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Advances in Epilepsy and Antiepileptic Drugs 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 18207

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Special Issue Editor

Prof. Dr. Jarogniew J. Luszczki

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Guest Editor

Department of Pathophysiology, Medical University of Lublin, 20-090 Lublin, Poland
Interests: antiepileptic drugs; cannabinoids; animal models of epilepsy; drug-resistant epilepsy in preclinical studies; drug interactions (all aspects—pharmacodynamic, pharmacokinetic, mixed); novel drugs in pipeline; experimental antiseizure medication; antiseizure screening programs; medicinal chemistry focused on antiseizure medication; naturally occurring compounds with antiseizure properties
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Special Issue Information

Dear Colleagues,

This Special Issue follows the publication of the first edition on “Advances in Epilepsy and Antiepileptic Drugs”, which presented 15 high-quality papers.

The treatment of epilepsy is still a challenging issue not only for clinicians, but also for preclinical researchers, who are working to design and develop novel efficacious drugs. Novel insights on epileptogenesis and all pathophysiological mechanisms in the brain that change and transform normal neurons into an over-excitable state, ultimately resulting in epilepsy, provide us with a better understanding of various treatment options. However, drug-resistant epilepsy in patients forces clinicians to combine drugs together in order to offer their patients efficacious treatment, which can lead to interactions between drugs whose nature may be pharmacodynamic, pharmacokinetic, or mixed. To elaborate an effective treatment in this clinical situation, medicinal chemistry specialists make efforts to design novel chemical formulas of antiepileptic drugs by transforming well-known molecules of antiepileptic drugs or combining various active molecules into one novel drug. On the other hand, serendipitous findings of some novel anticonvulsant substances during the antiseizure screening program in preclinical studies allows the discovery of novel drugs. Current research focuses not only on newly chemically synthesized drugs, but also on naturally occurring compounds of plant origin, including phyto-cannabinoids and their synthetic derivatives. Present advances in the treatment of epilepsy are possible due to the second- and third-generation as well as novel antiepileptic drugs, licensed and approved to treat refractory epilepsy, which in combination are able to adequately control seizure attacks in epilepsy patients. Epileptologists over the past five years have provided astonishing insights into the pharmacology and treatment of epilepsy by integrating various approaches from in silico methods and animal models to clinical settings, with drugs in the pipeline that will become novel treatment options.

Therefore, this Special Issue of IJMS will focus on the advances in the field of treatment in epilepsy over the last five years, their impact on our overall understanding of epileptogenesis and the pathophysiology of seizure attacks, and how this can inform the development of new therapeutics. This collection will include aspects of how novel antiseizure medications can be selected in preclinical testing, structurally modified and chemically improved, and combined with other antiseizure drugs in order to maximize their efficacy and minimize their toxicity. We are seeking novel research and achievements in the treatment of epilepsy or review articles focused on the keywords below, dedicated to developments from the last five years and how these have changed or enhanced our understanding of the pharmacotherapy of epilepsy.

Prof. Dr. Jarogniew J. Luszczki
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

antiepileptic drugs: classic, novel, second and third generations
antiseizure medications: novel therapeutic options
cannabinoids in epilepsy
animal models of epilepsy: from animals to humans
clinical trials in epilepsy: novel potentially efficacious drugs
interactions between antiepileptic drugs: pharmacodynamic and pharmacokinetic aspects
interactions of antiepileptic drugs with other drugs: pharmacodynamic and pharmacokinetic aspects
adverse effects of antiseizure medication
treatment of epilepsy in specific populations (elderly, childbearing women, children)
drug-resistant epilepsy in preclinical conditions
epileptogenesis: all pathophysiological and molecular aspects

Published Papers (9 papers)

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Research

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15 pages, 1826 KiB

Open AccessArticle

Stereoselective Analysis of the Antiseizure Activity of Fenfluramine and Norfenfluramine in Mice: Is l-Norfenfluramine a Better Follow-Up Compound to Racemic-Fenfluramine?

