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AZD 1390, an ataxia telangiectasia mutated inhibitor, attenuates microglia‐mediated neuroinflammation and ischemic brain injury
Abstract Aims Excessive neuroinflammation mediated mainly by microglia plays a crucial role in ischemic stroke. AZD1390, an ataxia telangiectasia mutated (ATM) specific inhibitor, has been shown to promote radio‐sensitization and survival in central nervous system malignancies, while the role of AZD...
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| Published in: | CNS neuroscience & therapeutics 2024-04, Vol.30 (4) |
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| Language: | English |
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| container_issue | 4 |
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| container_title | CNS neuroscience & therapeutics |
| container_volume | 30 |
| creator | Lan, Zhen Qu, Long‐jie Liang, Ying Chen, Li‐qiu Xu, Shuai Ge, Jian‐wei Xue, Zhi‐wei Bao, Xin‐yu Xia, Sheng‐nan Yang, Hai‐yan Huang, Jing Xu, Yun Zhu, Xiao‐lei |
| description | Abstract
Aims
Excessive neuroinflammation mediated mainly by microglia plays a crucial role in ischemic stroke. AZD1390, an ataxia telangiectasia mutated (ATM) specific inhibitor, has been shown to promote radio‐sensitization and survival in central nervous system malignancies, while the role of AZD1390 in ischemic stroke remains unknown.
Methods
Real‐time PCR, western blot, immunofluorescence staining, flow cytometry and enzyme‐linked immunosorbent assays were used to assess the activation of microglia and the release of inflammatory cytokines. Behavioral tests were performed to measure neurological deficits. 2,3,5‐Triphenyltetrazolium chloride staining was conducted to assess the infarct volume. The activation of NF‐κB signaling pathway was explored through immunofluorescence staining, western blot, co‐immunoprecipitation and proximity ligation assay.
Results
The level of pro‐inflammation cytokines and activation of NF‐κB signaling pathway was suppressed by AZD1390 in vitro and in vivo. The behavior deficits and infarct size were partially restored with AZD1390 treatment in experimental stroke. AZD1390 restrict ubiquitylation and sumoylation of the essential regulatory subunit of NF‐κB (NEMO) in an ATM‐dependent and ATM‐independent way respectively, which reduced the activation of the NF‐κB pathway.
Conclusion
AZD1390 suppressed NF‐κB signaling pathway to alleviate ischemic brain injury in experimental stroke, and attenuated microglia activation and neuroinflammation, which indicated that AZD1390 might be an attractive agent for the treatment of ischemic stroke. |
| doi_str_mv | 10.1111/cns.14696 |
| format | article |
| fullrecord | <record><control><sourceid>crossref</sourceid><recordid>TN_cdi_crossref_primary_10_1111_cns_14696</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>10_1111_cns_14696</sourcerecordid><originalsourceid>FETCH-crossref_primary_10_1111_cns_146963</originalsourceid><addsrcrecordid>eNqVj8FKAzEQhoNUsFYPvkGugm0Tt7s2x6IWH8CTlzDdzrZTNlnJZKG96Rv4jD6JYxHvncvMP3x88Ct1Y83EykzryBM7q1x1pob2oSzHpZu5wf9dmAt1ybwzprqfu_lQfS7enrQtnLnTEDVk2BPojC3EDWGdgSWGPkPGtaa4pRXlLgmbM8ZevqwD1anbtATfH18B13REI_apo9i0EAJk6kQdRcD1FoXXqwQUxbfr0-FKnTfQMl7_7ZG6XT6_Pr6MRcucsPHviQKkg7fG_3b00tEfOxansD-SY1us</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>AZD 1390, an ataxia telangiectasia mutated inhibitor, attenuates microglia‐mediated neuroinflammation and ischemic brain injury</title><source>PubMed (Medline)</source><source>Wiley Online Library Open Access</source><source>Publicly Available Content Database</source><creator>Lan, Zhen ; Qu, Long‐jie ; Liang, Ying ; Chen, Li‐qiu ; Xu, Shuai ; Ge, Jian‐wei ; Xue, Zhi‐wei ; Bao, Xin‐yu ; Xia, Sheng‐nan ; Yang, Hai‐yan ; Huang, Jing ; Xu, Yun ; Zhu, Xiao‐lei</creator><creatorcontrib>Lan, Zhen ; Qu, Long‐jie ; Liang, Ying ; Chen, Li‐qiu ; Xu, Shuai ; Ge, Jian‐wei ; Xue, Zhi‐wei ; Bao, Xin‐yu ; Xia, Sheng‐nan ; Yang, Hai‐yan ; Huang, Jing ; Xu, Yun ; Zhu, Xiao‐lei</creatorcontrib><description>Abstract
Aims
Excessive neuroinflammation mediated mainly by microglia plays a crucial role in ischemic stroke. AZD1390, an ataxia telangiectasia mutated (ATM) specific inhibitor, has been shown to promote radio‐sensitization and survival in central nervous system malignancies, while the role of AZD1390 in ischemic stroke remains unknown.
