Development Of Antiepileptic Drugs Research Articles

Herbal Extracts Exhibit Anti-Epilepsy Properties

Epilepsy refers to a group of persistent neurological illnesses characterized by seizures. It is a chronic brain disease that affects 50 million people in the world, being one of the most common neurological disorders. Developing countries account for over 90% of all epilepsy patients. Epileptic seizures are caused by aberrant, excessive, or hyper synchronized neuronal activity in the brain. The cause of most epileptic seizures is unknown. However, some people develop epilepsy as a result of a brain injury, stroke, brain tumor, or drug and alcohol abuse. Anti-seizure drugs remain the mainstay in the treatment of epilepsy and about 70% of epileptics become seizure-free when antiseizure medications are taken effectively. However, some of these medications have significant pharmacological interactions and undesirable side effects. Traditional utilization of plants extracts for treatment of epilepsy is widely practiced. Many plants extracts and herbal formulations have been studied to determine their efficacy in treatment of epilepsy. This paper presents a review on herbal extracts that have shown antiepileptic activity in animal models published in the last ten years (between 2014 and 2024). The study found that plant extracts from some 138 plant species belonging to 54 different plant families were evaluated for antiepileptic efficacy. The most studied plants belong to the Asteraceae family (19%) followed by Fabaceae (9%), Apiaceae (8%), Lamiaceae (8%), Apocynaceae (7%), Cucurbitaceae (3%), Euphorbiaceae (3%) and Rutaceae (3%). In most cases, the studies focused only on the crude extracts without any attempts to identify the antiepileptic compounds from the plants. The most commonly used model in the antiepileptic assays were found to be pentylenetetrazole and maximal electroshock models. The findings from this study confirm that plant extracts have significant efficacy that needs to be explored for antiepileptic formulation and drugs development. It is also necessary to perform bioassay guided phytochemical evaluation to isolate and characterize the antiepileptic principles.

Discovery of a potent, Kv7.3-selective potassium channel opener from a Polynesian traditional botanical anticonvulsant

Plants remain an important source of biologically active small molecules with high therapeutic potential. The voltage-gated potassium (Kv) channel formed by Kv7.2/3 (KCNQ2/3) heteromers is a major target for anticonvulsant drug development. Here, we screened 1444 extracts primarily from plants collected in California and the US Virgin Islands, for their ability to activate Kv7.2/3 but not inhibit Kv1.3, to select against tannic acid being the active component. We validated the 7 strongest hits, identified Thespesia populnea (miro, milo, portia tree) as the most promising, then discovered its primary active metabolite to be gentisic acid (GA). GA highly potently activated Kv7.2/3 (EC50, 2.8 nM). GA is, uniquely to our knowledge, 100% selective for Kv7.3 versus other Kv7 homomers; it requires S5 residue Kv7.3-W265 for Kv7.2/3 activation, and it ameliorates pentylenetetrazole-induced seizures in mice. Structure-activity studies revealed that the FDA-approved vasoprotective drug calcium dobesilate, a GA analog, is a previously unrecognized Kv7.2/3 channel opener. Also an active aspirin metabolite, GA provides a molecular rationale for the use of T. populnea as an anticonvulsant in Polynesian indigenous medicine and presents novel pharmacological prospects for potent, isoform-selective, therapeutic Kv7 channel activation.

Kindling Models of Epileptogenesis for Developing Disease-Modifying Drugs for Epilepsy.

Kindling models are widely used animal models to study the pathobiology of epilepsy and epileptogenesis. These models exhibit distinctive features whereby sub-threshold stimuli instigate the initial induction of brief focal seizures. Over time, the severity and duration of these seizures progressively increase, leading to a fully epileptic state, which is marked by consistent development of generalized tonic-clonic seizures. Kindling involves focal stimulation via implanted depth electrodes or repeated administration of chemoconvulsants such as pentylenetetrazol. Comparative analysis of preclinical and clinical findings has confirmed a high predictive validity of fully kindled animals for testing novel antiseizure medications. Thus, kindling models remain an essential component of anticonvulsant drug development programs. This article provides a comprehensive guide to working protocols, testing of therapeutic drugs, outcome parameters, troubleshooting, and data analysis for various electrical and chemical kindling epileptogenesis models for new therapeutic development and optimization. The use of pharmacological agents or genetically modified mice in kindling experiments is valuable, offering insights into the impact of a specific target on various aspects of seizures, including thresholds, initiation, spread, termination, and the generation of a hyperexcitable network. These kindling epileptogenesis paradigms are helpful in identifying mechanisms and disease-modifying interventions for epilepsy. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Hippocampal kindling Basic Protocol 2: Amygdala kindling Basic Protocol 3: Rapid hippocampal kindling Basic Protocol 4: Chemical kindling.

