PET Imaging with [(18)F]FSPG Evidences the Role of System xc(-) on Brain Inflammation Following Cerebral Ischemia in Rats
In vivo Positron Emission Tomography (PET) imaging of the cystine-glutamate antiporter (system xc(-)) activity with [(18)F]FSPG is meant to be an attractive tool for the diagnosis and therapy evaluation of brain diseases. However, the role of system xc(-) in cerebral ischemia and its involvement in...
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| Veröffentlicht in: | Theranostics 2016-01, Vol.6 (11), p.1753-1767 |
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| creator | Domercq, Maria Szczupak, Boguslaw Gejo, Jon Gómez-Vallejo, Vanessa Padro, Daniel Gona, Kiran Babu Dollé, Frédéric Higuchi, Makoto Matute, Carlos Llop, Jordi Martín, Abraham |
| description | In vivo Positron Emission Tomography (PET) imaging of the cystine-glutamate antiporter (system xc(-)) activity with [(18)F]FSPG is meant to be an attractive tool for the diagnosis and therapy evaluation of brain diseases. However, the role of system xc(-) in cerebral ischemia and its involvement in inflammatory reaction has been scarcely explored. In this work, we report the longitudinal investigation of the neuroinflammatory process following transient middle cerebral artery occlusion (MCAO) in rats using PET with [(18)F]FSPG and the translocator protein (TSPO) ligand [(18)F]DPA-714. In the ischemic territory, [(18)F]FSPG showed a progressive binding increase that peaked at days 3 to 7 and was followed by a progressive decrease from days 14 to 28 after reperfusion. In contrast, [(18)F]DPA-714 evidenced maximum binding uptake values over day 7 after reperfusion. Ex vivo immnunohistochemistry confirmed the up-regulation of system xc(-) in microglial cells and marginally in astrocytes. Inhibition of system xc(-) with sulfasalazine and S-4-CPG resulted in increased arginase (anti-inflammatory M2 marker) expression at day 7 after ischemia, together with a decrease in TSPO and microglial M1 proinflammatory markers (CCL2, TNF and iNOS) expression. Taken together, these results suggest that system xc(-) plays a key role in the inflammatory reaction underlying experimental stroke. |
| doi_str_mv | 10.7150/thno.15616 |
| format | Article |
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However, the role of system xc(-) in cerebral ischemia and its involvement in inflammatory reaction has been scarcely explored. In this work, we report the longitudinal investigation of the neuroinflammatory process following transient middle cerebral artery occlusion (MCAO) in rats using PET with [(18)F]FSPG and the translocator protein (TSPO) ligand [(18)F]DPA-714. In the ischemic territory, [(18)F]FSPG showed a progressive binding increase that peaked at days 3 to 7 and was followed by a progressive decrease from days 14 to 28 after reperfusion. In contrast, [(18)F]DPA-714 evidenced maximum binding uptake values over day 7 after reperfusion. Ex vivo immnunohistochemistry confirmed the up-regulation of system xc(-) in microglial cells and marginally in astrocytes. Inhibition of system xc(-) with sulfasalazine and S-4-CPG resulted in increased arginase (anti-inflammatory M2 marker) expression at day 7 after ischemia, together with a decrease in TSPO and microglial M1 proinflammatory markers (CCL2, TNF and iNOS) expression. Taken together, these results suggest that system xc(-) plays a key role in the inflammatory reaction underlying experimental stroke.</description><identifier>ISSN: 1838-7640</identifier><identifier>EISSN: 1838-7640</identifier><identifier>DOI: 10.7150/thno.15616</identifier><identifier>PMID: 27570548</identifier><language>eng</language><publisher>Australia: Ivyspring International Publisher</publisher><subject>Amino Acid Transport System y+ - analysis ; Animals ; Astrocytes - enzymology ; Astrocytes - physiology ; Brain Ischemia - complications ; Brain Ischemia - diagnostic imaging ; Disease Models, Animal ; Encephalitis - diagnostic imaging ; Encephalitis - pathology ; Glutamates - administration & dosage ; Longitudinal Studies ; Microglia - enzymology ; Microglia - physiology ; Positron-Emission Tomography - methods ; Pyrazoles - administration & dosage ; Pyrimidines - administration & dosage ; Rats ; Research Paper</subject><ispartof>Theranostics, 2016-01, Vol.6 (11), p.1753-1767</ispartof><rights>Ivyspring International Publisher. 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See http://ivyspring.com/terms for terms and conditions. 