robust CRA" in the "Li" versus the "AC or AAP" (p = 0.021) or "Li+AC or Li+AAP" groups (p = 0.047). These findings remained significant after adjustments (respectively p = 0.010 and p = 0.019). Post-hoc analyses suggested lower variability, higher stability and higher amplitude of CRA in the "Li" group. Medication groups were similar for the "late chronotype" dimension (p = 0.92). CONCLUSIONS: This actigraphy study is the first to show more favorable CRA in BD-I individuals receiving a Li monotherapy when compared with those receiving other classes or combinations of mood stabilizers. Replications in larger samples are required. Prospective studies are also warranted to elucidate whether the introduction of Li or other mood stabilizers might influence CRA in BD-I.

Polymorphism and Pharmacological Assessment of Carbamazepine.

This work provides insight into carbamazepine polymorphs (Forms I, II, III, IV, and V), with reports on the cytoprotective, exploratory, motor, CNS-depressant, and anticonvulsant properties of carbamazepine (CBZ), carbamazepine formulation (CBZ-F), topiramate (TOP), oxcarbazepine (OXC), and diazepam (DZP) in mice. Structural analysis highlighted the significant difference in molecular conformations, which directly influence the physicochemical properties; and density functional theory description provided indications about CBZ reactivity and stability. In addition to neuron viability assessment in vitro, animals were treated orally with vehicle 10 mL/kg, as well as CBZ, CBZ-F, TOP, OXC, and DZP at the dose of 5 mg/kg and exposed to open-field, rotarod, barbiturate sleep induction and pentylenetetrazol (PTZ 70 mg/kg)-induced seizure. The involvement of GABAergic mechanisms in the activity of these drugs was evaluated with the intraperitoneal pretreatment of flumazenil (2 mg/kg). The CBZ, CBZ-F, and TOP mildly preserved neuronal viability. The CBZ-F and the reference AEDs potentiated barbiturate sleep, altered motor activities, and attenuated PTZ-induced convulsion. However, flumazenil pretreatment blocked these effects. Additional preclinical assessments could further establish the promising utility of CBZ-F in clinical settings while expanding the scope of AED formulations and designs.

Development of Novel Alaninamide Derivatives with Anticonvulsant Activity and Favorable Safety Profiles in Animal Models.

In our current study, we developed a focused series of original ((benzyloxy)benzyl)propanamide derivatives that demonstrated potent activity across in vivo mouse seizure models, specifically, maximal electroshock (MES) and 6 Hz (32 mA) seizures. Among these derivatives, compound 5 emerged as a lead molecule, exhibiting robust protection following intraperitoneal (i.p.) injection, as follows: ED50 = 48.0 mg/kg in the MES test, ED50 = 45.2 mg/kg in the 6 Hz (32 mA) test, and ED50 = 201.3 mg/kg in the 6 Hz (44 mA) model. Additionally, compound 5 displayed low potential for inducing motor impairment in the rotarod test (TD50 > 300 mg/kg), indicating a potentially favorable therapeutic window. In vitro toxicity assays further supported its promising safety profile. We also attempted to identify a plausible mechanism of action of compound 5 by applying both binding and functional in vitro studies. Overall, the data obtained for this lead molecule justifies the more comprehensive preclinical development of compound 5 as a candidate for a potentially broad-spectrum and safe anticonvulsant.

Recent Progresses in Development of Heterocyclic Compounds For Epilepsy Treatment: Key Research Highlights From 2019-2024.

