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      Astrocyte-derived SerpinA3N promotes neuroinflammation and epileptic seizures by activating the NF-κB signaling pathway in mice with temporal lobe epilepsy

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          Abstract

          Impaired activation and regulation of the extinction of inflammatory cells and molecules in injured neuronal tissues are key factors in the development of epilepsy. SerpinA3N is mainly associated with the acute phase response and inflammatory response. In our current study, transcriptomics analysis, proteomics analysis, and Western blotting showed that the expression level of Serpin clade A member 3N (SerpinA3N) is significantly increased in the hippocampus of mice with kainic acid (KA)-induced temporal lobe epilepsy, and this molecule is mainly expressed in astrocytes. Notably, in vivo studies using gain- and loss-of-function approaches revealed that SerpinA3N in astrocytes promoted the release of proinflammatory factors and aggravated seizures. Mechanistically, RNA sequencing and Western blotting showed that SerpinA3N promoted KA-induced neuroinflammation by activating the NF-κB signaling pathway. In addition, co-immunoprecipitation revealed that SerpinA3N interacts with ryanodine receptor type 2 (RYR2) and promotes RYR2 phosphorylation. Overall, our study reveals a novel SerpinA3N-mediated mechanism in seizure-induced neuroinflammation and provides a new target for developing neuroinflammation-based strategies to reduce seizure-induced brain injury.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12974-023-02840-8.

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          Epilepsy in adults

          Roland Thijs, Rainer Surges, Terence J O'Brien … (2019)
          Epilepsy is one of the most common serious brain conditions, affecting over 70 million people worldwide. Its incidence has a bimodal distribution with the highest risk in infants and older age groups. Progress in genomic technology is exposing the complex genetic architecture of the common types of epilepsy, and is driving a paradigm shift. Epilepsy is a symptom complex with multiple risk factors and a strong genetic predisposition rather than a condition with a single expression and cause. These advances have resulted in the new classification of epileptic seizures and epilepsies. A detailed clinical history and a reliable eyewitness account of a seizure are the cornerstones of the diagnosis. Ancillary investigations can help to determine cause and prognosis. Advances in brain imaging are helping to identify the structural and functional causes and consequences of the epilepsies. Comorbidities are increasingly recognised as important aetiological and prognostic markers. Antiseizure medication might suppress seizures in up to two-thirds of all individuals but do not alter long-term prognosis. Epilepsy surgery is the most effective way to achieve long-term seizure freedom in selected individuals with drug-resistant focal epilepsy, but it is probably not used enough. With improved understanding of the gradual development of epilepsy, epigenetic determinants, and pharmacogenomics comes the hope for better, disease-modifying, or even curative, pharmacological and non-pharmacological treatment strategies. Other developments are clinical implementation of seizure detection devices and new neuromodulation techniques, including responsive neural stimulation.
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            The role of inflammation in epilepsy.

            Annamaria Vezzani, Jacqueline French, Tamas Bartfai … (2011)
            Epilepsy is the third most common chronic brain disorder, and is characterized by an enduring predisposition to generate seizures. Despite progress in pharmacological and surgical treatments of epilepsy, relatively little is known about the processes leading to the generation of individual seizures, and about the mechanisms whereby a healthy brain is rendered epileptic. These gaps in our knowledge hamper the development of better preventive treatments and cures for the approximately 30% of epilepsy cases that prove resistant to current therapies. Here, we focus on the rapidly growing body of evidence that supports the involvement of inflammatory mediators-released by brain cells and peripheral immune cells-in both the origin of individual seizures and the epileptogenic process. We first describe aspects of brain inflammation and immunity, before exploring the evidence from clinical and experimental studies for a relationship between inflammation and epilepsy. Subsequently, we discuss how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death. Further insight into the complex role of inflammation in the generation and exacerbation of epilepsy should yield new molecular targets for the design of antiepileptic drugs, which might not only inhibit the symptoms of this disorder, but also prevent or abrogate disease pathogenesis.
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              Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy

