Cilostazol Alleviates NLRP3 Inflammasome–Induced Allodynia/Hyperalgesia in Murine Cerebral Cortex Following Transient Ischemia: Focus on TRPA1/Glutamate and Akt/Dopamine/BDNF/Nrf2 Trajectories
Global cerebral ischemia/reperfusion (I/R) provokes inflammation that augments neuropathic pain. Cilostazol (CLZ) has pleiotropic effects including neuroprotection in several ravaging central disorders; nonetheless, its potential role in transient central ischemic-induced allodynia and hyperalgesia...
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| creator | Zaki, Omnia S. Nassar, Noha N. Abdallah, Dalaal M. Safar, Marwa M. Mohammed, Reham A. |
| description | Global cerebral ischemia/reperfusion (I/R) provokes inflammation that augments neuropathic pain. Cilostazol (CLZ) has pleiotropic effects including neuroprotection in several ravaging central disorders; nonetheless, its potential role in transient central ischemic-induced allodynia and hyperalgesia has not been asserted before. Rats were allocated into 4 groups; sham, sham + CLZ, and 45 min-bilateral carotid occlusion followed by a 48 h-reperfusion period either with or without CLZ (50 mg/kg; p.o) post-treatment. CLZ prolonged latency of hindlimb withdrawal following von Frey filaments, 4 °C cold, and noxious mechanical stimulations. Histopathological alterations and the immunoexpression of glial fibrillary acidic protein induced by I/R were reduced by CLZ in the anterior cingulate cortex (ACC) area, while, CLZ enhanced intact neuronal count. Meanwhile, CLZ modulated cerebral cortical glutamate, dopamine neurotransmission, and transient receptor potential ankyrin 1 (TRPA1). CLZ anti-inflammatory potential was mediated by the downregulated p65 NF-κB and sirtuin-1 enhancement to reduce nucleotide-binding domain-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), active caspase-1, and interleukin-1β, indicative of inflammasome deactivation. It also revealed an antioxidant capacity via boosting nuclear factor E2-related factor (Nrf2) enhancing glutathione through forkhead box protein O3a (FOXO3a) reduction. Additionally, CLZ triggered neuronal survival by promoting the p-content of Akt, TrkB, and CREB as well as BDNF content. A novel approach of CLZ in hindering global cerebral I/R–mediated neuropathy is firstly documented herein to forward its adjunct action via deactivating the NLRP3 inflammasome, besides enhancing Nrf2 axis, neuronal survival, and dopamine neurotransmission as well as inhibiting TRPA1 and excitotoxicity.
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| doi_str_mv | 10.1007/s12035-022-03024-w |
| format | Article |
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Graphical abstract</description><identifier>ISSN: 0893-7648</identifier><identifier>EISSN: 1559-1182</identifier><identifier>DOI: 10.1007/s12035-022-03024-w</identifier><identifier>PMID: 36127628</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>AKT protein ; Animals ; Ankyrins ; Apoptosis ; Biomedical and Life Sciences ; Biomedicine ; Brain Ischemia - metabolism ; Brain-derived neurotrophic factor ; Brain-Derived Neurotrophic Factor - metabolism ; Carrier Proteins - metabolism ; Caspase-1 ; Cell Biology ; Cerebral blood flow ; Cerebral cortex ; Cerebral Cortex - pathology ; Cilostazol ; Cortex (cingulate) ; Cyclic AMP response element-binding protein ; Deactivation ; Dopamine ; Excitotoxicity ; Filaments ; Forkhead protein ; FOXO3 protein ; Glial fibrillary acidic protein ; Glutamic Acid ; Glutathione ; Hyperalgesia ; Hyperalgesia - pathology ; Inflammasomes - metabolism ; Inflammation ; Ischemia ; Latency ; Mice ; Neurobiology ; Neurology ; Neuropathy ; Neuroprotection ; Neurosciences ; Neurotransmission ; NF-E2-Related Factor 2 - metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism ; Pain perception ; Proteins ; Proto-Oncogene Proteins c-akt - metabolism ; Rats ; Rats, Sprague-Dawley ; Reperfusion</subject><ispartof>Molecular neurobiology, 2022-12, Vol.59 (12), p.7194-7211</ispartof><rights>The Author(s) 2022</rights><rights>2022. The Author(s).