Methods
Real‐time PCR, western blot, immunofluorescence staining, flow cytometry and enzyme‐linked immunosorbent assays were used to assess the activation of microglia and the release of inflammatory cytokines. Behavioral tests were performed to measure neurological deficits. 2,3,5‐Triphenyltetrazolium chloride staining was conducted to assess the infarct volume. The activation of NF‐κB signaling pathway was explored through immunofluorescence staining, western blot, co‐immunoprecipitation and proximity ligation assay.
Results
The level of pro‐inflammation cytokines and activation of NF‐κB signaling pathway was suppressed by AZD1390 in vitro and in vivo. The behavior deficits and infarct size were partially restored with AZD1390 treatment in experimental stroke. AZD1390 restrict ubiquitylation and sumoylation of the essential regulatory subunit of NF‐κB (NEMO) in an ATM‐dependent and ATM‐independent way respectively, which reduced the activation of the NF‐κB pathway.
Conclusion
AZD1390 suppressed NF‐κB signaling pathway to alleviate ischemic brain injury in experimental stroke, and attenuated microglia activation and neuroinflammation, which indicated that AZD1390 might be an attractive agent for the treatment of ischemic stroke.</description><identifier>ISSN: 1755-5930</identifier><identifier>EISSN: 1755-5949</identifier><identifier>DOI: 10.1111/cns.14696</identifier><language>eng</language><ispartof>CNS neuroscience & therapeutics, 2024-04, Vol.30 (4)</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-crossref_primary_10_1111_cns_146963</cites><orcidid>0000-0001-5288-0319 ; 0000-0003-3729-7277 ; 0000-0003-4696-9696</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids></links><search><creatorcontrib>Lan, Zhen</creatorcontrib><creatorcontrib>Qu, Long‐jie</creatorcontrib><creatorcontrib>Liang, Ying</creatorcontrib><creatorcontrib>Chen, Li‐qiu</creatorcontrib><creatorcontrib>Xu, Shuai</creatorcontrib><creatorcontrib>Ge, Jian‐wei</creatorcontrib><creatorcontrib>Xue, Zhi‐wei</creatorcontrib><creatorcontrib>Bao, Xin‐yu</creatorcontrib><creatorcontrib>Xia, Sheng‐nan</creatorcontrib><creatorcontrib>Yang, Hai‐yan</creatorcontrib><creatorcontrib>Huang, Jing</creatorcontrib><creatorcontrib>Xu, Yun</creatorcontrib><creatorcontrib>Zhu, Xiao‐lei</creatorcontrib><title>AZD 1390, an ataxia telangiectasia mutated inhibitor, attenuates microglia‐mediated neuroinflammation and ischemic brain injury</title><title>CNS neuroscience & therapeutics</title><description>Abstract
Aims
Excessive neuroinflammation mediated mainly by microglia plays a crucial role in ischemic stroke. AZD1390, an ataxia telangiectasia mutated (ATM) specific inhibitor, has been shown to promote radio‐sensitization and survival in central nervous system malignancies, while the role of AZD1390 in ischemic stroke remains unknown.
Methods
Real‐time PCR, western blot, immunofluorescence staining, flow cytometry and enzyme‐linked immunosorbent assays were used to assess the activation of microglia and the release of inflammatory cytokines. Behavioral tests were performed to measure neurological deficits. 2,3,5‐Triphenyltetrazolium chloride staining was conducted to assess the infarct volume. The activation of NF‐κB signaling pathway was explored through immunofluorescence staining, western blot, co‐immunoprecipitation and proximity ligation assay.
Results
The level of pro‐inflammation cytokines and activation of NF‐κB signaling pathway was suppressed by AZD1390 in vitro and in vivo. The behavior deficits and infarct size were partially restored with AZD1390 treatment in experimental stroke. AZD1390 restrict ubiquitylation and sumoylation of the essential regulatory subunit of NF‐κB (NEMO) in an ATM‐dependent and ATM‐independent way respectively, which reduced the activation of the NF‐κB pathway.
