Animal Models of Drug-Resistant Epilepsy as Tools for Deciphering the Cellular and Molecular Mechanisms of Pharmacoresistance and Discovering More Effective Treatments

Cells, Год журнала: 2023, Номер 12(9), С. 1233 - 1233

Опубликована: Апрель 24, 2023

In the last 30 years, over 20 new anti-seizure medicines (ASMs) have been introduced into market for treatment of epilepsy using well-established preclinical seizure and models. Despite this success, approximately 20–30% patients with drug-resistant (DRE). The current approach to ASM discovery DRE relies largely on drug testing in various model systems that display varying degrees resistance. recent attempts made include more etiologically relevant models evaluation a investigational drug. Such played an important role advancing greater understanding at mechanistic level hypothesis as experimental evidence becomes available. This review provides critical discussion pharmacology adult focal allow selection responders nonresponders those pharmacoresistance per se two or ASMs. addition, animal major genetic epilepsies is discussed. Importantly, addition chemical compounds, several discussed here can be used evaluate other potential therapies such neurostimulation, dietary treatments, gene therapy, cell transplantation. also discusses challenges associated identifying novel absence mechanisms contribute DRE. Finally, lessons learned from profile recently approved highly efficacious broad-spectrum cenobamate.

Язык: Английский

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Understanding Lamotrigine’s Role in the CNS and Possible Future Evolution

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(7), С. 6050 - 6050

Опубликована: Март 23, 2023

The anti-epileptic drug lamotrigine (LTG) has been widely used to treat various neurological disorders, including epilepsy and bipolar disorder. However, its precise mechanism of action in the central nervous system (CNS) still needs be determined. Recent studies have highlighted involvement LTG modulating activity voltage-gated ion channels, particularly those related inhibition neuronal excitability. Additionally, found neuroprotective effects, potentially through glutamate release enhancement GABAergic neurotransmission. LTG's unique compared other drugs led investigation use treating CNS such as neuropathic pain, PTSD, major depressive Furthermore, combined with mood stabilizers, which may enhance therapeutic effects. In conclusion, potential modulate multiple neurotransmitters channels makes it a promising for disorders. As our understanding continues evolve, new indications will also explored.

Язык: Английский

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Pharmacological aspects of antiseizure medications: From basic mechanisms to clinical considerations of drug interactions and use of therapeutic drug monitoring

Epileptic Disorders, Год журнала: 2023, Номер 25(4), С. 454 - 471

Опубликована: Май 11, 2023

Abstract Antiseizure medications (ASMs) are the cornerstone of treatment for patients with epilepsy. Several new ASMs have recently been introduced to market, making it possible better tailor epilepsy, as well other indications (psychiatry and pain disorders). For this group drugs there numerous pharmacological challenges, updated knowledge on their pharmacodynamic pharmacokinetic properties is, therefore, crucial an optimal outcome. This review focuses educational approaches following learning outcomes described by International League Against Epilepsy (ILAE): To demonstrate pharmacokinetics pharmacodynamics, drug interactions concomitant medications, appropriate monitoring ASM serum levels (therapeutic monitoring, TDM). Basic principles in pharmacology, variability, clinically relevant manage discussed. Furthermore, recent improvements analytical technology sampling described. Future directions point combined implementation TDM genetic panels proper diagnosis, pharmacogenetic tests where relevant, use biochemical markers that will all contribute personalized treatment. These outcome various patient groups.

Язык: Английский

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Fenfluramine: a plethora of mechanisms?

Frontiers in Pharmacology, Год журнала: 2023, Номер 14

Опубликована: Май 12, 2023

Developmental and epileptic encephalopathies are rare, treatment-resistant epilepsies with high seizure burden non-seizure comorbidities. The antiseizure medication (ASM) fenfluramine is an effective treatment for reducing frequency, ameliorating comorbidities, potentially risk of sudden unexpected death in epilepsy (SUDEP) patients Dravet syndrome Lennox-Gastaut syndrome, among other rare epilepsies. Fenfluramine has a unique mechanism action (MOA) ASMs. Its primary MOA currently described as dual-action sigma-1 receptor serotonergic activity; however, mechanisms may be involved. Here, we conduct extensive review the literature to identify all previously fenfluramine. We also consider how these play role reports clinical benefit outcomes, including SUDEP everyday executive function. Our highlights importance serotonin maintaining balance between excitatory (glutamatergic) inhibitory (γ-aminobutyric acid [GABA]-ergic) neural networks, suggests that represent pharmacological MOAs seizures, SUDEP. describe ancillary roles GABA neurotransmission, noradrenergic endocrine system (especially such progesterone derivatives neuroactive steroids). Dopaminergic activity underlies appetite reduction, common side effect treatment, but any involvement reduction remains speculative. Further research underway evaluate promising new biological pathways A better understanding comorbidities allow rational drug design and/or improved decision-making when prescribing multi-ASM regimens.