by Natalia Erenburg, Emilio Perucca, Jeff Bechard, Celine Dube, Nina Weishaupt, Robin Sherrington and Meir Bialer

Int. J. Mol. Sci. 2024, 25(5), 2522; https://doi.org/10.3390/ijms25052522 - 21 Feb 2024

Viewed by 451

Abstract

The aim of this study was to investigate the comparative antiseizure activity of the l-enantiomers of d,l-fenfluramine and d,l-norfenfluramine and to evaluate the relationship between their concentration in plasma and brain and anticonvulsant activity. d,l-Fenfluramine, d,l-norfenfluramine and their individual enantiomers were evaluated in the mouse maximal electroshock seizure (MES) test. d,l-Fenfluramine, d,l-norfenfluramine and their individual l-enantiomers were also assessed in the DBA/2 mouse audiogenic seizure model. All compounds were administered intraperitoneally. Brain and plasma concentrations of the test compounds in DBA/2 mice were quantified and correlated with anticonvulsant activity. In the MES test, fenfluramine, norfenfluramine and their enantiomers showed comparable anticonvulsant activity, with ED₅₀ values between 5.1 and 14.8 mg/kg. In the audiogenic seizure model, l-norfenfluramine was 9 times more potent than d,l-fenfluramine and 15 times more potent than l-fenfluramine based on ED₅₀ (1.2 vs. 10.2 and 17.7 mg/kg, respectively). Brain concentrations of all compounds were about 20-fold higher than in plasma. Based on brain EC₅₀ values, l-norfenfluramine was 7 times more potent than d,l-fenfluramine and 13 times more potent than l-fenfluramine (1940 vs. 13,200 and 25,400 ng/g, respectively). EC₅₀ values for metabolically formed d,l-norfenfluramine and l-norfenfluramine were similar to brain EC₅₀ values of the same compounds administered as such, suggesting that, in the audiogenic seizure model, the metabolites were responsible for the antiseizure activity of the parent compounds. Because of the evidence linking d-norfenfluramine to d,l-fenfluramine to cardiovascular and metabolic adverse effects, their l-enantiomers could potentially be safer follow-up compounds to d,l-fenfluramine. We found that, in the models tested, the activity of l-fenfluramine and l-norfenfluramine was comparable to that of the corresponding racemates. Based on the results in DBA/2 mice and other considerations, l-norfenfluramine appears to be a particularly attractive candidate for further evaluation as a novel, enantiomerically pure antiseizure medication. Full article

(This article belongs to the Special Issue Advances in Epilepsy and Antiepileptic Drugs 2.0)

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17 pages, 6317 KiB

Open AccessArticle

Frontline Sodium Channel-Blocking Antiseizure Medicine Use Promotes Future Onset of Drug-Resistant Chronic Seizures

by Dannielle Zierath, Stephanie Mizuno and Melissa Barker-Haliski

Int. J. Mol. Sci. 2023, 24(5), 4848; https://doi.org/10.3390/ijms24054848 - 02 Mar 2023

