Phenothiazine Inhibits Neuroinflammation and Inflammasome Activation Independent of Hypothermia After Ischemic Stroke
A depressive or hibernation-like effect of chlorpromazine and promethazine (C + P) on brain activity was reported to induce neuroprotection, with or without induced-hypothermia. However, the underlying mechanisms remain unclear. The current study evaluated the pharmacological function of C + P on th...
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| Veröffentlicht in: | Molecular neurobiology 2021-12, Vol.58 (12), p.6136-6152 |
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| description | A depressive or hibernation-like effect of chlorpromazine and promethazine (C + P) on brain activity was reported to induce neuroprotection, with or without induced-hypothermia. However, the underlying mechanisms remain unclear. The current study evaluated the pharmacological function of C + P on the inhibition of neuroinflammatory response and inflammasome activation after ischemia/reperfusion. A total of 72 adult male Sprague–Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 6 or 24 h reperfusion. At the onset of reperfusion, rats received C + P (8 mg/kg) with temperature control. Brain cell death was detected by measuring CD68 and myeloperoxidase (MPO) levels. Inflammasome activation was measured by mRNA levels of NLRP3, IL-1β, and TXNIP, and protein quantities of NLRP3, IL-1β, TXNIP, cleaved-Caspase-1, and IL-18. Activation of JAK2/STAT3 pathway was detected by the phosphorylation of STAT3 (p-STAT3) and JAK2 (p-JAK2), and the co-localization of p-STAT3 and NLRP3. Activation of the p38 pathway was assessed with the protein levels of p-p38/p38. The mRNA and protein levels of HIF-1α, FoxO1, and p-FoxO1, and the co-localization of p-STAT3 with HIF-1α or FoxO1 were quantitated. As expected, C + P significantly reduced cell death and attenuated the neuroinflammatory response as determined by reduced CD68 and MPO. C + P decreased ischemia-induced inflammasome activation, shown by reduced mRNA and protein expressions of NLRP3, IL-1β, TXNIP, cleaved-Caspase-1, and IL-18. Phosphorylation of JAK2/STAT3 and p38 pathways and the co-localization of p-STAT3 with NLRP3 were also inhibited by C + P. Furthermore, mRNA levels of HIF-1α and FoxO1 were decreased in the C + P group. While C + P inhibited HIF-1α protein expression, it increased FoxO1 phosphorylation, which promoted the exclusion of FoxO1 from the nucleus and inhibited FoxO1 activity. At the same time, C + P reduced the co-localization of p-STAT3 with HIF-1α or FoxO1. In conclusion, C + P treatment conferred neuroprotection in stroke by suppressing neuroinflammation and NLRP3 inflammasome activation. The present study suggests that JAK2/STAT3/p38/HIF-1α/FoxO1 are vital regulators and potential targets for efficacious therapy following ischemic stroke. |
| doi_str_mv | 10.1007/s12035-021-02542-3 |
| format | Article |
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However, the underlying mechanisms remain unclear. The current study evaluated the pharmacological function of C + P on the inhibition of neuroinflammatory response and inflammasome activation after ischemia/reperfusion. A total of 72 adult male Sprague–Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 6 or 24 h reperfusion. At the onset of reperfusion, rats received C + P (8 mg/kg) with temperature control. Brain cell death was detected by measuring CD68 and myeloperoxidase (MPO) levels. Inflammasome activation was measured by mRNA levels of NLRP3, IL-1β, and TXNIP, and protein quantities of NLRP3, IL-1β, TXNIP, cleaved-Caspase-1, and IL-18. Activation of JAK2/STAT3 pathway was detected by the phosphorylation of STAT3 (p-STAT3) and JAK2 (p-JAK2), and the co-localization of p-STAT3 and NLRP3. Activation of the p38 pathway was assessed with the protein levels of p-p38/p38. The mRNA and protein levels of HIF-1α, FoxO1, and p-FoxO1, and the co-localization of p-STAT3 with HIF-1α or FoxO1 were quantitated. As expected, C + P significantly reduced cell death and attenuated the neuroinflammatory response as determined by reduced CD68 and MPO. C + P decreased ischemia-induced inflammasome activation, shown by reduced mRNA and protein expressions of NLRP3, IL-1β, TXNIP, cleaved-Caspase-1, and IL-18. Phosphorylation of JAK2/STAT3 and p38 pathways and the co-localization of p-STAT3 with NLRP3 were also inhibited by C + P. Furthermore, mRNA levels of HIF-1α and FoxO1 were decreased in the C + P group. While C + P inhibited HIF-1α protein expression, it increased FoxO1 phosphorylation, which promoted the exclusion of FoxO1 from the nucleus and inhibited FoxO1 activity. At the same time, C + P reduced the co-localization of p-STAT3 with HIF-1α or FoxO1. In conclusion, C + P treatment conferred neuroprotection in stroke by suppressing neuroinflammation and NLRP3 inflammasome activation. The present study suggests that JAK2/STAT3/p38/HIF-1α/FoxO1 are vital regulators and potential targets for efficacious therapy following ischemic stroke.