Epilepsy which is a chronic neurological disorder is characterized by recurrent seizure poses a significant challenge to healthcare professionals worldwide. Most of antiepileptic drugs have serious side effects that might affect the quality of life such as fatigue, dizziness, weight gain and cognitive impairments. In this context, the search for more effective and potential antiepileptic drug candidate has led to a growing interest in the field of synthesis of heterocyclic compounds. This review will focus on the utilization of heterocyclic moieties including imidazole, indole, thiazole, triazine, quinazoline and oxazole which show remarkable anticonvulsant properties. Furthermore, the exploration of various methodologies for the synthesis of heterocyclic anticonvulsant drugs such as green methodologies and microwave assisted protocols have contributed to the development of environment friendly,  more efficient and potential approaches. The review will distinguish from previous ones by specifically focusing on innovative synthetic methodologies, including greener methodologies and micro-assisted techniques, that contribute to eco-friendly and environment benign approaches during 2019-2024. In addition to this, the review will focus on the Structure Activity Relationship (SAR) studies of heterocyclic compounds in order to offer insight into the design of next generation antiepileptic drugs with improved efficacy and reduced side effects.

Pharmacology of Adenosine A1 Receptor Agonist in a Humanized Esterase Mouse Seizure Model Following Soman Intoxication.

Recently a novel genetically modified mouse strain with serum carboxylesterase knocked-out and the human acetylcholinesterase gene knocked-in (KIKO) was created to simulate human responses to nerve agent (NA) exposure and its standard medical treatment. A1 adenosine receptor (A1AR) agonist N-bicyclo-(2.2.1)-hept-2-yl-5'-chloro-5'-deoxyadenosine (ENBA) alone is a potent anticonvulsant and neuroprotectant (A/N) in both rat and KIKO mouse soman (GD) seizure models. In this study we utilized the KIKO mouse to evaluate further the basic pharmacologic A/N effects of ENBA as an adjunct to standard NA medical treatments (i.e., atropine sulfate, pralidoxime chloride [2-PAM], and midazolam). Male mice, implanted with cortical electroencephalographic (EEG) electrodes, were pretreated with asoxime (HI-6) and exposed to an epileptogenic dose of GD (33 µg/kg, s.c.) or saline (sham exposure) and then treated 15 min after seizure onset with ENBA at 15 mg/kg, i.p. (a minimum efficacy dose in suppressing NA-induced seizure) alone or as an adjunct to standard medical treatments. We collected EEG activity, seizure suppression outcomes, daily body temperature and weight, heart rate, toxic signs, neuropathology, and lethality data for up to 14 days. Without ENBA, death from NA exposure was 45%, while with ENBA, either alone or in combination with midazolam, the survival improved to 80% and 90%, respectively. Additionally, seizure was suppressed quickly and permanently, toxic signs, hypothermia, and bradycardia recovered by 48 h, and no neuropathology was evident. Our findings confirmed that ENBA is a potent A/N adjunct for delayed medical treatments of NA exposure.

Coronaridine congeners induce anticonvulsant activity in rodents by hippocampal mechanisms involving mainly potentiation of GABAA receptors.

The coronaridine congeners catharanthine and 18-methoxycoronaridine (18-MC) display sedative, anxiolytic, and antidepressant properties by acting on mechanisms involving GABAergic and/or monoaminergic transmissions. Here, we expanded their pharmacological properties by studying their anticonvulsant activity in male and female mice using the pentylenetetrazole (PTZ)-induced seizure test. To determine potential neurochemical mechanisms, the effect of congeners on monoamine content and kainic acid (KA)-induced epileptiform discharge was studied in the hippocampus. The behavioral results showed that coronaridine congeners induce acute anticonvulsant activity in a dose-dependent but sex-independent manner. Repeated treatment with a subthreshold dose (20 mg/kg) of each congener produced anticonvulsant activity in a sex-independent manner, but was significantly higher in male mice when compared to its acute effect. Using a behaviourally relevant regimen, we found that PTZ increased dopamine metabolites and serotonin tissue content. Coronaridine congeners, which induced distinct effects on monoamines, blunted the effect of PTZ instead of potentiating it, suggesting the existence of another mechanism in their anticonvulsant activity. The electrophysiological results indicated that both congeners inhibit KA-induced epileptiform discharges in hippocampal slices. A key aspect of this study is that the activity of both congeners was observed only in the presence of GABA, supporting the notion that hippocampal GABAAR potentiation plays an important role. Our study showed that coronaridine congeners induce acute anticonvulsant activity in a sex-independent manner. However, a comparatively higher susceptibility was observed in male mice after repeated treatment. The underlying hippocampal mechanisms mainly involve GABAAR potentiation, whereas monoamines play a minor role in the anticonvulsive action.