Comparison Efficacy of Phenobarbital versus Levetiracetam in Acute Neonatal Seizures: A Randomized Control Trial

AbstractSeizures in infancy are one of the main manifestations of disorders in the central nervous system that can have important etiologies. The development of anticonvulsant drugs and the importance of drug selection in infants, due to more complex underlying etiologies, compared with older ages, explicate the essentiality of executing clinical investigations to appraise the optimal therapeutic approach. The objective of the current investigation is to juxtapose two therapeutic approaches involving intravenous levetiracetam and intravenous phenobarbital in the management of neonatal seizures. This is a randomized controlled clinical trial study on 100 infants who were referred to the Hazrat Masoumeh (S) Hospital in Qom owing to convulsions. Infants with seizure who fulfilled the inclusion criteria were arbitrarily allocated to one of the two intervention cohorts: intravenous levetiracetam or intravenous phenobarbital, and therapeutic responses were compared. There was a substantial relationship between seizure time, seizure etiology, anticonvulsant therapy type, and treatment responsiveness. As a result, the risks of not responding to therapy and increasing the dose were approximately 6 and 5 times higher, respectively, in the group that experienced seizures in the fourth week than in the other groups. Infants with cerebrovascular anomalies were more prone to not responding to treatment. Furthermore, children administered phenobarbital had a 2.5-fold higher chance of not responding to treatment than those given levetiracetam (p = 0.043).

Phenytoin causes behavioral abnormalities and suppresses kisspeptin expression, reducing reproductive performance in Japanese medaka

Phenytoin, an antiepileptic drug, induces neurotoxicity and abnormal embryonic development and reduces spontaneous locomotor activity in fish. However, its effects on other endpoints remain unclear. Therefore, we investigated the effects of phenytoin on the swimming behavior and reproductive ability of Japanese medaka. Abnormalities in swimming behavior, such as imbalance, rotation, rollover, and vertical swimming, were observed. However, when phenytoin exposure was discontinued, the behavioral abnormality rates decreased. Phenytoin exposure also significantly reduced reproductive ability. By investigating reproduction-related gene expression of gnrh1, gnrh2, fshb, and lhb remained unchanged in males and females. In contrast, kiss1 expression was significantly suppressed due to phenytoin exposure in males and females. kiss2 expression was also significantly suppressed in females but not in males. We filmed videos to examine phenytoin exposure effects on sexual behavior. Females showed no interest in the male's courtship. As the kisspeptin 1 system controls sexual behavior in Japanese medaka, phenytoin exposure may have decreased kiss1 expression, which decreased female reproductive motivation; hence, they did not spawn eggs. This is the first study to show that phenytoin exposure induces behavioral abnormalities, and suppresses kiss1 expression and reproductive performance in Japanese medaka.

Analysis of the performance of PET/CT using 18F-fluorodeoxyglucose in comparison with other diagnostic methods in drug-resistant epilepsy in children

Background. Epilepsy is one of the most common neurological diseases characterized by a persistent predisposition to epileptic seizures and the neurobiological, cognitive, psychological, and social consequences. In recent decades, despite the continuous development of antiepileptic drugs, there are still many patients with epilepsy that progresses to drug-resistant epilepsy. Currently, surgical treatment is one of the most important ways to treat such epilepsy. Collaboration between multidisciplinary teams and the combination of multiple neuroimaging methods are key to determining the exact localization of the epileptogenic zone. New diagnostic methods are being developed and the number of indications for their use is growing. The purpose of the study was to analyze the scientific literature on the effectiveness of positron emission tomography combined with computed tomography (PET/CT) using 18F-fluorodeoxyglucose compared to other diagnostic methods in drug-resistant epilepsy in children. Materials and methods. A literature search using keywords was conducted in Web of Science, Scopus, PubMed, and Elsevier databases. Results. Surgical treatment of drug-resistant epilepsy in children has become a specialized area in neurosurgery. Surgical removal or disconnection of a part of the brain, in which the epileptogenic zone is suspected, allows for a complete cure or a significant reduction in seizure frequency. It has been shown that a prerequisite for postoperative success is the accurate determination of the epileptogenic zone during a multistage preoperative diagnosis. Among many studies, nuclear medicine technologies play an important role in the presurgical examination of children with drug-resistant epilepsy. In combination with other methods, nuclear medicine helps identify the epileptogenic zone, especially in case of conflicting data, negative magnetic resonance imaging — negative epilepsy, focal cortical dysplasia or extratemporal lobe epilepsy. Single-photon emission CT and PET using functional neuroimaging with nuclear medicine indicators are classical methods and are recommended by neuroimaging specialists. In addition, one of the leading modern methods is PET/CT with 18F-fluorodeoxyglucose. It provides information that might be missed when using anatomical methods such as magnetic resonance imaging, and the area of hypometabolism detected with 18F-fluorodeoxyglucose PET/CT may be larger than the area of anatomical lesion detected on magnetic resonance imaging. Conclusions. For children with drug-resistant epilepsy, PET/CT using 18F-fluorodeoxyglucose is the most optimal method of preoperative diagnosis.