Cited by 2 | Viewed by 1512

Abstract

The mechanisms of treatment-resistant epilepsy remain unclear. We have previously shown that frontline administration of therapeutic doses of lamotrigine (LTG), which preferentially inhibits the fast-inactivation state of sodium channels, during corneal kindling of mice promotes cross-resistance to several other antiseizure medicines (ASMs). However, whether this phenomenon extends to monotherapy with ASMs that stabilize the slow inactivation state of sodium channels is unknown. Therefore, this study assessed whether lacosamide (LCM) monotherapy during corneal kindling would promote future development of drug-resistant focal seizures in mice. Male CF-1 mice (n = 40/group; 18–25 g) were administered an anticonvulsant dose of LCM (4.5 mg/kg, i.p.), LTG (8.5 mg/kg, i.p.), or vehicle (0.5% methylcellulose) twice daily for two weeks during kindling. A subset of mice (n = 10/group) were euthanized one day after kindling for immunohistochemical assessment of astrogliosis, neurogenesis, and neuropathology. The dose-related antiseizure efficacy of distinct ASMs, including LTG, LCM, carbamazepine, levetiracetam, gabapentin, perampanel, valproic acid, phenobarbital, and topiramate, was then assessed in the remaining kindled mice. Neither LCM nor LTG administration prevented kindling: 29/39 vehicle-exposed mice were kindled; 33/40 LTG-exposed mice were kindled; and 31/40 LCM-exposed mice were kindled. Mice administered LCM or LTG during kindling became resistant to escalating doses of LCM, LTG, and carbamazepine. Perampanel, valproic acid, and phenobarbital were less potent in LTG- and LCM-kindled mice, whereas levetiracetam and gabapentin retained equivalent potency across groups. Notable differences in reactive gliosis and neurogenesis were also appreciated. This study indicates that early, repeated administration of sodium channel-blocking ASMs, regardless of inactivation state preference, promotes pharmacoresistant chronic seizures. Inappropriate ASM monotherapy in newly diagnosed epilepsy may thus be one driver of future drug resistance, with resistance being highly ASM class specific. Full article

(This article belongs to the Special Issue Advances in Epilepsy and Antiepileptic Drugs 2.0)

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34 pages, 5946 KiB

Open AccessArticle

Discovery and Validation of Circulating microRNAs as Biomarkers for Epileptogenesis after Experimental Traumatic Brain Injury–The EPITARGET Cohort

by Mette Heiskanen, Shalini Das Gupta, James D. Mills, Erwin A. van Vliet, Eppu Manninen, Robert Ciszek, Pedro Andrade, Noora Puhakka, Eleonora Aronica and Asla Pitkänen

Int. J. Mol. Sci. 2023, 24(3), 2823; https://doi.org/10.3390/ijms24032823 - 01 Feb 2023

Cited by 3 | Viewed by 2482

Abstract

Traumatic brain injury (TBI) causes 10–20% of structural epilepsies and 5% of all epilepsies. The lack of prognostic biomarkers for post-traumatic epilepsy (PTE) is a major obstacle to the development of anti-epileptogenic treatments. Previous studies revealed TBI-induced alterations in blood microRNA (miRNA) levels, and patients with epilepsy exhibit dysregulation of blood miRNAs. We hypothesized that acutely altered plasma miRNAs could serve as prognostic biomarkers for brain damage severity and the development of PTE. To investigate this, epileptogenesis was induced in adult male Sprague Dawley rats by lateral fluid-percussion-induced TBI. Epilepsy was defined as the occurrence of at least one unprovoked seizure during continuous 1-month video-electroencephalography monitoring in the sixth post-TBI month. Cortical pathology was analyzed by magnetic resonance imaging on day 2 (D2), D7, and D21, and by histology 6 months post-TBI. Small RNA sequencing was performed from tail-vein plasma samples on D2 and D9 after TBI (n = 16, 7 with and 9 without epilepsy) or sham operation (n = 4). The most promising miRNA biomarker candidates were validated by droplet digital polymerase chain reaction in a validation cohort of 115 rats (8 naïve, 17 sham, and 90 TBI rats [21 with epilepsy]). These included 7 brain-enriched plasma miRNAs (miR-434-3p, miR-9a-3p, miR-136-3p, miR-323-3p, miR-124-3p, miR-212-3p, and miR-132-3p) that were upregulated on D2 post-TBI (p < 0.001 for all compared with naïve rats). The acute post-TBI plasma miRNA profile did not predict the subsequent development of PTE or PTE severity. Plasma miRNA levels, however, predicted the cortical pathology severity on D2 (Spearman ρ = 0.345–0.582, p < 0.001), D9 (ρ = 0.287–0.522, p < 0.001–0.01), D21 (ρ = 0.269–0.581, p < 0.001–0.05) and at 6 months post-TBI (ρ = 0.230–0.433, p < 0.001–0.05). We found that the levels of 6 of 7 miRNAs also reflected mild brain injury caused by the craniotomy during sham operation (ROC AUC 0.76–0.96, p < 0.001–0.05). In conclusion, our findings revealed that increased levels of neuronally enriched miRNAs in the blood circulation after TBI reflect the extent of cortical injury in the brain but do not predict PTE development. Full article