Associations between specialized dementia care, COVID-19 and central nervous system medication use in assisted living: a population-based repeated cross-sectional study.

BACKGROUND: Assisted living (AL) is an increasingly common residential setting for persons with dementia; yet concerns exist about sub-optimal care of this population in AL given its lower levels of staffing and services. Our objectives were to (i) examine associations between AL setting (dementia care vs. other), COVID-19 pandemic waves, and prevalent antipsychotic, antidepressant, anti-dementia, benzodiazepine, and anticonvulsant drug use among residents with dementia/cognitive impairment, and (ii) explore associations between resident and home characteristics and prevalent medication use. METHODS: We conducted a population-based, repeated cross-sectional study using linked clinical and health administrative databases for all publicly funded AL homes in Alberta, Canada, examined between January 2018 - December 2021. The quarterly proportion of residents dispensed a study medication was examined for each setting and period (pandemic vs. comparable historical [2018/2019 combined]) focusing on four pandemic waves (March-May 2020, September 2020-February 2021, March-May 2021, September-December 2021). Log-binomial GEE models estimated prevalence ratios (PR) for period (pandemic vs. historical periods), setting (dementia care vs. other) and period-setting interactions, adjusting for resident (age, sex) and home (COVID-19 cases, health region, ownership) characteristics. RESULTS: On March 1, 2020, there were 2,779 dementia care and 3,013 other AL residents (mean age 83, 69% female) with dementia/cognitive impairment. Antipsychotic use increased during waves 2-4 in both settings, but this was more pronounced in dementia care than other AL during waves 3 and 4 (e.g., adjusted [adj]PR 1.20, 95% CI 1.14-1.27 vs. adjPR 1.09, 95% CI 1.02-1.17, interaction p = 0.023, wave 3). Both settings showed a statistically significant but modest increase in antidepressant use and decrease in benzodiazepine use. For dementia care AL residents only, there was a statistically significant increase in gabapentinoid use during several waves (e.g., adjPR 1.32, 95% CI 1.10-1.59, wave 3). Other than a modest decrease in prevalent anti-dementia drug use for both settings in wave 2, no other significant pandemic effects were observed. CONCLUSIONS: The persistence of the pandemic-associated increase in antipsychotic and antidepressant use in AL residents coupled with a greater increase in antipsychotic and gabapentinoid use for dementia care settings raises concerns about the attendant risks for residents with cognitive impairment.

Sodium Valproate-Induced Hyperammonemia: A Case Series in a Tertiary Care Hospital.