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c378t-98252582ffb5954c52914c8ab926da0fbfad2fe3f0d3d5bcea5180365d952bd33</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997234/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997234/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,886,27929,27930,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27570548$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Domercq, Maria</creatorcontrib><creatorcontrib>Szczupak, Boguslaw</creatorcontrib><creatorcontrib>Gejo, Jon</creatorcontrib><creatorcontrib>Gómez-Vallejo, Vanessa</creatorcontrib><creatorcontrib>Padro, Daniel</creatorcontrib><creatorcontrib>Gona, Kiran Babu</creatorcontrib><creatorcontrib>Dollé, Frédéric</creatorcontrib><creatorcontrib>Higuchi, Makoto</creatorcontrib><creatorcontrib>Matute, Carlos</creatorcontrib><creatorcontrib>Llop, Jordi</creatorcontrib><creatorcontrib>Martín, Abraham</creatorcontrib><title>PET Imaging with [(18)F]FSPG Evidences the Role of System xc(-) on Brain Inflammation Following Cerebral Ischemia in Rats</title><title>Theranostics</title><addtitle>Theranostics</addtitle><description>In vivo Positron Emission Tomography (PET) imaging of the cystine-glutamate antiporter (system xc(-)) activity with [(18)F]FSPG is meant to be an attractive tool for the diagnosis and therapy evaluation of brain diseases. However, the role of system xc(-) in cerebral ischemia and its involvement in inflammatory reaction has been scarcely explored. In this work, we report the longitudinal investigation of the neuroinflammatory process following transient middle cerebral artery occlusion (MCAO) in rats using PET with [(18)F]FSPG and the translocator protein (TSPO) ligand [(18)F]DPA-714. In the ischemic territory, [(18)F]FSPG showed a progressive binding increase that peaked at days 3 to 7 and was followed by a progressive decrease from days 14 to 28 after reperfusion. In contrast, [(18)F]DPA-714 evidenced maximum binding uptake values over day 7 after reperfusion. Ex vivo immnunohistochemistry confirmed the up-regulation of system xc(-) in microglial cells and marginally in astrocytes. Inhibition of system xc(-) with sulfasalazine and S-4-CPG resulted in increased arginase (anti-inflammatory M2 marker) expression at day 7 after ischemia, together with a decrease in TSPO and microglial M1 proinflammatory markers (CCL2, TNF and iNOS) expression. Taken together, these results suggest that system xc(-) plays a key role in the inflammatory reaction underlying experimental stroke.</description><subject>Amino Acid Transport System y+ - analysis</subject><subject>Animals</subject><subject>Astrocytes - enzymology</subject><subject>Astrocytes - physiology</subject><subject>Brain Ischemia - complications</subject><subject>Brain Ischemia - diagnostic imaging</subject><subject>Disease Models, Animal</subject><subject>Encephalitis - diagnostic imaging</subject><subject>Encephalitis - pathology</subject><subject>Glutamates - administration & dosage</subject><subject>Longitudinal Studies</subject><subject>Microglia - enzymology</subject><subject>Microglia - physiology</subject><subject>Positron-Emission Tomography - methods</subject><subject>Pyrazoles - administration & dosage</subject><subject>Pyrimidines - administration & dosage</subject><subject>Rats</subject><subject>Research Paper</subject><issn>1838-7640</issn><issn>1838-7640</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkdtq3DAQhkVpaUKamz5A0eUm4FQHy5ZuCu2ymy4EGnK4KkXI8mitYkuppU2yb19vTiRzM8PMxz8z_Ah9puSkpoJ8zV2IJ1RUtHqH9qnksqirkrx_Ve-hw5T-kilKwhRVH9Eeq0VNRCn30fZ8cYVXg1n7sMZ3Pnf494zKo-Wf5eX5KV7c-haChYRzB_gi9oCjw5fblGHA93ZWHOEY8I_R-IBXwfVmGEz2U2sZ-z7e7TTnMEIzmh6vku1g8AZP7IXJ6RP64Eyf4PApH6Dr5eJq_rM4-3W6mn8_KyyvZS6UZIIJyZxrhBKlFdMLpZWmUaxqDXGNMy1zwB1peSsaC0ZQSXglWiVY03J-gL496t5smgFaCyFP5-ib0Q9m3OpovH47Cb7T63irS6VqxstJYPYkMMZ_G0hZDz5Z6HsTIG6SppIKXkmp6IQeP6J2jCmN4F7WUKJ3dumdXfrBrgn-8vqwF_TZHP4fK2WQpQ</recordid><startdate>20160101</startdate><enddate>20160101</enddate><creator>Domercq, Maria</creator><creator>Szczupak, Boguslaw</creator><creator>Gejo, Jon</creator><creator>Gómez-Vallejo, Vanessa</creator><creator>Padro, Daniel</creator><creator>Gona, Kiran Babu</creator><creator>Dollé, Frédéric</creator><creator>Higuchi, Makoto</creator><creator>Matute, Carlos</creator><creator>Llop, Jordi</creator><creator>Martín, Abraham</creator><general>Ivyspring International Publisher</general><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160101</creationdate><title>PET Imaging with [(18)F]FSPG Evidences the Role of System xc(-) on Brain Inflammation Following Cerebral Ischemia in Rats</title><author>Domercq, Maria ; Szczupak, Boguslaw ; Gejo, Jon ; Gómez-Vallejo, Vanessa ; Padro, Daniel ; Gona, Kiran Babu ; Dollé, Frédéric ; Higuchi, Makoto ; Matute, Carlos ; Llop, Jordi ; Martín, Abraham</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c378t-98252582ffb5954c52914c8ab926da0fbfad2fe3f0d3d5bcea5180365d952bd33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Amino Acid Transport System y+ - analysis</topic><topic>Animals</topic><topic>Astrocytes - enzymology</topic><topic>Astrocytes - physiology</topic><topic>Brain Ischemia - complications</topic><topic>Brain Ischemia - diagnostic imaging</topic><topic>Disease Models, Animal</topic><topic>Encephalitis - diagnostic imaging</topic><topic>Encephalitis - pathology</topic><topic>Glutamates - administration & dosage</topic><topic>Longitudinal Studies</topic><topic>Microglia - enzymology</topic><topic>Microglia - physiology</topic><topic>Positron-Emission Tomography - methods</topic><topic>Pyrazoles - administration & dosage</topic><topic>Pyrimidines - administration & dosage</topic><topic>Rats</topic><topic>Research Paper</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Domercq, Maria</creatorcontrib><creatorcontrib>Szczupak, Boguslaw</creatorcontrib><creatorcontrib>Gejo, Jon</creatorcontrib><creatorcontrib>Gómez-Vallejo, Vanessa</creatorcontrib><creatorcontrib>Padro, Daniel</creatorcontrib><creatorcontrib>Gona, Kiran Babu</creatorcontrib><creatorcontrib>Dollé, Frédéric</creatorcontrib><creatorcontrib>Higuchi, Makoto</creatorcontrib><creatorcontrib>Matute, Carlos</creatorcontrib><creatorcontrib>Llop, Jordi</creatorcontrib><creatorcontrib>Martín, Abraham</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Theranostics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Domercq, Maria</au><au>Szczupak, Boguslaw</au><au>Gejo, Jon</au><au>Gómez-Vallejo, Vanessa</au><au>Padro, Daniel</au><au>Gona, Kiran Babu</au><au>Dollé, Frédéric</au><au>Higuchi, Makoto</au><au>Matute, Carlos</au><au>Llop, Jordi</au><au>Martín, Abraham</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PET Imaging with [(18)F]FSPG Evidences the Role of System xc(-) on Brain Inflammation Following Cerebral Ischemia in Rats</atitle><jtitle>Theranostics</jtitle><addtitle>Theranostics</addtitle><date>2016-01-01</date><risdate>2016</risdate><volume>6</volume><issue>11</issue><spage>1753</spage><epage>1767</epage><pages>1753-1767</pages><issn>1838-7640</issn><eissn>1838-7640</eissn><abstract>In vivo Positron Emission Tomography (PET) imaging of the cystine-glutamate antiporter (system xc(-)) activity with [(18)F]FSPG is meant to be an attractive tool for the diagnosis and therapy evaluation of brain diseases. However, the role of system xc(-) in cerebral ischemia and its involvement in inflammatory reaction has been scarcely explored. In this work, we report the longitudinal investigation of the neuroinflammatory process following transient middle cerebral artery occlusion (MCAO) in rats using PET with [(18)F]FSPG and the translocator protein (TSPO) ligand [(18)F]DPA-714. In the ischemic territory, [(18)F]FSPG showed a progressive binding increase that peaked at days 3 to 7 and was followed by a progressive decrease from days 14 to 28 after reperfusion. In contrast, [(18)F]DPA-714 evidenced maximum binding uptake values over day 7 after reperfusion. Ex vivo immnunohistochemistry confirmed the up-regulation of system xc(-) in microglial cells and marginally in astrocytes. Inhibition of system xc(-) with sulfasalazine and S-4-CPG resulted in increased arginase (anti-inflammatory M2 marker) expression at day 7 after ischemia, together with a decrease in TSPO and microglial M1 proinflammatory markers (CCL2, TNF and iNOS) expression. Taken together, these results suggest that system xc(-) plays a key role in the inflammatory reaction underlying experimental stroke.</abstract><cop>Australia</cop><pub>Ivyspring International Publisher</pub><pmid>27570548</pmid><doi>10.7150/thno.15616</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amino Acid Transport System y+ - analysis Animals Astrocytes - enzymology Astrocytes - physiology Brain Ischemia - complications Brain Ischemia - diagnostic imaging Disease Models, Animal Encephalitis - diagnostic imaging Encephalitis - pathology Glutamates - administration & dosage Longitudinal Studies Microglia - enzymology Microglia - physiology Positron-Emission Tomography - methods Pyrazoles - administration & dosage Pyrimidines - administration & dosage Rats Research Paper |
| title | PET Imaging with [(18)F]FSPG Evidences the Role of System xc(-) on Brain Inflammation Following Cerebral Ischemia in Rats |
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