(This article belongs to the Special Issue Advances in Epilepsy and Antiepileptic Drugs 2.0)

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18 pages, 2774 KiB

Open AccessArticle

Antiseizure Effects of Scoparone, Borneol and Their Impact on the Anticonvulsant Potency of Four Classic Antiseizure Medications in the Mouse MES Model—An Isobolographic Transformation

by Jarogniew J. Łuszczki, Hubert Bojar, Agnieszka Góralczyk and Krystyna Skalicka-Woźniak

Int. J. Mol. Sci. 2023, 24(2), 1395; https://doi.org/10.3390/ijms24021395 - 11 Jan 2023

Cited by 4 | Viewed by 1452

Abstract

Numerous botanical drugs containing coumarins and terpenes are used in ethnomedicine all over the world for their various therapeutic properties, especially those affecting the CNS system. The treatment of epilepsy is based on antiseizure medications (ASMs), although novel strategies using naturally occurring substances with confirmed antiseizure properties are being developed nowadays. The aim of this study was to determine the anticonvulsant profiles of scoparone (a simple coumarin) and borneol (a bicyclic monoterpenoid) when administered separately and in combination, as well as their impact on the antiseizure effects of four classic ASMs (carbamazepine, phenytoin, phenobarbital and valproate) in the mouse model of maximal electroshock-induced (MES) tonic-clonic seizures. MES-induced seizures were evoked in mice receiving the respective doses of the tested natural compounds and classic ASMs (when applied alone or in combinations). Interactions for two-drug and three-drug mixtures were assessed by means of isobolographic transformation of data. Polygonograms were used to illustrate the types of interactions occurring among drugs. The total brain content of ASMs was measured in mice receiving the respective drug treatments with fluorescent polarization immunoassay. Scoparone and borneol, when administered alone, exerted anticonvulsant properties in the mouse MES model. The two-drug mixtures of scoparone with valproate, borneol with phenobarbital and borneol with valproate produced synergistic interactions in the mouse MES model, while the remaining tested two-drug mixtures produced additivity. The three-drug mixtures of scoparone + borneol with valproate and phenobarbital produced synergistic interactions in the mouse MES model. Verification of total brain concentrations of valproate and phenobarbital revealed that borneol elevated the total brain concentrations of both ASMs, while scoparone did not affect the brain content of these ASMs in mice. The synergistic interaction of scoparone with valproate observed in the mouse MES model is pharmacodynamic in nature. Borneol elevated the brain concentrations of the tested ASMs, contributing to the pharmacokinetic nature of the observed synergistic interactions with valproate and phenobarbital in the mouse MES model. Full article

(This article belongs to the Special Issue Advances in Epilepsy and Antiepileptic Drugs 2.0)

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14 pages, 4711 KiB

Open AccessArticle

A Potent Antagonist of Smoothened in Hedgehog Signaling for Epilepsy

by Junwan Fan, Zichen Zhao, Ru Liu, Haowen Li, Wenyan He, Jianping Wu, Yongjun Wang and Wei Chen

Int. J. Mol. Sci. 2022, 23(23), 14505; https://doi.org/10.3390/ijms232314505 - 22 Nov 2022