Heparin-Modified Superparamagnetic Iron Oxide Nanoparticles Suppress Lithium Chloride/Pilocarpine-Induced Temporal Lobe Epilepsy in Rats through Attenuation of Inflammation and Oxidative Stress.

The development of antiepileptic drugs is still a long process. In this study, heparin-modified superparamagnetic iron oxide nanoparticles (UFH-SPIONs) were prepared, and their antiepileptic effect and underlying mechanism were investigated. UFH-SPIONs are stable, homogeneous nanosystems with antioxidant enzyme activity that are able to cross the blood-brain barrier (BBB) and enriched in hippocampal epileptogenic foci. The pretreatment with UFH-SPIONs effectively prolonged the onset of seizures and reduced seizure severity after lithium/pilocarpine (LP)-induced seizures in rats. The pretreatment with UFH-SPIONs significantly decreased the expression of inflammatory factors in hippocampal tissues, including IL-6, IL-1β, and TNF-α. LP-induced oxidative stress in hippocampal tissues was in turn reduced upon pretreatment with UFH-SPIONs, as evidenced by an increase in the levels of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) and a decrease in the level of lipid peroxidation (MDA). Moreover, the LP-induced upregulation of apoptotic cells was decreased upon pretreatment with UFH-SPIONs. Together, these observations suggest that the pretreatment with UFH-SPIONs ameliorates LP-induced seizures and downregulates the inflammatory response and oxidative stress, which exerts neuronal protection during epilepsy.

The suppressive effect of the specific KCC2 modulator CLP290 on seizure in mice

Epilepsy is a chronic neurological disorder characterized by episodic dysfunction of central nervous system. The most basic mechanism of epilepsy falls to the imbalance between excitation and inhibition. In adults, GABAA receptor (GABAAR) is the main inhibitory receptor to prevent neurons from developing hyperexcitability, while its inhibition relies on the low intracellular chloride anion concentration ([Cl-]i). Neuronal-specific electroneutral K+-Cl− cotransporter (KCC2) can mediate chloride efflux to lower [Cl-]i for GABAAR mediated inhibition. Our previous study has revealed that the coordinated downregulation of KCC2 and GABAAR participates in epilepsy. According to a high-throughout screen for compounds that reduce [Cl−]i, CLP290 turns out to be a specific KCC2 functional modulator. In current study, we first confirmed that CLP290 could dose-dependently suppress convulsant-induced seizures in mice in vivo as well as the epileptiform burst activities in cultured hippocampal neurons in vitro. Then, we discovered that CLP290 functioned through preventing the downregulation of the KCC2 phosphorylation at Ser940 and hence the KCC2 membrane expression during convulsant stimulation, and consequently restored the GABA inhibition. In addition, while CLP290 was given in early epileptogenesis period, it also effectively decreased the spontaneous recurrent seizures. Generally, our current results demonstrated that CLP290, as a specific KCC2 modulator by enhancing KCC2 function, not only inhibits the occurrence of the ictal seizures, but also suppresses the epileptogenic process. Therefore, we believe KCC2 may be a suitable target for future anti-epileptic drug development.

Synthesis, in silico screening, and biological evaluation of novel pyridine congeners as anti-epileptic agents targeting AMPA (α-amino-3-hydroxy-5-methylisoxazole) receptors.