</description><identifier>ISSN: 0893-7648</identifier><identifier>EISSN: 1559-1182</identifier><identifier>DOI: 10.1007/s12035-021-02542-3</identifier><identifier>PMID: 34455546</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Animals ; Apoptosis ; Biomedical and Life Sciences ; Biomedicine ; Caspase-1 ; Cell Biology ; Cell death ; Cell Death - drug effects ; Cerebral blood flow ; Chlorpromazine ; Cytokines - metabolism ; Disease Models, Animal ; FOXO1 protein ; Hibernation ; Hypothermia ; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism ; Hypoxia-inducible factor 1a ; IL-1β ; Inflammasomes ; Inflammasomes - drug effects ; Inflammation ; Interleukin 18 ; Ischemia ; Ischemic Stroke - drug therapy ; Ischemic Stroke - metabolism ; Janus kinase 2 ; Life Sciences & Biomedicine ; Localization ; Male ; mRNA ; Neurobiology ; Neuroinflammatory Diseases - drug therapy ; Neuroinflammatory Diseases - metabolism ; Neurology ; Neuroprotection ; Neurosciences ; Neurosciences & Neurology ; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism ; Peroxidase ; Phenothiazine ; Phenothiazines - pharmacology ; Phenothiazines - therapeutic use ; Phosphorylation ; Phosphorylation - drug effects ; Promethazine ; Proteins ; Rats ; Rats, Sprague-Dawley ; Reperfusion ; Science & Technology ; Signal Transduction - drug effects ; Stat3 protein ; Stroke</subject><ispartof>Molecular neurobiology, 2021-12, Vol.58 (12), p.6136-6152</ispartof><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021</rights><rights>2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.</rights><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>17</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000690811700001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c419t-15b54908ca9e8e4f7a8469f7c00309ca29b80161c41624730c57c19dd841812a3</citedby><cites>FETCH-LOGICAL-c419t-15b54908ca9e8e4f7a8469f7c00309ca29b80161c41624730c57c19dd841812a3</cites><orcidid>0000-0001-5358-1660 ; 0000-0001-8918-8748 ; 0000-0003-0339-671X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s12035-021-02542-3$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s12035-021-02542-3$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>315,781,785,27929,27930,39263,41493,42562,51324</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34455546$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Guo, Sichao</creatorcontrib><creatorcontrib>Geng, Xiaokun</creatorcontrib><creatorcontrib>Lee, Hangil</creatorcontrib><creatorcontrib>Ding, Yuchuan</creatorcontrib><title>Phenothiazine Inhibits Neuroinflammation and Inflammasome Activation Independent of Hypothermia After Ischemic Stroke</title><title>Molecular neurobiology</title><addtitle>Mol Neurobiol</addtitle><addtitle>MOL NEUROBIOL</addtitle><addtitle>Mol Neurobiol</addtitle><description>A depressive or hibernation-like effect of chlorpromazine and promethazine (C + P) on brain activity was reported to induce neuroprotection, with or without induced-hypothermia. However, the underlying mechanisms remain unclear. The current study evaluated the pharmacological function of C + P on the inhibition of neuroinflammatory response and inflammasome activation after ischemia/reperfusion. A total of 72 adult male Sprague–Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 6 or 24 h reperfusion. At the onset of reperfusion, rats received C + P (8 mg/kg) with temperature control. Brain cell death was detected by measuring CD68 and myeloperoxidase (MPO) levels. Inflammasome activation was measured by mRNA levels of NLRP3, IL-1β, and TXNIP, and protein quantities of NLRP3, IL-1β, TXNIP, cleaved-Caspase-1, and IL-18. Activation of JAK2/STAT3 pathway was detected by the phosphorylation of STAT3 (p-STAT3) and JAK2 (p-JAK2), and the co-localization of p-STAT3 and NLRP3. Activation of the p38 pathway was assessed with the protein levels of p-p38/p38. The mRNA and protein levels of HIF-1α, FoxO1, and p-FoxO1, and the co-localization of p-STAT3 with HIF-1α or FoxO1 were quantitated. As expected, C + P