Viewed by 1276

Abstract

Epilepsy is one of the common encephalopathies caused by sudden abnormal discharges of neurons in the brain. About 30% of patients with epilepsy are insensitive and refractory to existing antiseizure medications. The sonic hedgehog signaling pathway is essential to the development and homeostasis of brain. Aberrant sonic hedgehog signaling is increased in refractory epileptic lesions and may involve the etiology of epilepsy. Thus, new inhibitors of Smoothened, a key signal transducer of this signaling pathway are urgently need for refractory epilepsy. We have established a high-throughput screening platform and discovered several active small molecules targeting Smoothened including TT22. Here we show that the novel Smoothened inhibitor TT22 could block the translocation of βarrestin2-GFP to Smoothened, reduce the accumulation of Smoothened on primary cilia, displace Bodipy-cyclopamine binding to Smoothened, and inhibit the expression of downstream Gli transcription factor. Moreover, TT22 inhibits the abnormal seizure-like activity in neurons. Furthermore, we demonstrated that FDA-approved Smoothened inhibitor GDC-0449 and LDE-225 are able to inhibit abnormal seizure-like activity in neurons. Thus, our study suggests that targeting the sonic hedgehog signaling with new small-molecule Smoothened inhibitors might provide a potential new therapeutic avenue for refractory epilepsy. Full article

(This article belongs to the Special Issue Advances in Epilepsy and Antiepileptic Drugs 2.0)

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18 pages, 6312 KiB

Open AccessArticle

Delayed Impairment of Hippocampal Synaptic Plasticity after Pentylenetetrazole-Induced Seizures in Young Rats

by Tatyana Y. Postnikova, Alina M. Trofimova, Maria V. Zakharova, Olga I. Nosova, Alexey R. Brazhe, Dmitry E. Korzhevskii, Alexey V. Semyanov and Aleksey V. Zaitsev

Int. J. Mol. Sci. 2022, 23(21), 13461; https://doi.org/10.3390/ijms232113461 - 03 Nov 2022

Cited by 1 | Viewed by 1643

Abstract

Data on the long-term consequences of a single episode of generalized seizures in infants are inconsistent. In this study, we examined the effects of pentylenetetrazole-induced generalized seizures in three-week-old rats. One month after the seizures, we detected a moderate neuronal loss in several hippocampal regions: CA1, CA3, and hilus, but not in the dentate gyrus. In addition, long-term synaptic potentiation (LTP) was impaired. We also found that the mechanism of plasticity induction was altered: additional activation of metabotropic glutamate receptors (mGluR1) is required for LTP induction in experimental rats. This disturbance of the plasticity induction mechanism is likely due to the greater involvement of perisynaptic NMDA receptors compared to receptors located in the core part of the postsynaptic density. This hypothesis is supported by experiments with selective blockades of core-located NMDA receptors by the use-dependent blocker MK-801. MK-801 had no effect on LTP induction in experimental rats and suppressed LTP in control animals. The weakening of the function of core-located NMDA receptors may be due to the disturbed clearance of glutamate from the synaptic cleft since the distribution of the astrocytic glutamate transporter EAAT2 in experimental animals was found to be altered. Full article

(This article belongs to the Special Issue Advances in Epilepsy and Antiepileptic Drugs 2.0)

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Review

Jump to: Research

18 pages, 639 KiB

Open AccessReview

Second Generation of Antiepileptic Drugs and Oxidative Stress

by Kamil Kośmider, Maciej Kamieniak, Stanisław J. Czuczwar and Barbara Miziak

Int. J. Mol. Sci. 2023, 24(4), 3873; https://doi.org/10.3390/ijms24043873 - 15 Feb 2023