The research involves the synthesis of a series of new pyridine analogs 5(i-x) and their evaluation for anti-epileptic potential using in silico and invivo models. Synthesis of the compounds was accomplished by using the Vilsmeier-Haack reaction principle. AutoDock 4.2 was used for their in silico screening against AMPA (-amino-3-hydroxy-5-methylisoxazole) receptor (PDB ID:3m3f). For invivo testing, the maximal electroshock seizure (MES) model was used. The physicochemical, pharmacokinetic, drug-like, and drug-score features of all synthesized compounds were assessed using the online Swiss ADME and Protein Plus software. The in silico results showed that all the synthesized compounds 5(i-x) had 1-3 interactions and affinities ranging from -6.5 to -8.0 kJ/mol with the targeted receptor compared to the binding affinities of the standard drug phenytoin and the original ligand of the target (P99), which were -7.6 and -6.8 kJ/mol, respectively. Invivo study results showed that the compound 5-Carbamoyl-2-formyl-1-[2-(4-nitrophenyl)-2-oxo-ethyl]-pyridinium gave 60% protection against epileptic seizures compared to 59% protection afforded by regular phenytoin. All of them met Lipinski's rule of five and had drug-likeness and drug score values of 0.55 and 0.8, respectively, making them chemically and functionally like phenytoin. According to the findings of the studies, the synthesized derivatives have the potential to be employed as a stepping stone in the development of novel anti-epileptic drugs.

Efficacy and tolerability of rufinamide in the treatment of Lennox–Gastaut syndrome (experience of the Svt. Luka’s Association of Medical Institutions)

Background. Lennox–Gastaut syndrome (LGS) is a classic developmental and epileptic encephalopathy with a debut in childhood, characterized by resistance to therapy, a severe course, and an unfavorable prognosis. Due to the existing difficulties in treatment of LGS, hopes are pinned on development of new antiepileptic drugs with fundamentally different mechanisms of action, aimed specifically at the treatment of this severe form of epilepsy.Rufinamide (Inovelon®) is a new antiepileptic drug registered in the Russian Federation for use in the adjunctive therapy of LGS in patients older than 1 year. The main mechanism of action of rufinamide is the restriction of neuronal discharges associated with the blocking effect on sodium channels (regulation of sodium channels activity by increasing duration of their inactive state), and stabilization of neuronal membranes. The drug has a number of advantages concernung pharmacokinetic parameters and efficacy (including a wide spectrum of antiepileptic activity, good oral absorption, absence of active metabolites, urinary excretion, low affinity for plasma proteins, biotransformation without cytochrome P450 isoenzymes, low risk of drug interactions) and fairly good tolerability. The daily dose of rufinamide varies from 600 mg (with simultaneous administration of valproate) to 1000 mg (if the patient does not take valproate) in children over 4 years of age with a body weight of less than 30 kg and up to 2200–3200 mg in children over 4 years of age with a body weight of more than 30 kg and in adults; in children under 4 years of age, the maximum daily dose in combination with valproate is 30 mg/kg, and without valproic acid – 45 mg/kg.Aim. To analyze the efficacy and tolerability of rufinamide in the treatment of epilepsy based on the long-term experience of using the drug in the Svt. Luka’s Association of Medical Institutions.Materials and methods. We observed 64 patients aged from 1.5 to 26 years (44 men, 20 women) treated with rufinamide (Inovelon®). Among them, the structural etiology LGS was diagnosed in 36 patients, the genetic and presumably genetic etiology LGS – in 28. In all cases, rufinamide was used in accordance with approved indications as an additional antiepileptic drug, more often in combination with valproate, topiramate, levetiracetam or lamotrigine. Titration of the drug was carried out according to the recommendations in the instructions for use, up to a therapeutic dose that ranged from 200 to 1600 mg/day (in most cases from 400 to 1200 mg/day), depending on age and concomitant therapy.Results and conclusion. Remission of all types of seizures was registered in 17 (26.6 %) patients, and a decrease in the incidence of seizures by more than 50 % was recorded in 28 (43.8 %) patients. Of them, 13 patients demonstrated reduction in seizures frequency by more than 75–90 % and remission of one of several types of seizures. In general, the therapeutic effect (reduction of seizures frequency by at least 50 %) was achieved in 45 (70.3 %) of 64 patients. A decrease in seizures frequency of by at least 50 % was observed in 8 (12.5 %) patients; in 10 (15.6 %) patients, rufinamide therapy was not effective; in 1 (1.56 %) case an aggravation of bilateral convulsive seizures was noted when rufinamide was administered.In most cases, rufinamide is well tolerated. Our patients had side effects in 10 (15.6 %) cases. Only in 2 (3.1 %) cases, rufinamide was withdrawn directly due to side effects (the reason for withdrawal in these cases was an allergic reaction and psychosis).The retention rate for therapy lasting 1 year or more is 65.6 % (42 of 64 patients).Thus, our data have demonstrated efficacy and good tolerability of rufinamide in treating epileptic seizures associated with LGS, confirming numerous literature data. However, in our analysis, a higher rate of seizure remission was obtained, although we have included patients with mainly resistant forms of epilepsy in the analysis.