BACKGROUND: Sodium valproate (VPA) is an extensively used anti-convulsant, which is an effective drug for treatment of epilepsy in adults and children, as well as for conditions like migraine, bipolar disorder, mania, and trigeminal neuralgia. Sedation, vertigo, ataxia, dose-dependent tremors, headaches, and gastrointestinal side effects are the most often reported adverse effects associated with VPA. A potential life-threatening event reported with VPA is hyperammonemia (HA), which is defined as an increase in serum level of ammonia. Only 587 reported cases of HA were found in the VigiAccess database, representing a mere 0.6% of the 95,000 reported adverse events linked to VPA. Hence, this case series was conducted with emphasis on monitoring of increased serum ammonia levels with or without hepatic enzymes increase for patients who are on VPA. AIMS AND OBJECTIVES: To assess elevated serum ammonia levels following VPA administration, and to ascertain the percentage of individuals with hepatic enzymes increased who took VPA and subsequently had elevated serum ammonia levels. METHODS: This study was conducted at the adverse drug reaction (ADR) monitoring centre (AMC) of the Pharmacovigilance Programme of India (PvPI) and Department of Psychiatry, Christian Medical College and Hospital (CMC&H), Ludhiana. The study comprised of 12 patients who were exclusively on VPA and exhibited symptoms related to elevated serum ammonia. An informed consent form (ICF) was provided to the patient prior to taking their personal details. Laboratory investigations were done to establish the diagnosis and liver function tests (LFTs), chiefly ALT (alanine transferase) and AST (aspartate aminotransferase) were also performed. It is a descriptive study which was for a time period of six months.  Results: This study includes 12 patients who had HA confirmed by laboratory investigation. Out of these 12 patients, two patients (17%) had a corresponding increase in LFT. The average as of the patients was 53.08 years and average serum ammonia levels were 219.15. None of the patients who presented with HA progressed to hyperammonemic encephalopathy (HAE). CONCLUSION:  This case series on valproate-induced HA should be of interest to psychiatrists, physicians, internists, family medicine physicians, hospitalists, and surgeons who will have patients on VPA. Delay in recognition of HA can result in the development of potentially life-threatening complications. Rapid diagnosis and management will help in reducing the number of cases which progress to encephalopathy which is highly fatal.

Insights into clinical phenotypes and treatment responses in a Small cohort of Taiwanese patients with SCN1A variants: A Preliminary study.

BACKGROUND: SCN1A channelopathy is the most well-known cause for epileptic encephalopathies and contributes to a wide phenotypic spectrum. The variable expressivity is troublesome for the interpretation of clinical significance and prognoses. To investigate the clinical manifestations, medications and outcomes of patients with SCN1A channelopathies, we conducted this observation retrospective study in Taiwan. METHODS: A cohort consisting of 16 patients (5 males and 11 females) from multiple centers with identified SCN1A variants was investigated and phenotypically relevant factors were recorded. The variants were identified using NGS and confirmed by Sanger sequencing. A panel of 90 epileptic-related genes was used to identify SCN1A variants and to evaluate some of the potential SCN1A modifier genes. RESULTS: The mean age of seizure onset was 10.4 months. Twelve of the sixteen patients (75%) had different degrees of neurocognitive sequela and psychobehavioral comorbidity in our cohort. Cognitive impairment was noted in all ten patients with Dravet syndrome (DS) and in two of the patients with non-DS phenotypes. A lower response rate to medications was also noted in patients with DS. Notably, a medication-specific tendency towards valproic acid (VPA), clobazam (CLB), and levetiracetam (LEV) was observed, revealing the effective pharmacotherapies for SCN1A-related seizures. An asymptomatic carrier with a reported pathogenic SCN1A variant was reviewed along with her monozygotic twin sister with DS. Nine novel SCN1A mutations are herein reported, eight of which being classified as pathogenic. CONCLUSION: Our study revealed unfavorable outcomes for patients with SCN1A variants. Some patients with SCN1A channelopathy showed specific responsiveness to the pharmacotherapies previously either recommended or contraindicated for these patients. Our study also expands the genotype and provides valuable prognostic insights in patients with SCN1A channelopathy.

Exposure to anti-seizure medication during pregnancy and the risk of autism and ADHD in offspring: a systematic review and meta-analysis.