Cited by 7 | Viewed by 2807

Abstract

Epilepsy is a chronic disease of the central nervous system characterized by recurrent epileptic seizures. As a result of epileptic seizure or status epilepticus oxidants are excessively formed, which may be one of the causes of neuronal death. Given the role of oxidative stress in epileptogenesis, as well as the participation of this process in other neurological conditions, we decided to review the latest state of knowledge regarding the relationship between selected newer antiepileptic drugs (AEDs), also known as antiseizure drugs, and oxidative stress. The literature review indicates that drugs enhancing GABA-ergic transmission (e.g., vigabatrin, tiagabine, gabapentin, topiramate) or other antiepileptics (e.g., lamotrigine, levetiracetam) reduce neuronal oxidation markers. In particular, levetiracetam may produce ambiguous effects in this regard. However, when a GABA-enhancing drug was applied to the healthy tissue, it tended to increase oxidative stress markers in a dose-dependent manner. Studies on diazepam have shown that it exerts a neuroprotective effect in a “U-shaped” dose-dependent manner after excitotoxic or oxidative stress. Its lower concentrations are insufficient to protect against neuronal damage, while higher concentrations produce neurodegeneration. Therefore, a conclusion follows that newer AEDs, enhancing GABA-ergic neurotransmission, may act similarly to diazepam, causing neurodegeneration and oxidative stress when used in high doses. Full article

(This article belongs to the Special Issue Advances in Epilepsy and Antiepileptic Drugs 2.0)

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17 pages, 1305 KiB

Open AccessReview

Insight into Drug Resistance in Status Epilepticus: Evidence from Animal Models

by Fei Wang, Qingyang Zhang, Yu Wang, Junzi Chen and Yi Wang

Int. J. Mol. Sci. 2023, 24(3), 2039; https://doi.org/10.3390/ijms24032039 - 20 Jan 2023

Cited by 4 | Viewed by 1685

Abstract

Status epilepticus (SE), a condition with abnormally prolonged seizures, is a severe type of epilepsy. At present, SE is not well controlled by clinical treatments. Antiepileptic drugs (AEDs) are the main therapeutic approaches, but they are effective for SE only with a narrow intervening window, and they easily induce resistance. Thus, in this review, we provide an updated summary for an insight into drug-resistant SE, hoping to add to the understanding of the mechanism of refractory SE and the development of active compounds. Firstly, we briefly outline the limitations of current drug treatments for SE by summarizing the extensive experimental literature and clinical data through a search of the PubMed database, and then summarize the common animal models of refractory SE with their advantages and disadvantages. Notably, we also briefly review some of the hypotheses about drug resistance in SE that are well accepted in the field, and furthermore, put forward future perspectives for follow-up research on SE. Full article

(This article belongs to the Special Issue Advances in Epilepsy and Antiepileptic Drugs 2.0)

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22 pages, 1055 KiB

Open AccessReview

Advances and Challenges of Cannabidiol as an Anti-Seizure Strategy: Preclinical Evidence

by Cecilia Zavala-Tecuapetla, Hiram Luna-Munguia, María-Leonor López-Meraz and Manola Cuellar-Herrera

Int. J. Mol. Sci. 2022, 23(24), 16181; https://doi.org/10.3390/ijms232416181 - 19 Dec 2022

Cited by 3 | Viewed by 3808

Abstract

The use of Cannabis for medicinal purposes has been documented since ancient times, where one of its principal cannabinoids extracted from Cannabis sativa, cannabidiol (CBD), has emerged over the last few years as a promising molecule with anti-seizure potential. Here, we present an overview of recent literature pointing out CBD’s pharmacological profile (solubility, metabolism, drug-drug interactions, etc.,), CBD’s interactions with multiple molecular targets as well as advances in preclinical research concerning its anti-seizure effect on both acute seizure models and chronic models of epilepsy. We also highlight the recent attention that has been given to other natural cannabinoids and to synthetic derivatives of CBD as possible compounds with therapeutic anti-seizure potential. All the scientific research reviewed here encourages to continue to investigate the probable therapeutic efficacy of CBD and its related compounds not only in epilepsy but also and specially in drug-resistant epilepsy, since there is a dire need for new and effective drugs to treat this disease. Full article

(This article belongs to the Special Issue Advances in Epilepsy and Antiepileptic Drugs 2.0)

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