</rights><rights>The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-4304f134bfae2d61c2f9e551328bcadde5464d66ad37de5bc2d51f4c33097d063</citedby><cites>FETCH-LOGICAL-c474t-4304f134bfae2d61c2f9e551328bcadde5464d66ad37de5bc2d51f4c33097d063</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s12035-022-03024-w$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s12035-022-03024-w$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36127628$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zaki, Omnia S.</creatorcontrib><creatorcontrib>Nassar, Noha N.</creatorcontrib><creatorcontrib>Abdallah, Dalaal M.</creatorcontrib><creatorcontrib>Safar, Marwa M.</creatorcontrib><creatorcontrib>Mohammed, Reham A.</creatorcontrib><title>Cilostazol Alleviates NLRP3 Inflammasome–Induced Allodynia/Hyperalgesia in Murine Cerebral Cortex Following Transient Ischemia: Focus on TRPA1/Glutamate and Akt/Dopamine/BDNF/Nrf2 Trajectories</title><title>Molecular neurobiology</title><addtitle>Mol Neurobiol</addtitle><addtitle>Mol Neurobiol</addtitle><description>Global cerebral ischemia/reperfusion (I/R) provokes inflammation that augments neuropathic pain. Cilostazol (CLZ) has pleiotropic effects including neuroprotection in several ravaging central disorders; nonetheless, its potential role in transient central ischemic-induced allodynia and hyperalgesia has not been asserted before. Rats were allocated into 4 groups; sham, sham + CLZ, and 45 min-bilateral carotid occlusion followed by a 48 h-reperfusion period either with or without CLZ (50 mg/kg; p.o) post-treatment. CLZ prolonged latency of hindlimb withdrawal following von Frey filaments, 4 °C cold, and noxious mechanical stimulations. Histopathological alterations and the immunoexpression of glial fibrillary acidic protein induced by I/R were reduced by CLZ in the anterior cingulate cortex (ACC) area, while, CLZ enhanced intact neuronal count. Meanwhile, CLZ modulated cerebral cortical glutamate, dopamine neurotransmission, and transient receptor potential ankyrin 1 (TRPA1). CLZ anti-inflammatory potential was mediated by the downregulated p65 NF-κB and sirtuin-1 enhancement to reduce nucleotide-binding domain-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), active caspase-1, and interleukin-1β, indicative of inflammasome deactivation. It also revealed an antioxidant capacity via boosting nuclear factor E2-related factor (Nrf2) enhancing glutathione through forkhead box protein O3a (FOXO3a) reduction. Additionally, CLZ triggered neuronal survival by promoting the p-content of Akt, TrkB, and CREB as well as BDNF content. A novel approach of CLZ in hindering global cerebral I/R–mediated neuropathy is firstly documented herein to forward its adjunct action via deactivating the NLRP3 inflammasome, besides enhancing Nrf2 axis, neuronal survival, and dopamine neurotransmission as well as inhibiting TRPA1 and excitotoxicity.
Graphical abstract</description><subject>AKT protein</subject><subject>Animals</subject><subject>Ankyrins</subject><subject>Apoptosis</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Brain Ischemia - metabolism</subject><subject>Brain-derived neurotrophic factor</subject><subject>Brain-Derived Neurotrophic Factor - metabolism</subject><subject>Carrier Proteins - metabolism</subject><subject>Caspase-1</subject><subject>Cell Biology</subject><subject>Cerebral blood flow</subject><subject>Cerebral cortex</subject><subject>Cerebral Cortex - pathology</subject><subject>Cilostazol</subject><subject>Cortex (cingulate)</subject><subject>Cyclic AMP response element-binding protein</subject><subject>Deactivation</subject><subject>Dopamine</subject><subject>Excitotoxicity</subject><subject>Filaments</subject><subject>Forkhead protein</subject><subject>FOXO3 protein</subject><subject>Glial fibrillary acidic protein</subject><subject>Glutamic Acid</subject><subject>Glutathione</subject><subject>Hyperalgesia</subject><subject>Hyperalgesia - pathology</subject><subject>Inflammasomes - metabolism</subject><subject>Inflammation</subject><subject>Ischemia</subject><subject>Latency</subject><subject>Mice</subject><subject>Neurobiology</subject><subject>Neurology</subject><subject>Neuropathy</subject><subject>Neuroprotection</subject><subject>Neurosciences</subject><subject>Neurotransmission</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>NLR Family, Pyrin Domain-Containing 3 Protein - metabolism</subject><subject>Pain perception</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Reperfusion</subject><issn>0893-7648</issn><issn>1559-1182</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9UctuEzEUHSEQDYUfYIEssR7Gr3mxQAopaSOFUFVhbTn2ndRhxk7tmYaw4h_4Iz6FL8EhpcCGlXV9zj3nXJ0keU7wK4JxmQVCMctTTGmKGaY83T1IRiTP65SQij5MRriqWVoWvDpJnoSwwZFJcPk4OWEFoWVBq1HyfWJaF3r5xbVo3LZwa2QPAS3mV5cMzWzTyq6TwXXw4-u3mdWDAn3gOb23RmYX-y142a4hGImMRe8HbyygCXhYxX80cb6Hz2jq4sbO2DVaemmDAdujWVDX0Bn5OqJqCMhZtLy6HJPsvB162cUUSNro9anPztxWdlE3e3u2mGYL39CDzgZU77yB8DR51Mg2wLO79zT5OH23nFyk8w_ns8l4nipe8j7lDPOGML5qJFBdEEWbGvKcMFqtlNQacl5wXRRSszIOK0V1ThquGMN1qXHBTpM3R93tsOpAq3hFvFFsvemk3wsnjfgXseZarN2tqAtSlGUVBV7eCXh3M0DoxcYN3sbMgpa0LimpOY4semQp70Lw0Nw7ECwOvYtj7yK2KX71LnZx6cXf2e5XfhcdCexICBGya_B_vP8j-xNnW75P</recordid><startdate>20221201</startdate><enddate>20221201</enddate><creator>Zaki, Omnia S.</creator><creator>Nassar, Noha N.</creator><creator>Abdallah, Dalaal M.</creator><creator>Safar, Marwa M.</creator><creator>Mohammed, Reham A.</creator><general>Springer US</general><general>Springer Nature B.V</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QR</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88G</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M2P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>5PM</scope></search><sort><creationdate>20221201</creationdate><title>Cilostazol Alleviates NLRP3 Inflammasome–Induced Allodynia/Hyperalgesia in Murine Cerebral Cortex Following Transient Ischemia: Focus on TRPA1/Glutamate and Akt/Dopamine/BDNF/Nrf2 Trajectories</title><author>Zaki, Omnia S. ; Nassar, Noha N. ; Abdallah, Dalaal M. ; Safar, Marwa M. ; Mohammed, Reham A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-4304f134bfae2d61c2f9e551328bcadde5464d66ad37de5bc2d51f4c33097d063</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>AKT protein</topic><topic>Animals</topic><topic>Ankyrins</topic><topic>Apoptosis</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Brain Ischemia - metabolism</topic><topic>Brain-derived neurotrophic factor</topic><topic>Brain-Derived Neurotrophic Factor - metabolism</topic><topic>Carrier Proteins - metabolism</topic><topic>Caspase-1</topic><topic>Cell Biology</topic><topic>Cerebral blood flow</topic><topic>Cerebral cortex</topic><topic>Cerebral Cortex - pathology</topic><topic>Cilostazol</topic><topic>Cortex (cingulate)</topic><topic>Cyclic AMP response element-binding protein</topic><topic>Deactivation</topic><topic>Dopamine</topic><topic>Excitotoxicity</topic><topic>Filaments</topic><topic>Forkhead protein</topic><topic>FOXO3 protein</topic><topic>Glial fibrillary acidic protein</topic><topic>Glutamic Acid</topic><topic>Glutathione</topic><topic>Hyperalgesia</topic><topic>Hyperalgesia - pathology</topic><topic>Inflammasomes - metabolism</topic><topic>Inflammation</topic><topic>Ischemia</topic><topic>Latency</topic><topic>Mice</topic><topic>Neurobiology</topic><topic>Neurology</topic><topic>Neuropathy</topic><topic>Neuroprotection</topic><topic>Neurosciences</topic><topic>Neurotransmission</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>NLR Family, Pyrin Domain-Containing 3 Protein - metabolism</topic><topic>Pain perception</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Reperfusion</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zaki, Omnia S.</creatorcontrib><creatorcontrib>Nassar, Noha N.</creatorcontrib><creatorcontrib>Abdallah, Dalaal M.</creatorcontrib><creatorcontrib>Safar, Marwa M.</creatorcontrib><creatorcontrib>Mohammed, Reham A.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest Psychology</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular neurobiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zaki, Omnia S.