Язык: Английский

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Which terms should be used to describe medications used in the treatment of seizure disorders? An ILAE position paper

Epilepsia, Год журнала: 2024, Номер 65(3), С. 533 - 541

Опубликована: Янв. 27, 2024

Abstract A variety of terms, such as “antiepileptic,” “anticonvulsant,” and “antiseizure” have been historically applied to medications for the treatment seizure disorders. Terminology is important because using terms that do not accurately reflect action specific treatments may result in a misunderstanding their effects inappropriate use. The present International League Against Epilepsy (ILAE) position paper used Delphi approach develop recommendations on English‐language terminology applicable pharmacological agents currently approved treating There was consensus these should be collectively named “antiseizure medications”. This term reflects primarily symptomatic effect against seizures reduces possibility health care practitioners, patients, or caregivers having undue expectations an incorrect understanding real medications. describe does exclude beneficial course disease comorbidities from downstream seizures, whenever can explained solely by suppression activity. It acknowledged other treatments, mostly under development, exert direct favorable actions underlying its progression, “antiepileptogenic” “disease‐modifying” effects. more‐refined precisely needs developed.

Язык: Английский

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The Contribution of Microglia and Brain-Infiltrating Macrophages to the Pathogenesis of Neuroinflammatory and Neurodegenerative Diseases during TMEV Infection of the Central Nervous System

Viruses, Год журнала: 2024, Номер 16(1), С. 119 - 119

Опубликована: Янв. 13, 2024

The infection of the central nervous system (CNS) with neurotropic viruses induces neuroinflammation and is associated development neuroinflammatory neurodegenerative diseases, including multiple sclerosis epilepsy. activation innate adaptive immune response, microglial, macrophages, T B cells, while required for efficient viral control within CNS, also neuropathology. Under healthy conditions, resident microglia play a pivotal role in maintaining CNS homeostasis. However, during pathological events, such as infection, become reactive, cells from periphery infiltrate into brain, disrupting homeostasis contributing to disease development. Theiler's murine encephalomyelitis virus (TMEV), picornavirus, used two distinct mouse models: TMEV-induced demyelination (TMEV-IDD) seizures, representing models epilepsy, respectively. These have contributed substantially our understanding pathophysiology MS seizures/epilepsy following serving critical tools identifying pharmacological targetable pathways modulate This review aims discuss host-pathogen interaction picornavirus shed light on current multifaceted roles played by macrophages context these complexes viral-induced disease.

Язык: Английский

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Prenatal exposure to antiseizure medications and fetal growth: a population-based cohort study from the Nordic countries

The Lancet Regional Health - Europe, Год журнала: 2024, Номер 38, С. 100849 - 100849

Опубликована: Фев. 8, 2024

The short- and long-term consequences of restricted fetal growth cause considerable concern, how prenatal exposure to different antiseizure medications (ASMs) affects remains uncertain. This was a population-based cohort study liveborn singleton children born in Denmark, Finland, Iceland, Norway, Sweden from 1996 2017. Prenatal defined as maternal filling prescriptions for ASM during pregnancy registered national prescription registries primary outcomes were adjusted odds ratios (aORs) microcephaly or being small gestational age. We identified 4,494,918 (males: 51.3%, 2,306,991/4,494,918), including 38,714 (0.9%) mothers with epilepsy. In the overall population, monotherapy carbamazepine (aOR: 1.25 (95% CI: 1.12–1.40)), pregabalin 1.16 1.02–1.31)), oxcarbazepine 1.48 1.28–1.71)), clonazepam 1.27 1.10–1.48)), topiramate 1.18–1.85)) associated risk age, 1.43 1.17–1.75)). epilepsy, 1.11–1.47)), 1.42 1.18–1.70)), 1.40 1.03–1.89)), 1.86 1.36–2.54)) age; carbamazepine, 1.51 1.17–1.95)). No associations age after lamotrigine, valproate, gabapentin, levetiracetam, phenobarbital, acetazolamide, phenytoin, clobazam, primidone, zonisamide, vigabatrin, ethosuximide lacosamide, but except numbers exposed small. oxcarbazepine, clonazepam, increased both population women epilepsy suggesting that these drugs is restriction. NordForsk Nordic Program on Health Welfare (83539), Independent Research Fund Denmark (1133-00026B), Danish Epilepsy Association, Central Region, Novo Nordisk Foundation (NNF16OC0019126 NNF22OC0075033), Lundbeck (R400-2022-1205).