Background: Evidence of an association between maternal use of anti-seizure medication (ASM) during pregnancy and the risk of autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD) in children is conflicting. This systematic review and meta-analysis aimed to summarize the relationship between fetal exposure to ASM and the development of ASD or ADHD in offspring. Methods: A comprehensive literature search was conducted in PubMed and other databases to identify relevant epidemiological studies published from inception until 1 March 2024. Results: Seven cohort studies were included in the meta-analysis. The results showed that maternal exposure to ASMs during pregnancy was associated with an increased risk of ASD [odds ratio (OR): 2.1, 95% confidence interval (CI): 1.63-2.71; p < 0.001] in the general population. This association became weaker (ASD: OR: 1.38, 95% CI: 1.11-1.73; p = 0.004) when the reference group was mothers with a psychiatric disorder or epilepsy not treated during pregnancy. Furthermore, an increased risk of ADHD was observed when the study data adjusted for drug indications were pooled (OR: 1.43, 95% CI: 1.07-1.92; p = 0.015). In subgroup analyses based on individual ASM use, only exposure to valproate preconception was significantly associated with an increased risk of ASD or ADHD. Conclusion: The significant association between maternal ASM use during pregnancy and ASD or ADHD in offspring may be partially explained by the drug indication or driven by valproate.

Rationalising the dose threshold for severe carbamazepine toxicity: a retrospective series.

INTRODUCTION: Carbamazepine causes dose-dependent toxicity in overdose. Resources commonly state that severe toxicity occurs with ingestions >50 mg/kg without supporting evidence. We aimed to compare ingested dose with clinical toxicity. METHODS: This was a retrospective series of patients reportedly ingesting carbamazepine >2,000 mg referred to a clinical toxicology unit and state poisons information centre. Medical records were reviewed to extract patient demographics, ingestion details, clinical effects and management. Severe toxicity was defined as the presence of coma (Glasgow Coma Scale <9), seizure, or hypotension (systolic blood pressure <90 mmHg). RESULTS: There were 69 presentations in 42 patients with a median ingested carbamazepine dose of 113 mg/kg (IQR: 71-151 mg/kg). Coma occurred in 10 cases, eight having ingested >200 mg/kg and the remaining two ingesting 113 mg/kg and 151 mg/kg, respectively. Seizures occurred in four cases (lowest ingested dose 143 mg/kg). Hypotension occurred in five cases (lowest ingested dose 113 mg/kg). DISCUSSION: Severe carbamazepine toxicity did not occur with reported ingestions <100 mg/kg and was uncommon in ingestions <200 mg/kg. CONCLUSION: Severe toxicity was common in ingestions >200 mg/kg. Using the suggested threshold of severe toxicity of >50 mg/kg appeared overly conservative in this series.

A Comprehensive Review of the Pharmacological Effects of Genus Ferula on Central Nervous System Disorders.

BACKGROUND: Plants of the genus Ferula have long been used to treat neurological diseases such as Alzheimer's disease (AD), pain, depression, and seizures. The main compounds include coumarins, monoterpenes, sulfide compounds, and polyphenol compounds, which can improve the functioning of the nervous system. OBJECTIVE: This article has been compiled with the aim of collecting evidence and articles related to the Ferula effects on central nervous system disease. METHODS: This review article was prepared by searching the terms Ferula and analgesic, anticonvulsant, antidepressant, anti-multiple sclerosis, anti-dementia, and neuroprotective effects.The relevant information was collected through searching electronic databases such as ISI Web of Knowledge, PubMed, and Google Scholar. RESULTS: Genus Ferula has a protective effect on nerve cells by reducing cytokines such as IL-6, IL- 1b, and TNF-α. Therefore, the effects of Ferula plants and their effective ingredients can be used to prevent or improve diseases that destroy the nervous system. The members of this genus play a role in strengthening and improving the antioxidant system, reducing the level of oxidative stress, and inhibiting or reducing inflammatory factors in the nervous system. CONCLUSION: Although the effects of several species of Ferula on the nervous system have been investigated, most studies have not clearly identified the molecular mechanisms as well as the specific functional regions of the brain. The present study was compiled in order to investigate different aspects of the effects of Ferula plants on the central nervous system.

Site specific binding pattern of benzodiazepines with GABAA receptor and related impact on their activities in the human body: An in silico method based study.