A Novel Rat Infant Model of Medial Temporal Lobe Epilepsy Reveals New Insight into the Molecular Biology and Epileptogenesis in the Developing Brain.

Although several adult rat models of medial temporal lobe epilepsy (mTLE) have been described in detail, our knowledge of mTLE epileptogenesis in infant rats is limited. Here, we present a novel infant rat model of mTLE (InfRPil-mTLE) based on a repetitive, triphasic injection regimen consisting of low-dose pilocarpine administrations (180 mg/kg. i.p.) on days 9, 11, and 15 post partum (pp). The model had a survival rate of >80% and exhibited characteristic spontaneous recurrent electrographic seizures (SRES) in both the hippocampus and cortex that persisted into adulthood. Using implantable video-EEG radiotelemetry, we quantified a complex set of seizure parameters that demonstrated the induction of chronic electroencephalographic seizure activity in our InfRPil-mTLE model, which predominated during the dark cycle. We further analyzed selected candidate genes potentially relevant to epileptogenesis using a RT-qPCR approach. Several candidates, such as the low-voltage-activated Ca2+ channel Cav3.2 and the auxiliary subunits β 1 and β 2, which were previously reported to be upregulated in the hippocampus of the adult pilocarpine mTLE model, were found to be downregulated (together with Cav2.1, Cav2.3, M1, and M3) in the hippocampus and cortex of our InfRPil-mTLE model. From a translational point of view, our model could serve as a blueprint for childhood epileptic disorders and further contribute to antiepileptic drug research and development in the future.

Impacted spike frequency adaptation associated with reduction of KCNQ2/3 exacerbates seizure activity in temporal lobe epilepsy.

Numerous epilepsy-related genes have been identified in recent decades by unbiased genome-wide screens. However, the available druggable targets for temporal lobe epilepsy (TLE) remain limited. Furthermore, a substantial pool of candidate genes potentially applicable to TLE therapy awaits further validation. In this study, we reveal the significant role of KCNQ2 and KCNQ3, two M-type potassium channel genes, in the onset of seizures in TLE. Our investigation began with a quantitative analysis of two publicly available TLE patient databases to establish a correlation between seizure onset and the downregulated expression of KCNQ2/3. We then replicated these pathological changes in a pilocarpine seizure mouse model and observed a decrease in spike frequency adaptation due to the affected M-currents in dentate gyrus granule neurons. In addition, we performed a small-scale simulation of the dentate gyrus network and confirmed that the impaired spike frequency adaptation of granule cells facilitated epileptiform activity throughout the network. This, in turn, resulted in prolonged seizure duration and reduced interictal intervals. Our findings shed light on an underlying mechanism contributing to ictogenesis in the TLE hippocampus and suggest a promising target for the development of antiepileptic drugs.

Ligand activation mechanisms of human KCNQ2 channel

The human voltage-gated potassium channel KCNQ2/KCNQ3 carries the neuronal M-current, which helps to stabilize the membrane potential. KCNQ2 can be activated by analgesics and antiepileptic drugs but their activation mechanisms remain unclear. Here we report cryo-electron microscopy (cryo-EM) structures of human KCNQ2-CaM in complex with three activators, namely the antiepileptic drug cannabidiol (CBD), the lipid phosphatidylinositol 4,5-bisphosphate (PIP2), and HN37 (pynegabine), an antiepileptic drug in the clinical trial, in an either closed or open conformation. The activator-bound structures, along with electrophysiology analyses, reveal the binding modes of two CBD, one PIP2, and two HN37 molecules in each KCNQ2 subunit, and elucidate their activation mechanisms on the KCNQ2 channel. These structures may guide the development of antiepileptic drugs and analgesics that target KCNQ2.

