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      Celastrol Treatment Ameliorated Acute Ischemic Stroke-Induced Brain Injury by Microglial Injury Inhibition and Nrf2/HO-1 Pathway Activations

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          Abstract

          Background

          Stroke is the third main reason of mortality, which is the leading reason for adult disability in the globe. Poststroke inflammation is well known to cause acute ischemic stroke- (AIS-) induced brain injury (BI) exacerbation. Celastrol (CL) has exhibited anti-inflammatory activities in various inflammatory traits though underlying mechanisms remain unknown. So, the present investigation is aimed at studying CL protective mechanism against AIS-induced BI.

          Methods

          A mouse model regarding middle cerebral artery occlusion and an oxygen-glucose deprivation (OGD) cell model with or not CL treatment were constructed to study CL protective effects. NF-E2-related factor 2 (Nrf2) was then silenced in BV2 microglia cells (BV2) to study Nrf2 role regarding CL-mediated neuroprotection.

          Results

          The results showed that CL treatment suppressed AIS-induced BI by inhibiting NLRP3/caspase-1 pathway activations and induction of apoptosis and pyroptosis in vivo and in vitro. NLRP3/caspase-1 pathway blocking activation suppressed OGD-induced cell pyroptosis and apoptosis. Also, CL treatment reversed OGD-induced microglial injury by promoting Nrf2/heme oxygenase-1 (HO-1) pathway activations. Nrf2 downregulation reversed CL protective effects against OGD-induced microglial injury, pyroptosis, and apoptosis.

          Conclusion

          The findings advise that CL treatment ameliorated AIS-induced BI by inhibiting microglial injury and activating the Nrf2/HO-1 pathway.

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          Most cited references33

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          The inflammasomes: guardians of the body.

          Fabio Martinon, Annick Mayor, Jurg Tschopp (2009)
          The innate immune system relies on its capacity to rapidly detect invading pathogenic microbes as foreign and to eliminate them. The discovery of Toll-like receptors (TLRs) provided a class of membrane receptors that sense extracellular microbes and trigger antipathogen signaling cascades. More recently, intracellular microbial sensors have been identified, including NOD-like receptors (NLRs). Some of the NLRs also sense nonmicrobial danger signals and form large cytoplasmic complexes called inflammasomes that link the sensing of microbial products and metabolic stress to the proteolytic activation of the proinflammatory cytokines IL-1beta and IL-18. The NALP3 inflammasome has been associated with several autoinflammatory conditions including gout. Likewise, the NALP3 inflammasome is a crucial element in the adjuvant effect of aluminum and can direct a humoral adaptive immune response. In this review, we discuss the role of NLRs, and in particular the inflammasomes, in the recognition of microbial and danger components and the role they play in health and disease.
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            The inflammasome NLRs in immunity, inflammation, and associated diseases.

            Beckley K. Davis, Haitao Wen, Jenny P.-Y. Ting (2011)
            Inflammasome activation leads to caspase-1 activation, which causes the maturation and secretion of pro-IL-1β and pro-IL-18 among other substrates. A subgroup of the NLR (nucleotide-binding domain, leucine-rich repeat containing) proteins are key mediators of the inflammasome. Studies of gene-deficient mice and cells have implicated NLR inflammasomes in a host of responses to a wide range of microbial pathogens, inflammatory diseases, cancer, and metabolic and autoimmune disorders. Determining exactly how the inflammasome is activated in these diseases and disease models remains a challenge. This review presents and integrates recent progress in the field.
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              Mitochondrial dysfunction induces NLRP3 inflammasome activation during cerebral ischemia/reperfusion injury

              Zhe Gong, Jingrui Pan, Qingyu Shen … (2018)
              Background Nod-like receptor protein 3 (NLRP3) inflammasome is a crucial factor in mediating inflammatory responses after cerebral ischemia/reperfusion (I/R), but the cellular location of NLRP3 inflammasome in cerebral I/R has yet come to a conclusion, and there is still no specific evidence to state the relationship between mitochondria and the NLRP3 inflammasome in cerebral I/R. Methods In the present study, we detected the cellular localization of NLRP3 inflammasomes in a transient middle cerebral artery occlusion (tMCAO) rat model and a transwell co-culture cell system under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions. Then, we investigated the relationship between mitochondrial dysfunction and the activation of NLRP3 inflammasomes in different cell types after OGD/R and cerebral I/R injury. Results Our results showed that NLRP3 inflammasomes were first activated in microglia soon after cerebral I/R injury onset and then were expressed in neurons and microvascular endothelial cells later, but they were mainly in neurons. Furthermore, mitochondrial dysfunction played an important role in activating NLRP3 inflammasomes in microglia after OGD/R, and mitochondrial protector could inhibit the activation of NLRP3 inflammasomes in cerebral I/R rats. Conclusion Our findings may provide novel insights into the cell type-dependent activation of NLRP3 inflammasomes at different stages of cerebral I/R injury and the role of mitochondrial dysfunction in activating the NLRP3 inflammasome pathway. Electronic supplementary material The online version of this article (10.1186/s12974-018-1282-6) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                Mei Jiang:
                ORCID: https://orcid.org/0000-0003-2915-7274
                Xinghui Liu:
                ORCID: https://orcid.org/0000-0001-9472-2984
                Denghai Zhang:
                ORCID: https://orcid.org/0000-0003-2797-6081
                Limin Xu:
                ORCID: https://orcid.org/0000-0002-3466-8290
                Journal
                Journal ID (nlm-ta): Biomed Res Int
                Journal ID (iso-abbrev): Biomed Res Int
                Journal ID (publisher-id): BMRI
                Title: BioMed Research International
                Publisher: Hindawi
                ISSN (Print): 2314-6133
                ISSN (Electronic): 2314-6141
                Publication date Collection: 2023
                Publication date (Electronic): 11 April 2023
                Volume: 2023
                Electronic Location Identifier: 1076522
                Affiliations
                1Sino-French Cooperative Central Lab, Gongli Hospital of Shanghai Pudong New Area, No. 207, Juye Rd., Pudong New District, Shanghai 200135, China
                2Ningxia Medical University, Ningxia 750000, China
                3Department of Clinical Laboratory, Gongli Hospital of Shanghai Pudong New Area, 207 Juye Road, Pudong New Area, Shanghai 200135, China
                4Department of Neurology, Gongli Hospital of Shanghai Pudong New Area, Shanghai 200135, China
                Author notes

                Academic Editor: Mauro S. Oliveira

                Author information
                https://orcid.org/0000-0003-2915-7274
                https://orcid.org/0000-0001-9472-2984
                https://orcid.org/0000-0003-2797-6081
                https://orcid.org/0000-0002-3466-8290
                Article
                DOI: 10.1155/2023/1076522
                PMC ID: 10113063
                SO-VID: b37c1484-5d51-48d2-82b1-d57fa6b7dbfb
                Copyright statement: Copyright © 2023 Fanfan Cao et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 28 August 2022
                Date revision received : 8 December 2022
                Date accepted : 20 January 2023
                Funding
                Funded by: Disciplines Group Construction Project of Pudong Health Bureau of Shanghai
                Award ID: PWZxq2022-08
                Funded by: Discipline Leader Project of Pudong Health Bureau of Shanghai
                Award ID: PWRd2020-04
                Funded by: Pudong New Area Science and Technology Development Foundation Project of Pudong New Area Science and Technology Commission
                Award ID: PKJ2022-Y25
                Categories
                Subject: Research Article

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