Despite of being the drugs of the same therapeutic class (Benzodiazepines), each of them shows different actions prominently. It is commonly seen that Bromazepam, Clonazepam, and, Alprazolam are prescribed for the treatment of anxiety disorders, panic disorders, and phobias. On the other hand, Midazolam, Temazepam, Flurazepam, and Nitrazepam are indicated for the treatment of insomnia and Lorazepam is considered as a drug having anticonvulsant effects. As the mechanism of action is the same, there should be some differences in the binding patterns with the proteins that create differences in their impacts on the body. A deep screening of the binding patterns of the available Benzodiazepines in the market to the GABAA receptor will be beneficial to find out the responsible amino acids for being accountable for showing any specific action. This reveal will help design new molecules with the highest beneficial effect and lowest toxicity in the body. The in silico method provides the initial level of understanding regarding the binding patterns, performing in vitro and in vivo experiments will be more specific to claim the benefits of newly designed drugs.

Targeting Adipokines: A Promising Therapeutic Strategy for Epilepsy.

Epilepsy affects 65 million people globally and causes neurobehavioral, cognitive, and psychological defects. Although research on the disease is progressing and a wide range of treatments are available, approximately 30% of people have refractory epilepsy that cannot be managed with conventional medications. This underlines the importance of further understanding the condition and exploring cutting-edge targets for treatment. Adipokines are peptides secreted by adipocyte's white adipose tissue, involved in controlling food intake and metabolism. Their regulatory functions in the central nervous system (CNS) are multifaceted and identified in several physiology and pathologies. Adipokines play a role in oxidative stress and neuroinflammation which are associated with brain degeneration and connected neurological diseases. This review aims to highlight the potential impacts of leptin, adiponectin, apelin, vaspin, visfatin, and chimerin in the pathogenesis of epilepsy.

Padsevonil suppresses seizures without inducing cell death in neonatal rats.

BACKGROUND: Padsevonil (PSL) is a rationally designed anti-seizure medication (ASM) which has overlapping mechanisms of action with the two most common ASMs used for neonatal seizures, phenobarbital (PB) and levetiracetam (LEV). Here we evaluated the anti-seizure properties of PSL across the neonatal and adolescent period in rats in the pentlyenetetrazole (PTZ) induced seizures model. METHODS: Postnatal day (P)7, P14 and P21 Sprague-Dawley rat pups were pre-treated with PSL (1-30 mg/kg), and assessed for seizure latency and severity 30 min later following injection of PTZ. A separate cohort of P7 pups were treated with neonatal ASMs and euthanized 24 h later (on P8) to assess induction of cell death, a feature common to many ASMs when given to P7 rodents. This effect has been extensively reported with PB, but not with LEV. Cell death was assessed by PathoGreen staining. RESULTS: PSL suppressed PTZ-evoked seizures across multiple age groups, particularly at higher doses, without producing increased cell death compared to vehicle. The effects of PSL were particularly notable at suppressing tonic-clonic seizure manifestations (82% of P7 and 100% of P14 and P21 animals were protected from tonic-clonic seizures with the 30 mg/kg dose). CONCLUSIONS: PSL displayed dose-dependent anti-seizure effects in immature rodents in the PTZ model of seizures in immature rats. While many ASMs, including PB, induce cell death in neonatal rats, PSL does not. This suggests that PSL may offer therapeutic benefit and a favorable safety profile for the treatment of neonatal seizures.

Development of new chiral 1,2,4-triazole-3-thiones and 1,3,4-thiadiazoles with promising in vivo anticonvulsant activity targeting GABAergic system and voltage-gated sodium channels (VGSCs).