              Annamaria Vezzani, Silvia Balosso, Teresa Ravizza (2019)
              Epilepsy is a chronic neurological disease characterized by an enduring propensity for generation of seizures. The pathogenic processes of seizure generation and recurrence are the subject of intensive preclinical and clinical investigations as their identification would enable development of novel treatments that prevent epileptic seizures and reduce seizure burden. Such treatments are particularly needed for pharmacoresistant epilepsies, which affect ~30% of patients. Neuroinflammation is commonly activated in epileptogenic brain regions in humans and is clearly involved in animal models of epilepsy. An increased understanding of neuroinflammatory mechanisms in epilepsy has identified cellular and molecular targets for new mechanistic therapies or existing anti-inflammatory drugs that could overcome the limitations of current medications, which provide only symptomatic control of seizures. Moreover, inflammatory mediators in the blood and molecular imaging of neuroinflammation could provide diagnostic, prognostic and predictive biomarkers for epilepsy, which will be instrumental for patient stratification in future clinical studies. In this Review, we focus on our understanding of the IL-1 receptor-Toll-like receptor 4 axis, the arachidonic acid-prostaglandin cascade, oxidative stress and transforming growth factor-β signalling associated with blood-brain barrier dysfunction, all of which are pathways that are activated in pharmacoresistant epilepsy in humans and that can be modulated in animal models to produce therapeutic effects on seizures, neuronal cell loss and neurological comorbidities.
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                Author and article information

                Contributors
                Chong Liu: liuch@ccmu.edu.cn
                Xue-Min Zhao: zhaoxuemin0220@126.com
                Qiao Wang: justicejoking@126.com
                Ting-Ting Du: tingting.du@ccmu.edu.cn
                Mo-Xuan Zhang: mxzhang91@163.com
                Hui-Zhi Wang: 17865195200@163.com
                Ren-Peng Li: renpengli1024@163.com
                Kun Liang: liangkun96@126.com
                Yuan Gao: yuan1998gao@163.com
                Si-Yu Zhou: zhousiyu@mail.ccmu.edu.cn
                Tao Xue: 2992326676@qq.com
                Jian-Guo Zhang: zjguo73@126.com
                Chun-Lei Han: hanchunlei622@163.com
                Lin Shi: shilin2015@foxmail.com
                Liang-Wen Zhang: zhanglw@email.sdu.edu.cn
                Fan-Gang Meng: mengfg@ccmu.edu.cn
                Journal
                Journal ID (nlm-ta): J Neuroinflammation
                Journal ID (iso-abbrev): J Neuroinflammation
                Title: Journal of Neuroinflammation
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1742-2094
                Publication date (Electronic): 8 July 2023
                Publication date PMC-release: 8 July 2023
                Publication date Collection: 2023
                Volume: 20
                Electronic Location Identifier: 161
                Affiliations
                [1 ]GRID grid.24696.3f, ISNI 0000 0004 0369 153X, Beijing Neurosurgical Institute, Capital Medical University, ; Beijing, 100070 China
                [2 ]GRID grid.413259.8, ISNI 0000 0004 0632 3337, Beijing Key Laboratory of Neurostimulation, ; Beijing, 100070 China
                [3 ]GRID grid.411617.4, ISNI 0000 0004 0642 1244, Beijing Tiantan Hospital, Capital Medical University, ; No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070 China
                [4 ]GRID grid.410638.8, ISNI 0000 0000 8910 6733, Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, ; Jinan, 250021 Shandong China
                [5 ]GRID grid.510934.a, ISNI 0000 0005 0398 4153, Chinese Institute for Brain Research, ; Beijing, 102206 China
                Article
                Publisher ID: 2840
                DOI: 10.1186/s12974-023-02840-8
                PMC ID: 10329806
                PubMed ID: 37422673
                SO-VID: ea2ca085-f9aa-4527-add0-fb4b2ddd7467
                Copyright © © The Author(s) 2023
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                Date received : 14 November 2022
                Date accepted : 22 June 2023
                Funding
                Funded by: 2021 Reform Development of Beijing Neurosurgical Institute
                Award ID: Institute Youth-3
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 82101514
                Award ID: 82171442
                Award ID: 81901314
                Award ID: 81971070
                Award Recipient :
                Funded by: Beijing Natural Science Foundation Program, Scientific Research Key Program of Beijing Municipal Commission of Education
                Award ID: KZ201910025036
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © BioMed Central Ltd., part of Springer Nature 2023

                ScienceOpen disciplines: Neurosciences
                Keywords: astrocytes,serpina3n,neuroinflammation,epileptic seizures,temporal lobe epilepsy,multi-omics analysis
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: astrocytes, serpina3n, neuroinflammation, epileptic seizures, temporal lobe epilepsy, multi-omics analysis

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