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      Drug‐resistant epilepsy: Drug target hypothesis and beyond the receptors

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          Abstract

          Epilepsy is a chronic neurological disorder that affects more than 50 million people worldwide. Despite a recent introduction of antiseizure drugs for the treatment of epileptic seizures, one‐third of these patients suffer from drug‐resistant epilepsy (DRE). The therapeutic target hypothesis is a cited theory to explain DRE. According to the target hypothesis, the failure to achieve seizure freedom leads to alteration of the structure and/or function of the antiseizure medication (ASM) target. However, this hypothesis fails to explain why patients with DRE do not respond to antiseizure medications of different targets. This review presents different conditions, such as epigenetic mechanisms and protein‐protein interactions that may result in alterations of diverse drug targets using different mechanisms. These novel conditions represent new targets to control DRE.

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          Gene regulation by long non-coding RNAs and its biological functions

          Luisa Statello, Chun-Jie Guo, Ling-Ling Chen … (2020)
          Evidence accumulated over the past decade shows that long non-coding RNAs (lncRNAs) are widely expressed and have key roles in gene regulation. Recent studies have begun to unravel how the biogenesis of lncRNAs is distinct from that of mRNAs and is linked with their specific subcellular localizations and functions. Depending on their localization and their specific interactions with DNA, RNA and proteins, lncRNAs can modulate chromatin function, regulate the assembly and function of membraneless nuclear bodies, alter the stability and translation of cytoplasmic mRNAs and interfere with signalling pathways. Many of these functions ultimately affect gene expression in diverse biological and physiopathological contexts, such as in neuronal disorders, immune responses and cancer. Tissue-specific and condition-specific expression patterns suggest that lncRNAs are potential biomarkers and provide a rationale to target them clinically. In this Review, we discuss the mechanisms of lncRNA biogenesis, localization and functions in transcriptional, post-transcriptional and other modes of gene regulation, and their potential therapeutic applications.
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            Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies.

            Patrick Kwan, Alexis Arzimanoglou, Anne T. Berg … (2010)
            To improve patient care and facilitate clinical research, the International League Against Epilepsy (ILAE) appointed a Task Force to formulate a consensus definition of drug resistant epilepsy. The overall framework of the definition has two "hierarchical" levels: Level 1 provides a general scheme to categorize response to each therapeutic intervention, including a minimum dataset of knowledge about the intervention that would be needed; Level 2 provides a core definition of drug resistant epilepsy using a set of essential criteria based on the categorization of response (from Level 1) to trials of antiepileptic drugs. It is proposed as a testable hypothesis that drug resistant epilepsy is defined as failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. This definition can be further refined when new evidence emerges. The rationale behind the definition and the principles governing its proper use are discussed, and examples to illustrate its application in clinical practice are provided.
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              A brain-specific microRNA regulates dendritic spine development.

              Gerhard M Schratt, Fabian Tuebing, Elizabeth Nigh … (2006)
              MicroRNAs are small, non-coding RNAs that control the translation of target messenger RNAs, thereby regulating critical aspects of plant and animal development. In the mammalian nervous system, the spatiotemporal control of mRNA translation has an important role in synaptic development and plasticity. Although a number of microRNAs have been isolated from the mammalian brain, neither the specific microRNAs that regulate synapse function nor their target mRNAs have been identified. Here we show that a brain-specific microRNA, miR-134, is localized to the synapto-dendritic compartment of rat hippocampal neurons and negatively regulates the size of dendritic spines--postsynaptic sites of excitatory synaptic transmission. This effect is mediated by miR-134 inhibition of the translation of an mRNA encoding a protein kinase, Limk1, that controls spine development. Exposure of neurons to extracellular stimuli such as brain-derived neurotrophic factor relieves miR-134 inhibition of Limk1 translation and in this way may contribute to synaptic development, maturation and/or plasticity.
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                Author and article information

                Contributors
                Luisa Rocha:
                ORCID: https://orcid.org/0000-0003-4495-9427
                lrocha@cinvestav.mx
                Journal
                Journal ID (nlm-ta): Epilepsia Open
                Journal ID (iso-abbrev): Epilepsia Open
                Journal ID (doi): 10.1002/(ISSN)2470-9239
                Journal ID (publisher-id): EPI4
                Title: Epilepsia Open
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Electronic): 2470-9239
                Publication date (Electronic): 22 October 2021
                Publication date Collection: August 2022
                Volume: 7
                Issue: Suppl 1 , Redesigning The Hypotheses For Drug‐Resistant Epilepsy ( doiID: 10.1002/epi4.v7.s1 )
                Pages: S23-S33
                Affiliations
                [ 1 ] Pharmacobiology Department Center for Research and Advanced Studies México City México
                [ 2 ] Plan of Combined Studies in Medicine (PECEM) Faculty of Medicine UNAM México City Mexico
                [ 3 ] Escuela Nacional de Medicina y Homeopatía Instituto Politécnico Nacional Mexico City México
                [ 4 ] Biomedicum Karolinska Institutet Stockholm Sweden
                Author notes
                [*] [* ] Correspondence

                Luisa Rocha, Biomedicum, Karolinska Institutet, Stockholm, Sweden.

                Email: lrocha@ 123456cinvestav.mx

                Author information
                https://orcid.org/0000-0002-7884-1593
                https://orcid.org/0000-0002-9712-2543
                https://orcid.org/0000-0003-4495-9427
                Article
                Publisher ID: EPI412539
                DOI: 10.1002/epi4.12539
                PMC ID: 9340308
                PubMed ID: 34542940
                SO-VID: 72364ce0-bd82-4cc3-8af7-82b14890e983
                Copyright © © 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date revision received : 21 August 2021
                Date received : 31 May 2021
                Date accepted : 27 August 2021
                Page count
                Figures: 3, Tables: 0, Pages: 11, Words: 24580
                Funding
                Funded by: Consejo Nacional de Ciencia y Tecnología , doi 10.13039/501100003141;
                Award ID: A3‐S‐26782
                Categories
                Subject: Critical Review
                Subject: Critical Reviews
                Custom metadata
                source-schema-version-number 2.0
                cover-date August 2022
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:01.08.2022

                Keywords: antiseizure medications,drug‐resistant,epigenetics,epilepsy,mosaics,oligomers,receptors,target hypothesis
                Data availability:
                Keywords: antiseizure medications, drug‐resistant, epigenetics, epilepsy, mosaics, oligomers, receptors, target hypothesis

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