DISCOVERY OF NOVEL PHTHALIMIDE ANALOGOUS BASED ANTI-EPILEPTIC BY MOLECULAR DOCKING

Aim: The development of innovative compounds for managing seizures with greater therapeutic efficacy and fewer side effects by molecular docking.
 Introduction: One of the major global problems is epilepsy, a severe brain illness that affects around 1% of people globally. Vigabatrin, sodium valproate, phenytoin, and other strong medications for the treatment of epilepsy causes side effects and patient resistance. Despite the antiepileptic drug development process seems to be successful, more effective and safer, still antiepileptic drugs are needed, especially for the treatment of refractory seizures. The study’s focus was on phthalimide analogs with strong GABA-AT inhibitory effects by molecular docking. 
 Methodology: Since protein-ligand interactions are important for drug design, The protein data bank was used to retrieve the 3D structures of GABA-AT, and the Chem Office tool was used to dock the 3D structures of Novel Ligand (Chem Draw 16.0). 
 Result: By using Lipinski’s rule of five on the novel analogs to assess their anti-epileptic activity, and the drug-likeness property was verified. All the compounds had docking energies over 6.11 kcal/mol for the anti-epileptic GABA-AT receptors.
 Conclusion: These concluded that novel compounds can be the promising lead for further study as an Anti-Epileptic for the management and prevention of Epilepsy

Dual-pocket inhibition of Nav channels by the antiepileptic drug lamotrigine

Voltage-gated sodium (Nav) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Nav channels serve as the primary targets for several classes of widely used and investigational drugs, including local anesthetics, antiepileptic drugs, antiarrhythmics, and analgesics. In this study, we present cryogenic electron microscopy (cryo-EM) structures of human Nav1.7 bound to two clinical drugs, riluzole (RLZ) and lamotrigine (LTG), at resolutions of 2.9 Å and 2.7 Å, respectively. A 3D EM reconstruction of ligand-free Nav1.7 was also obtained at 2.1 Å resolution. RLZ resides in the central cavity of the pore domain and is coordinated by residues from repeats III and IV. Whereas one LTG molecule also binds to the central cavity, the other is found beneath the intracellular gate, known as site BIG. Therefore, LTG, similar to lacosamide and cannabidiol, blocks Nav channels via a dual-pocket mechanism. These structures, complemented with docking and mutational analyses, also explain the structure-activity relationships of the LTG-related linear 6,6 series that have been developed for improved efficacy and subtype specificity on different Nav channels. Our findings reveal the molecular basis for these drugs' mechanism of action and will aid the development of novel antiepileptic and pain-relieving drugs.

Recent Progress in the Development of New Antiepileptic Drugs with Novel Targets.

Epilepsy is a chronic neurological disorder that affects approximately 50-70 million people worldwide. Epilepsy has a significant economic and social burden on patients as well as on the country. The recurrent, spontaneous seizure activity caused by abnormal neuronal firing in the brain is a hallmark of epilepsy. The current antiepileptic drugs provide symptomatic relief by restoring the balance of excitatory and inhibitory neurotransmitters. Besides, about 30% of epileptic patients do not achieve seizure control. The prevalence of adverse drug reactions, including aggression, agitation, irritability, and associated comorbidities, is also prevalent. Therefore, researchers should focus on developing more effective, safe, and disease-modifying agents based on new molecular targets and signaling cascades. This review overviews several clinical trials that help identify promising new targets like lactate dehydrogenase inhibitors, c-jun n-terminal kinases, high mobility group box-1 antibodies, astrocyte reactivity inhibitors, cholesterol 24-hydroxylase inhibitors, glycogen synthase kinase-3 beta inhibitors, and glycolytic inhibitors to develop a new antiepileptic drug. Approximately 30% of epileptic patients do not achieve seizure control. The current anti-seizure drugs are not disease modifying, cure or prevent epilepsy. Lactate dehydrogenase inhibitor, cholesterol 24-hydroxylase inhibitor, glycogen synthase kinase-3 beta inhibitors, and mTOR inhibitors have a promising antiepileptogenic effect.