Язык: Английский

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Cenobamate as an Early Adjunctive Treatment in Drug-Resistant Focal-Onset Seizures: An Observational Cohort Study

CNS Drugs, Год журнала: 2024, Номер 38(9), С. 733 - 742

Опубликована: Авг. 3, 2024

Cenobamate (CNB) is a new antiseizure medication (ASM) to treat drug-resistant, focal-onset seizures. Data on its use in early therapy lines are not yet available, and clinicians frequently consider CNB be later ASM drug choice. We investigated the efficacy safety of as an adjunctive treatment The study population were patients with seizures who initiated after they did respond two or three lifetime ASMs, including all prior concomitant ASMs. These matched (1:2) by sex, age, seizure frequency controls any other than CNB. All participants participated Mainz Epilepsy Registry. evaluated retention rate 12 months each control group. In addition, freedom response (reduction ≥ 50% from baseline) estimated. included 231 aged 44.4 ± 15.8 years. Of these, 33.3% (n = 77) CNB, 19.0% 44) valproate (VPA), 17.3% 40) lacosamide (LCS), 16.4% 38) levetiracetam (LEV), 13.9% 32) topiramate (TPM). highest since beginning was observed (92.0%), compared LCS (80.0%), LEV (73.3%), VPA (68.2%), TPM (62.5%) (p < 0.05). Seizure also best (19.5% 71.4%, respectively) ASMs (8.3% 52.5%, respectively; p No significant differences adverse events between observed. Our provides evidence that effective good profile This data should support medical decision making management refractory epilepsy. NCT05267405.

Язык: Английский

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Acetylcholine receptor based chemogenetics engineered for neuronal inhibition and seizure control assessed in mice

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 18, 2024

Abstract Epilepsy is a prevalent disorder involving neuronal network hyperexcitability, yet existing therapeutic strategies often fail to provide optimal patient outcomes. Chemogenetic approaches, where exogenous receptors are expressed in defined brain areas and specifically activated by selective agonists, appealing methods constrain overactive activity. We developed BARNI (Bradanicline- Acetylcholine-activated Receptor for Neuronal Inhibition), an engineered channel comprised of the α7 nicotinic acetylcholine receptor ligand-binding domain coupled α1 glycine anion pore domain. Here we demonstrate that activation clinical stage receptor-selective agonist bradanicline effectively suppressed targeted activity, controlled both acute chronic seizures male mice. Our results evidence use inhibitory acetylcholine-based activatable endogenous agonists as potential approach treating epilepsy.

Язык: Английский

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Using artificial intelligence to optimize anti-seizure treatment and EEG-guided decisions in severe brain injury

Neurotherapeutics, Год журнала: 2025, Номер unknown, С. e00524 - e00524

Опубликована: Янв. 1, 2025

Electroencephalography (EEG) is invaluable in the management of acute neurological emergencies. Characteristic EEG changes have been identified diverse neurologic conditions including stroke, trauma, and anoxia, increased utilization continuous (cEEG) has potentially harmful activity even patients without overt clinical signs or diagnoses. Manual annotation by expert neurophysiologists a major resource limitation investigating prognostic therapeutic implications these patterns expanding use to broader set who are likely benefit. Artificial intelligence (AI) already demonstrated success guiding cEEG allocation for at risk seizures, its potential uses neurocritical care alongside improvements AI itself. We review both current EEG-guided as well ongoing research directions automated seizure ischemia detection, prognostication, guidance medical surgical treatment.

Язык: Английский

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