Antiepileptic drugs (AEDs) are used in the treatment of epilepsy, a neurodegenerative disease characterized by recurrent and untriggered seizures that aim to prevent seizures as a symptomatic treatment. However, they still have significant side effects as well as drug resistance. In recent years, especially 1,3,4-thiadiazoles and 1,2,4-triazoles have attracted attention in preclinical and clinical studies as important drug candidates owing to their anticonvulsant properties. Therefore, in this study, which was conducted to discover AED candidate molecules with reduced side effects at low doses, a series of chiral 2,5-disubstituted-1,3,4-thiadiazoles (4a-d) and 4,5-disubstituted-1,2,4-triazole-3 thiones (5a-d) were designed and synthesized starting from l-phenylalanine ethyl ester hydrochloride. The anticonvulsant activities of the new chiral compounds were assessed in several animal seizure models in mice and rats for initial (phase I) screening after their chemical structures including the configuration of the chiral center were elucidated using spectroscopic methods and elemental analysis. First, all chiral compounds were pre-screened using acute seizure tests induced electrically (maximal electroshock test, 6 Hz psychomotor seizure model) and induced chemically (subcutaneous metrazol seizure model) in mice and also their neurotoxicity (TOX) was determined in the rotorad assay. Two of the tested compounds were used for quantitative testing, and (S)-(+)5-[1-(4-fluorobenzamido)-2-phenylethyl]-4-(4-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (5b) and (S)-(+)-(5-[1-(4-fluorobenzamido)-2-phenylethyl]-4-(4-methoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (5c) emerged as the most promising anticonvulsant drug candidates and also showed low neurotoxicity. The antiepileptogenic potential of these compounds was determined using a chronic seizure induced electrically corneal kindled mouse model. Furthermore, all chiral compounds were tested for their neuroprotective effect against excitotoxic kainic acid (KA) and N-methyl-d-aspartate (NMDA) induced in vitro neuroprotection assay using an organotypic hippocampal slice culture. The KA-induced neuroprotection assay results revealed that compounds 5b and 5c, which are the leading compounds for anticonvulsant activity, also had the strongest neuroprotective effects with IC50 values of 103.30 ± 1.14 and 113.40 ± 1.20 µM respectively. Molecular docking studies conducted to investigate the molecular binding mechanism of the tested compounds on the GABAA receptor showed that compound 5b exhibits a strong affinity to the benzodiazepine (BZD) binding site on GABA. It also revealed that the NaV1.3 binding interactions were consistent with the experimental data and the reported binding mode of the ICA121431 inhibitor. This suggests that compound 5b has a high affinity for these specific binding sites, indicating its potential as a ligand for modulating GABAA and NaV1.3 receptor activity. Furthermore, the ADME properties displayed that all the physicochemical and pharmacological parameters of the compounds stayed within the specified limits and revealed a high bioavailability profile.

A Systematic Review of the Anti-seizure and Antiepileptic Effects and Mechanisms of Piperine.

INTRODUCTION AND AIM: Seizures due to epilepsy in any form cause a wide range of problems in a patient's physical, psychological, and social health. This study aimed to investigate piperine's anti-seizure and antiepileptic effects and mechanisms. METHODS: In this systematic review study, which was conducted according to the principles of PRISMA 2020, the initial search was conducted on November 2, 2023, using EndNote software. Various databases such as PubMed, Cochrane Library, Web of Science, Embase, and Scopus were searched using specific keywords. After screening the articles, a form was designed according to the objectives of the study, and the information related to the included articles was entered in the form, and the studies were reviewed. RESULTS: Piperine showed its antiepileptic activity by affecting the brain's antioxidant, anti-inflammatory, and anti-apoptotic activity. It also, by modulating brain-derived neurotrophic factor (BDNF) and gamma-aminobutyric acid (GABA)ergic activity, can control seizures. In addition, piperine can help treat seizures and epilepsy by elevating 5-HT levels in the brain, modulating astrocyte and microglia function, modulatory effects on Ca2+ and NA+ channels, increasing antiepileptic drugs bioavailability and influencing protein and gene expression. CONCLUSION: In vivo and in vitro studies showed beneficial effects on treating epilepsy. Although clinical studies also showed similar results, these needed to be increased, and more clinical studies needed to be designed in this field.