</au><au>Nassar, Noha N.</au><au>Abdallah, Dalaal M.</au><au>Safar, Marwa M.</au><au>Mohammed, Reham A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cilostazol Alleviates NLRP3 Inflammasome–Induced Allodynia/Hyperalgesia in Murine Cerebral Cortex Following Transient Ischemia: Focus on TRPA1/Glutamate and Akt/Dopamine/BDNF/Nrf2 Trajectories</atitle><jtitle>Molecular neurobiology</jtitle><stitle>Mol Neurobiol</stitle><addtitle>Mol Neurobiol</addtitle><date>2022-12-01</date><risdate>2022</risdate><volume>59</volume><issue>12</issue><spage>7194</spage><epage>7211</epage><pages>7194-7211</pages><issn>0893-7648</issn><eissn>1559-1182</eissn><abstract>Global cerebral ischemia/reperfusion (I/R) provokes inflammation that augments neuropathic pain. Cilostazol (CLZ) has pleiotropic effects including neuroprotection in several ravaging central disorders; nonetheless, its potential role in transient central ischemic-induced allodynia and hyperalgesia has not been asserted before. Rats were allocated into 4 groups; sham, sham + CLZ, and 45 min-bilateral carotid occlusion followed by a 48 h-reperfusion period either with or without CLZ (50 mg/kg; p.o) post-treatment. CLZ prolonged latency of hindlimb withdrawal following von Frey filaments, 4 °C cold, and noxious mechanical stimulations. Histopathological alterations and the immunoexpression of glial fibrillary acidic protein induced by I/R were reduced by CLZ in the anterior cingulate cortex (ACC) area, while, CLZ enhanced intact neuronal count. Meanwhile, CLZ modulated cerebral cortical glutamate, dopamine neurotransmission, and transient receptor potential ankyrin 1 (TRPA1). CLZ anti-inflammatory potential was mediated by the downregulated p65 NF-κB and sirtuin-1 enhancement to reduce nucleotide-binding domain-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), active caspase-1, and interleukin-1β, indicative of inflammasome deactivation. It also revealed an antioxidant capacity via boosting nuclear factor E2-related factor (Nrf2) enhancing glutathione through forkhead box protein O3a (FOXO3a) reduction. Additionally, CLZ triggered neuronal survival by promoting the p-content of Akt, TrkB, and CREB as well as BDNF content. A novel approach of CLZ in hindering global cerebral I/R–mediated neuropathy is firstly documented herein to forward its adjunct action via deactivating the NLRP3 inflammasome, besides enhancing Nrf2 axis, neuronal survival, and dopamine neurotransmission as well as inhibiting TRPA1 and excitotoxicity.
Graphical abstract</abstract><cop>New York</cop><pub>Springer US</pub><pmid>36127628</pmid><doi>10.1007/s12035-022-03024-w</doi><tpages>18</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Molecular neurobiology, 2022-12, Vol.59 (12), p.7194-7211 |
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| subjects | AKT protein Animals Ankyrins Apoptosis Biomedical and Life Sciences Biomedicine Brain Ischemia - metabolism Brain-derived neurotrophic factor Brain-Derived Neurotrophic Factor - metabolism Carrier Proteins - metabolism Caspase-1 Cell Biology Cerebral blood flow Cerebral cortex Cerebral Cortex - pathology Cilostazol Cortex (cingulate) Cyclic AMP response element-binding protein Deactivation Dopamine Excitotoxicity Filaments Forkhead protein FOXO3 protein Glial fibrillary acidic protein Glutamic Acid Glutathione Hyperalgesia Hyperalgesia - pathology Inflammasomes - metabolism Inflammation Ischemia Latency Mice Neurobiology Neurology Neuropathy Neuroprotection Neurosciences Neurotransmission NF-E2-Related Factor 2 - metabolism NLR Family, Pyrin Domain-Containing 3 Protein - metabolism Pain perception Proteins Proto-Oncogene Proteins c-akt - metabolism Rats Rats, Sprague-Dawley Reperfusion |
| title | Cilostazol Alleviates NLRP3 Inflammasome–Induced Allodynia/Hyperalgesia in Murine Cerebral Cortex Following Transient Ischemia: Focus on TRPA1/Glutamate and Akt/Dopamine/BDNF/Nrf2 Trajectories |
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