Conclusion
AZD1390 suppressed NF‐κB signaling pathway to alleviate ischemic brain injury in experimental stroke, and attenuated microglia activation and neuroinflammation, which indicated that AZD1390 might be an attractive agent for the treatment of ischemic stroke.</description><issn>1755-5930</issn><issn>1755-5949</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNqVj8FKAzEQhoNUsFYPvkGugm0Tt7s2x6IWH8CTlzDdzrZTNlnJZKG96Rv4jD6JYxHvncvMP3x88Ct1Y83EykzryBM7q1x1pob2oSzHpZu5wf9dmAt1ybwzprqfu_lQfS7enrQtnLnTEDVk2BPojC3EDWGdgSWGPkPGtaa4pRXlLgmbM8ZevqwD1anbtATfH18B13REI_apo9i0EAJk6kQdRcD1FoXXqwQUxbfr0-FKnTfQMl7_7ZG6XT6_Pr6MRcucsPHviQKkg7fG_3b00tEfOxansD-SY1us</recordid><startdate>202404</startdate><enddate>202404</enddate><creator>Lan, Zhen</creator><creator>Qu, Long‐jie</creator><creator>Liang, Ying</creator><creator>Chen, Li‐qiu</creator><creator>Xu, Shuai</creator><creator>Ge, Jian‐wei</creator><creator>Xue, Zhi‐wei</creator><creator>Bao, Xin‐yu</creator><creator>Xia, Sheng‐nan</creator><creator>Yang, Hai‐yan</creator><creator>Huang, Jing</creator><creator>Xu, Yun</creator><creator>Zhu, Xiao‐lei</creator><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0001-5288-0319</orcidid><orcidid>https://orcid.org/0000-0003-3729-7277</orcidid><orcidid>https://orcid.org/0000-0003-4696-9696</orcidid></search><sort><creationdate>202404</creationdate><title>AZD 1390, an ataxia telangiectasia mutated inhibitor, attenuates microglia‐mediated neuroinflammation and ischemic brain injury</title><author>Lan, Zhen ; Qu, Long‐jie ; Liang, Ying ; Chen, Li‐qiu ; Xu, Shuai ; Ge, Jian‐wei ; Xue, Zhi‐wei ; Bao, Xin‐yu ; Xia, Sheng‐nan ; Yang, Hai‐yan ; Huang, Jing ; Xu, Yun ; Zhu, Xiao‐lei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-crossref_primary_10_1111_cns_146963</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lan, Zhen</creatorcontrib><creatorcontrib>Qu, Long‐jie</creatorcontrib><creatorcontrib>Liang, Ying</creatorcontrib><creatorcontrib>Chen, Li‐qiu</creatorcontrib><creatorcontrib>Xu, Shuai</creatorcontrib><creatorcontrib>Ge, Jian‐wei</creatorcontrib><creatorcontrib>Xue, Zhi‐wei</creatorcontrib><creatorcontrib>Bao, Xin‐yu</creatorcontrib><creatorcontrib>Xia, Sheng‐nan</creatorcontrib><creatorcontrib>Yang, Hai‐yan</creatorcontrib><creatorcontrib>Huang, Jing</creatorcontrib><creatorcontrib>Xu, Yun</creatorcontrib><creatorcontrib>Zhu, Xiao‐lei</creatorcontrib><collection>CrossRef</collection><jtitle>CNS neuroscience & therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lan, Zhen</au><au>Qu, Long‐jie</au><au>Liang, Ying</au><au>Chen, Li‐qiu</au><au>Xu, Shuai</au><au>Ge, Jian‐wei</au><au>Xue, Zhi‐wei</au><au>Bao, Xin‐yu</au><au>Xia, Sheng‐nan</au><au>Yang, Hai‐yan</au><au>Huang, Jing</au><au>Xu, Yun</au><au>Zhu, Xiao‐lei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>AZD 1390, an ataxia telangiectasia mutated inhibitor, attenuates microglia‐mediated neuroinflammation and ischemic brain injury</atitle><jtitle>CNS neuroscience & therapeutics</jtitle><date>2024-04</date><risdate>2024</risdate><volume>30</volume><issue>4</issue><issn>1755-5930</issn><eissn>1755-5949</eissn><abstract>Abstract
Aims
Excessive neuroinflammation mediated mainly by microglia plays a crucial role in ischemic stroke. AZD1390, an ataxia telangiectasia mutated (ATM) specific inhibitor, has been shown to promote radio‐sensitization and survival in central nervous system malignancies, while the role of AZD1390 in ischemic stroke remains unknown.
Methods
Real‐time PCR, western blot, immunofluorescence staining, flow cytometry and enzyme‐linked immunosorbent assays were used to assess the activation of microglia and the release of inflammatory cytokines. Behavioral tests were performed to measure neurological deficits. 2,3,5‐Triphenyltetrazolium chloride staining was conducted to assess the infarct volume. The activation of NF‐κB signaling pathway was explored through immunofluorescence staining, western blot, co‐immunoprecipitation and proximity ligation assay.
Results
The level of pro‐inflammation cytokines and activation of NF‐κB signaling pathway was suppressed by AZD1390 in vitro and in vivo. The behavior deficits and infarct size were partially restored with AZD1390 treatment in experimental stroke. AZD1390 restrict ubiquitylation and sumoylation of the essential regulatory subunit of NF‐κB (NEMO) in an ATM‐dependent and ATM‐independent way respectively, which reduced the activation of the NF‐κB pathway.
Conclusion
AZD1390 suppressed NF‐κB signaling pathway to alleviate ischemic brain injury in experimental stroke, and attenuated microglia activation and neuroinflammation, which indicated that AZD1390 might be an attractive agent for the treatment of ischemic stroke.</abstract><doi>10.1111/cns.14696</doi><orcidid>https://orcid.org/0000-0001-5288-0319</orcidid><orcidid>https://orcid.org/0000-0003-3729-7277</orcidid><orcidid>https://orcid.org/0000-0003-4696-9696</orcidid></addata></record> |
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| source | PubMed (Medline); Wiley Online Library Open Access; Publicly Available Content Database |
| title | AZD 1390, an ataxia telangiectasia mutated inhibitor, attenuates microglia‐mediated neuroinflammation and ischemic brain injury |
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