significantly reduced cell death and attenuated the neuroinflammatory response as determined by reduced CD68 and MPO. C + P decreased ischemia-induced inflammasome activation, shown by reduced mRNA and protein expressions of NLRP3, IL-1β, TXNIP, cleaved-Caspase-1, and IL-18. Phosphorylation of JAK2/STAT3 and p38 pathways and the co-localization of p-STAT3 with NLRP3 were also inhibited by C + P. Furthermore, mRNA levels of HIF-1α and FoxO1 were decreased in the C + P group. While C + P inhibited HIF-1α protein expression, it increased FoxO1 phosphorylation, which promoted the exclusion of FoxO1 from the nucleus and inhibited FoxO1 activity. At the same time, C + P reduced the co-localization of p-STAT3 with HIF-1α or FoxO1. In conclusion, C + P treatment conferred neuroprotection in stroke by suppressing neuroinflammation and NLRP3 inflammasome activation. The present study suggests that JAK2/STAT3/p38/HIF-1α/FoxO1 are vital regulators and potential targets for efficacious therapy following ischemic stroke.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Caspase-1</subject><subject>Cell Biology</subject><subject>Cell death</subject><subject>Cell Death - drug effects</subject><subject>Cerebral blood flow</subject><subject>Chlorpromazine</subject><subject>Cytokines - metabolism</subject><subject>Disease Models, Animal</subject><subject>FOXO1 protein</subject><subject>Hibernation</subject><subject>Hypothermia</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</subject><subject>Hypoxia-inducible factor 1a</subject><subject>IL-1β</subject><subject>Inflammasomes</subject><subject>Inflammasomes - drug effects</subject><subject>Inflammation</subject><subject>Interleukin 18</subject><subject>Ischemia</subject><subject>Ischemic Stroke - drug therapy</subject><subject>Ischemic Stroke - metabolism</subject><subject>Janus kinase 2</subject><subject>Life Sciences & Biomedicine</subject><subject>Localization</subject><subject>Male</subject><subject>mRNA</subject><subject>Neurobiology</subject><subject>Neuroinflammatory Diseases - drug therapy</subject><subject>Neuroinflammatory Diseases - metabolism</subject><subject>Neurology</subject><subject>Neuroprotection</subject><subject>Neurosciences</subject><subject>Neurosciences & Neurology</subject><subject>NLR Family, Pyrin Domain-Containing 3 Protein - metabolism</subject><subject>Peroxidase</subject><subject>Phenothiazine</subject><subject>Phenothiazines - pharmacology</subject><subject>Phenothiazines - therapeutic use</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Promethazine</subject><subject>Proteins</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Reperfusion</subject><subject>Science & Technology</subject><subject>Signal Transduction - 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drug effects</topic><topic>Cerebral blood flow</topic><topic>Chlorpromazine</topic><topic>Cytokines - metabolism</topic><topic>Disease Models, Animal</topic><topic>FOXO1 protein</topic><topic>Hibernation</topic><topic>Hypothermia</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</topic><topic>Hypoxia-inducible factor 1a</topic><topic>IL-1β</topic><topic>Inflammasomes</topic><topic>Inflammasomes - drug effects</topic><topic>Inflammation</topic><topic>Interleukin 18</topic><topic>Ischemia</topic><topic>Ischemic Stroke - drug therapy</topic><topic>Ischemic Stroke - metabolism</topic><topic>Janus kinase 2</topic><topic>Life Sciences & Biomedicine</topic><topic>Localization</topic><topic>Male</topic><topic>mRNA</topic><topic>Neurobiology</topic><topic>Neuroinflammatory Diseases - drug therapy</topic><topic>Neuroinflammatory Diseases - metabolism</topic><topic>Neurology</topic><topic>Neuroprotection</topic><topic>Neurosciences</topic><topic>Neurosciences & Neurology</topic><topic>NLR Family, Pyrin Domain-Containing 3 Protein - 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Academic</collection><jtitle>Molecular neurobiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Guo, Sichao</au><au>Geng, Xiaokun</au><au>Lee, Hangil</au><au>Ding, Yuchuan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phenothiazine Inhibits Neuroinflammation and Inflammasome Activation Independent of Hypothermia After Ischemic Stroke</atitle><jtitle>Molecular neurobiology</jtitle><stitle>Mol Neurobiol</stitle><stitle>MOL NEUROBIOL</stitle><addtitle>Mol Neurobiol</addtitle><date>2021-12-01</date><risdate>2021</risdate><volume>58</volume><issue>12</issue><spage>6136</spage><epage>6152</epage><pages>6136-6152</pages><issn>0893-7648</issn><eissn>1559-1182</eissn><abstract>A