Neuroprotective anticonvulsant and anxiolytic effects of octreotide in wistar rats

Somatostatin interneurons exhibited anti-epileptic activity. As a result, somatostatin agonists appear to be a promising target for antiepileptic drug development (AEDs). In this regard, we investigated the effects of octreotide, a somatostatin analog, on pentylenetetrazol (PTZ)-induced seizures in male Wistar rats. Animals were given octreotide at doses of 50 or 100 µg/kg for seven days. The anxiolytic effects of octreotide were then evaluated using open field and elevated plus-maze tests. Following that, mice were intraperitoneally given a single convulsive dosage of PTZ (60 mg/kg) and then monitored for 30 min for symptoms of seizures. Finally, the antioxidant capacity of brain tissue and histopathological changes in the hippocampus were investigated. Octreotide therapy for seven days at 50 or 100 µg/kg was more effective than diazepam in preventing acute PTZ-induced seizures (P < 0.05). Furthermore, both octreotide dosages revealed substantial anxiolytic effects in open-field and elevated plus-maze tests compared to untreated rats. Nonetheless, octreotide's anxiolytic impact was less effective than diazepam's. On the other hand, octreotide also suppressed neuronal apoptosis and attenuated oxidative stress. Our results suggest that chronic administration of octreotide has anticonvulsant, anxiolytic, and antioxidant activity in the male Wistar rat model.

Metabotropic glutamate receptors (mGluRs) in epileptogenesis: an update on abnormal mGluRs signaling and its therapeutic implications.

Epilepsy is a neurological disorder characterized by high morbidity, high recurrence, and drug resistance. Enhanced signaling through the excitatory neurotransmitter glutamate is intricately associated with epilepsy. Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors activated by glutamate and are key regulators of neuronal and synaptic plasticity. Dysregulated mGluR signaling has been associated with various neurological disorders, and numerous studies have shown a close relationship between mGluRs expression/activity and the development of epilepsy. In this review, we first introduce the three groups of mGluRs and their associated signaling pathways. Then, we detail how these receptors influence epilepsy by describing the signaling cascades triggered by their activation and their neuroprotective or detrimental roles in epileptogenesis. In addition, strategies for pharmacological manipulation of these receptors during the treatment of epilepsy in experimental studies is also summarized. We hope that this review will provide a foundation for future studies on the development of mGluR-targeted antiepileptic drugs.

Pilot-Scale Synthesis and Purification of α-Asaronol for Antiepileptic Drug Development

A simple and efficient pilot-scale process was developed for the synthesis and purification of α-asaronol ((E)-3′-hydroxyasarone). 4.29 kg of α-asaronol 4 (purity 99.92%) was produced in one batch, starting with 2,4,5-trimethoxybenzaldehyde 1 and ethyl hydrogen malonate 2 as raw materials to form intermediate ethyl (E)-3-(2,4,5-trimethoxyphenyl)acrylate 3 (yield 93.3%) by the Knoevenagel condensation reaction, which was then reduced by diisobutylaluminum hydride to produce α-asaronol 4 with a yield of 89.2%. Liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) spectroscopy analysis revealed four major impurities in the synthesis process, namely, (2,4,5-trimethoxyphenyl)methanol, 3-(2,4,5-trimethoxyphenyl)propan-1-ol, 5,5′-((1E,1′E)-oxybis(prop-1-ene-3,1-diyl)) bis(1,2,4-trimethoxybenzene), and diethyl 2-(2,4,5-trimethoxybenzyl)malonate. By adapting a commonly used recrystallization process through optimization, a large-scale purification method was developed for the purification of α-asaronol, achieving a purity of 99.92% by recrystallization. The pilot study lays the groundwork for the large-scale, high-yield, and high-purity preparation of the candidate drug.

Development of Antiepileptic Drugs throughout History: From Serendipity to Artificial Intelligence.

This article provides a comprehensive narrative review of the history of antiepileptic drugs (AEDs) and their development over time. Firstly, it explores the significant role of serendipity in the discovery of essential AEDs that continue to be used today, such as phenobarbital and valproic acid. Subsequently, it delves into the historical progression of crucial preclinical models employed in the development of novel AEDs, including the maximal electroshock stimulation test, pentylenetetrazol-induced test, kindling models, and other animal models. Moving forward, a concise overview of the clinical advancement of major AEDs is provided, highlighting the initial milestones and the subsequent refinement of this process in recent decades, in line with the emergence of evidence-based medicine and the implementation of increasingly rigorous controlled clinical trials. Lastly, the article explores the contributions of artificial intelligence, while also offering recommendations and discussing future perspectives for the development of new AEDs.