Selected Molecular Targets for Antiepileptogenesis

Pawlik, Marek J.; Miziak, Barbara; Walczak, Aleksandra M.; Konarzewska, Agnieszka; Chrościńska–Krawczyk, Magdalena; Albrecht, Jan; Czuczwar, Stanisław J.

doi:10.3390/ijms22189737

Cited by 14 publications

(11 citation statements)

References 96 publications

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“…Epileptogenesis is thought to involve three stages: (1) the initial insult or precipitating event, (2) the latent period, and (3) the chronic epilepsy phase [110,111]. Neurogenesis, gliosis, neurodegeneration, dendritic plasticity, axonal damage or sprouting, recruitment of inflammatory cells into brain tissue, damage to the blood-brain barrier, reorganization of the extracellular matrix, and reorganization of the molecular architecture of specific neuronal cells are changes that can occur in the epileptogenic brain [112].…”

Section: Oxidative Stress Neuronal Death and Neurodegeneration In Epi...mentioning

confidence: 99%

Oxidative Stress and Neurodegeneration in Animal Models of Seizures and Epilepsy

Łukawski

Czuczwar

2023

Antioxidants

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Free radicals are generated in the brain, as well as in other organs, and their production is proportional to the brain activity. Due to its low antioxidant capacity, the brain is particularly sensitive to free radical damage, which may affect lipids, nucleic acids, and proteins. The available evidence clearly points to a role for oxidative stress in neuronal death and pathophysiology of epileptogenesis and epilepsy. The present review is devoted to the generation of free radicals in some animal models of seizures and epilepsy and the consequences of oxidative stress, such as DNA or mitochondrial damage leading to neurodegeneration. Additionally, antioxidant properties of antiepileptic (antiseizure) drugs and a possible use of antioxidant drugs or compounds in patients with epilepsy are reviewed. In numerous seizure models, the brain concentration of free radicals was significantly elevated. Some antiepileptic drugs may inhibit these effects; for example, valproate reduced the increase in brain malondialdehyde (a marker of lipid peroxidation) concentration induced by electroconvulsions. In the pentylenetetrazol model, valproate prevented the reduced glutathione concentration and an increase in brain lipid peroxidation products. The scarce clinical data indicate that some antioxidants (melatonin, selenium, vitamin E) may be recommended as adjuvants for patients with drug-resistant epilepsy.

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Section: Oxidative Stress Neuronal Death and Neurodegeneration In Epi...mentioning

confidence: 99%

Oxidative Stress and Neurodegeneration in Animal Models of Seizures and Epilepsy

Łukawski

Czuczwar

2023

Antioxidants

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“…However, there is a current lack of effective seizure controlling medication for treatment of DEE. Drug re-purposing for epilepsy, particularly the use of anti-inflammatory and anti-oxidant medications with known, and manageable, side effect profiles, is increasingly desirable (for recent reviews, see (R adu et al 2017; K lein et al 2020; L oscher 2020; P awlik et al 2021). We tested two drugs, the commonly used anti-seizure drug VPA, and the anti- inflammatory drug Losartan, to determine the potential for seizure reduction.…”

Section: Resultsmentioning

confidence: 99%

Knockdown ofNeuroD2leads to seizure-like behaviour, brain neuronal hyperactivity and a leaky blood-brain barrier in aXenopus laevistadpole model of DEE75

Banerjee,

Szyszka,

Beck

2023

Preprint

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Developmental and Epileptic Encephalopathies (DEE) are a genetically diverse group of severe, early onset seizure disorders. DEE are normally identified clinically in the first six months of life by the presence of frequent, difficult to control seizures and accompanying stalling or regression of development. DEE75 results fromde novomutations of theNEUROD2gene that result in loss of activity of the encoded transcription factor, and the seizure phenotype was shown to be recapitulated inXenopus tropicalistadpoles. We used CRISPR/Cas9 to make a DEE75 model inXenopus laevis, to further investigate the developmental aetiology.NeuroD2.SCRISPR/Cas9 edited tadpoles were more active, swam faster on average, and had more unprovoked escape responses (C-starts) than their sibling controls. Live imaging of Ca2+signalling revealed prolongued, strong signals sweeping through the brain, indicative of neuronal hyperactivity. While the resulting tadpole brain appeared grossly normal, the blood-brain barrier was found to be leakier than that of controls. Additionally, the TGFβ antagonist Losartan was shown to have a short-term protective effect, reducing neuronal hyperactivity and reducing permeability of the blood- brain barrier. Severity of the behavioral phenotype correlated with increased with editing efficiency. Our results support a haploinsufficiency model of DEE75 resulting from reduced NeuroD2 activity during vertebrate brain development, and indicate that a leaky blood- brain barrier contributes to epileptogenesis.

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“…In less than 65–70% of patients with epilepsy, AEDs effectively control seizures ( Pawlik et al, 2021 ). Novel AEDs, including zonisamide and lamotrigine, have been developed and have a broader spectrum of activity in specific epileptic syndromes and seizure types ( Rosenow et al, 2012 ; Mula, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Global trends in research of glutamate in epilepsy during past two decades: A bibliometric analysis

Wang

Gao²,

Z³

et al. 2022

Front. Neurosci.

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Epilepsy affects more than 70 million people in the world. It is characterized by recurrent spontaneous seizures, and it is related to many neurological, cognitive, and psychosocial consequences. Glutamate neurotransmitter dysfunction has essential functions in the pathophysiology of epilepsy. In this work, bibliometric analysis was conducted to explore the trends, frontiers, and hotspots of the global scientific output of glutamate in epilepsy research in the past 20 years. The Science Citation Index Expanded of the Web of Science Core Collection (WoSCC) was searched to obtain information on publications and records published between 2002 and 2021. VOSviewer and CiteSpace were used to conduct bibliometric and visual analyses on the overall distribution of annual output, major countries, active institutions, journals, authors, commonly cited literature, and keywords. The impact and quality of the papers were assessed using the global citation score (GCS). Four thousand eight hundred ninety-one publications were retrieved in total. During the past two decades, the number of publications (Np) associated with glutamate in epilepsy has risen yearly. The United States has published the most papers; its H-index and number of citations are also the highest. The League of European Research Universities (LERU) was the most productive institution. In 2016, the total score of the paper written by Zhang Y was 854, ranking first. The keywords that appear most frequently are “epilepsy,” “glutamate,” “temporal lobe epilepsy (TLE),” “hippocampus,” and “seizures.” This study showed that although the publications related to epileptic glutamate fluctuated slightly, the Np increased overall. The United States is a great creator and influential country in this field. The first three authors are Eid, T., Aronica, E., and Smolders, I. “spectrum,” “animal model,” “inflammation,” “mutation,” “dysfunction,” and “prefrontal cortex” are increasing research hotspots. By recognizing the most critical indicators (researchers, countries, research institutes, and journals of glutamate release in epilepsy research), the research hotspot of glutamate in epilepsy could help countries, scholars, and policymakers in this field enhance their understanding of the role of glutamate in epilepsy and make decisions.

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Selected Molecular Targets for Antiepileptogenesis

Cited by 14 publications

References 96 publications

Oxidative Stress and Neurodegeneration in Animal Models of Seizures and Epilepsy

Oxidative Stress and Neurodegeneration in Animal Models of Seizures and Epilepsy

Knockdown ofNeuroD2leads to seizure-like behaviour, brain neuronal hyperactivity and a leaky blood-brain barrier in aXenopus laevistadpole model of DEE75

Global trends in research of glutamate in epilepsy during past two decades: A bibliometric analysis

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