depressive or hibernation-like effect of chlorpromazine and promethazine (C + P) on brain activity was reported to induce neuroprotection, with or without induced-hypothermia. However, the underlying mechanisms remain unclear. The current study evaluated the pharmacological function of C + P on the inhibition of neuroinflammatory response and inflammasome activation after ischemia/reperfusion. A total of 72 adult male Sprague–Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 6 or 24 h reperfusion. At the onset of reperfusion, rats received C + P (8 mg/kg) with temperature control. Brain cell death was detected by measuring CD68 and myeloperoxidase (MPO) levels. Inflammasome activation was measured by mRNA levels of NLRP3, IL-1β, and TXNIP, and protein quantities of NLRP3, IL-1β, TXNIP, cleaved-Caspase-1, and IL-18. Activation of JAK2/STAT3 pathway was detected by the phosphorylation of STAT3 (p-STAT3) and JAK2 (p-JAK2), and the co-localization of p-STAT3 and NLRP3. Activation of the p38 pathway was assessed with the protein levels of p-p38/p38. The mRNA and protein levels of HIF-1α, FoxO1, and p-FoxO1, and the co-localization of p-STAT3 with HIF-1α or FoxO1 were quantitated. As expected, C + P significantly reduced cell death and attenuated the neuroinflammatory response as determined by reduced CD68 and MPO. C + P decreased ischemia-induced inflammasome activation, shown by reduced mRNA and protein expressions of NLRP3, IL-1β, TXNIP, cleaved-Caspase-1, and IL-18. Phosphorylation of JAK2/STAT3 and p38 pathways and the co-localization of p-STAT3 with NLRP3 were also inhibited by C + P. Furthermore, mRNA levels of HIF-1α and FoxO1 were decreased in the C + P group. While C + P inhibited HIF-1α protein expression, it increased FoxO1 phosphorylation, which promoted the exclusion of FoxO1 from the nucleus and inhibited FoxO1 activity. At the same time, C + P reduced the co-localization of p-STAT3 with HIF-1α or FoxO1. In conclusion, C + P treatment conferred neuroprotection in stroke by suppressing neuroinflammation and NLRP3 inflammasome activation. The present study suggests that JAK2/STAT3/p38/HIF-1α/FoxO1 are vital regulators and potential targets for efficacious therapy following ischemic stroke.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>34455546</pmid><doi>10.1007/s12035-021-02542-3</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0001-5358-1660</orcidid><orcidid>https://orcid.org/0000-0001-8918-8748</orcidid><orcidid>https://orcid.org/0000-0003-0339-671X</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_proquest_miscellaneous_2566263519 |
| source | MEDLINE; Springer journals; Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /> |
| subjects | Animals Apoptosis Biomedical and Life Sciences Biomedicine Caspase-1 Cell Biology Cell death Cell Death - drug effects Cerebral blood flow Chlorpromazine Cytokines - metabolism Disease Models, Animal FOXO1 protein Hibernation Hypothermia Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Hypoxia-inducible factor 1a IL-1β Inflammasomes Inflammasomes - drug effects Inflammation Interleukin 18 Ischemia Ischemic Stroke - drug therapy Ischemic Stroke - metabolism Janus kinase 2 Life Sciences & Biomedicine Localization Male mRNA Neurobiology Neuroinflammatory Diseases - drug therapy Neuroinflammatory Diseases - metabolism Neurology Neuroprotection Neurosciences Neurosciences & Neurology NLR Family, Pyrin Domain-Containing 3 Protein - metabolism Peroxidase Phenothiazine Phenothiazines - pharmacology Phenothiazines - therapeutic use Phosphorylation Phosphorylation - drug effects Promethazine Proteins Rats Rats, Sprague-Dawley Reperfusion Science & Technology Signal Transduction - drug effects Stat3 protein Stroke |
| title | Phenothiazine Inhibits Neuroinflammation and Inflammasome Activation Independent of Hypothermia After Ischemic Stroke |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-13T17%3A18%3A26IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Phenothiazine%20Inhibits%20Neuroinflammation%20and%20Inflammasome%20Activation%20Independent%20of%20Hypothermia%20After%20Ischemic%20Stroke&rft.jtitle=Molecular%20neurobiology&rft.au=Guo,%20Sichao&rft.date=2021-12-01&rft.volume=58&rft.issue=12&rft.spage=6136&rft.epage=6152&rft.pages=6136-6152&rft.issn=0893-7648&rft.eissn=1559-1182&rft_id=info:doi/10.1007/s12035-021-02542-3&rft_dat=%3Cproquest_pubme%3E2605425269%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2605425269&rft_id=info:pmid/34455546&rfr_iscdi=true |