Treatment with minocycline after disease onset alters astrocyte reactivity and increases microgliosis in SOD1 mutant mice
Several reports have demonstrated that attenuation of microglial activation by minocycline, an antimicrobial drug with anti-inflammatory properties, delays disease progression in a mouse model of ALS. However, the negative results obtained in recent clinical trials raised some questions regarding th...
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| Veröffentlicht in: | Experimental neurology 2011-03, Vol.228 (1), p.69-79 |
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| description | Several reports have demonstrated that attenuation of microglial activation by minocycline, an antimicrobial drug with anti-inflammatory properties, delays disease progression in a mouse model of ALS. However, the negative results obtained in recent clinical trials raised some questions regarding the role of inflammatory response and glial cells as a therapeutic target in ALS. To investigate this controversy we took advantage of a mouse model for live imaging of neuroinflammatory responses in ALS (GFAP-luc/ SOD1
G93A reporter mouse) and analyzed in real time the effects of minocycline treatment initiated at different stages of the disease. To our surprise, unlike neuroprotection that is conferred when minocycline is administered pre-symptomatically, treatment with minocycline initiated after the disease onset significantly altered glial responses and exaggerated neuroinflammation. Further analysis revealed that the late minocycline treatment was associated with significant induction of the end-stage GFAP-biophotonic signals, expression levels of connexin 43, a major protein of astrocytic gap junction and markers of microglial activation, such as Iba1 and CD68. The results of our study suggest that when administered at later stages of disease, once microglial cells are chronically reactive, minocycline may not have anti-inflammatory properties, and contrary to expectations, may alter astrocyte reactivity and increase microgliosis. Finally, our results further suggest the existence of close interactions/communication between activated microglia and astrocytes in late stage ALS.
► Previous reports showed that minocycline is neuroprotective in a mouse model of ALS. ► Recent clinical trials raised some questions regarding the efficacy of minocycline. ► Using live imaging of neuroinflammation we analyzed in real time the effects of minocycline. ► Treatment with minocycline initiated after disease onset exaggerated neuroinflammation. |
| doi_str_mv | 10.1016/j.expneurol.2010.12.010 |
| format | Article |
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G93A reporter mouse) and analyzed in real time the effects of minocycline treatment initiated at different stages of the disease. To our surprise, unlike neuroprotection that is conferred when minocycline is administered pre-symptomatically, treatment with minocycline initiated after the disease onset significantly altered glial responses and exaggerated neuroinflammation. Further analysis revealed that the late minocycline treatment was associated with significant induction of the end-stage GFAP-biophotonic signals, expression levels of connexin 43, a major protein of astrocytic gap junction and markers of microglial activation, such as Iba1 and CD68. The results of our study suggest that when administered at later stages of disease, once microglial cells are chronically reactive, minocycline may not have anti-inflammatory properties, and contrary to expectations, may alter astrocyte reactivity and increase microgliosis. Finally, our results further suggest the existence of close interactions/communication between activated microglia and astrocytes in late stage ALS.
► Previous reports showed that minocycline is neuroprotective in a mouse model of ALS. ► Recent clinical trials raised some questions regarding the efficacy of minocycline. ► Using live imaging of neuroinflammation we analyzed in real time the effects of minocycline. ► Treatment with minocycline initiated after disease onset exaggerated neuroinflammation.</description><identifier>ISSN: 0014-4886</identifier><identifier>EISSN: 1090-2430</identifier><identifier>DOI: 10.1016/j.expneurol.2010.12.010</identifier><identifier>PMID: 21168408</identifier><identifier>CODEN: EXNEAC</identifier><language>eng</language><publisher>Amsterdam: Elsevier Inc</publisher><subject>ALS ; Amyotrophic Lateral Sclerosis - drug therapy ; Amyotrophic Lateral Sclerosis - enzymology ; Amyotrophic Lateral Sclerosis - genetics ; Animals ; Astrocytes - drug effects ; Astrocytes - metabolism ; Biological and medical sciences ; Bioluminescence/biophotonic imaging ; CD68 ; Connexin-43 ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Female ; GFAP-reporter mouse ; Male ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Neurologic Mutants ; Mice, Transgenic ; Microglia - drug effects ; Microglia - metabolism ; Minocycline - pharmacology ; Minocycline - therapeutic use ; Neurology ; Random Allocation ; Superoxide Dismutase - genetics ; Superoxide Dismutase-1 ; Treatment Outcome</subject><ispartof>Experimental neurology, 2011-03, Vol.228 (1), p.69-79</ispartof><rights>2010</rights><rights>2015 INIST-CNRS</rights><rights>Crown Copyright © 2010. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c432t-f69dd33174f41801d7c8c9ee4f658c43d1438aaa3d44f9c10164c879c92ef2d43</citedby><cites>FETCH-LOGICAL-c432t-f69dd33174f41801d7c8c9ee4f658c43d1438aaa3d44f9c10164c879c92ef2d43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0014488610004322$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23947243$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21168408$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Keller, A. Florence</creatorcontrib><creatorcontrib>Gravel, Mathieu</creatorcontrib><creatorcontrib>Kriz, Jasna</creatorcontrib><title>Treatment with minocycline after disease onset alters astrocyte reactivity and increases microgliosis in SOD1 mutant mice</title><title>Experimental neurology</title><addtitle>Exp Neurol</addtitle><description>Several reports have demonstrated that attenuation of microglial activation by minocycline, an antimicrobial drug with anti-inflammatory properties, delays disease progression in a mouse model of ALS. However, the negative results obtained in recent clinical trials raised some questions regarding the role of inflammatory response and glial cells as a therapeutic target in ALS. To investigate this controversy we took advantage of a mouse model for live imaging of neuroinflammatory responses in ALS (GFAP-luc/ SOD1
G93A reporter mouse) and analyzed in real time the effects of minocycline treatment initiated at different stages of the disease. To our surprise, unlike neuroprotection that is conferred when minocycline is administered pre-symptomatically, treatment with minocycline initiated after the disease onset significantly altered glial responses and exaggerated neuroinflammation. Further analysis revealed that the late minocycline treatment was associated with significant induction of the end-stage GFAP-biophotonic signals, expression levels of connexin 43, a major protein of astrocytic gap junction and markers of microglial activation, such as Iba1 and CD68. The results of our study suggest that when administered at later stages of disease, once microglial cells are chronically reactive, minocycline may not have anti-inflammatory properties, and contrary to expectations, may alter astrocyte reactivity and increase microgliosis. Finally, our results further suggest the existence of close interactions/communication between activated microglia and astrocytes in late stage ALS.
► Previous reports showed that minocycline is neuroprotective in a mouse model of ALS. ► Recent clinical trials raised some questions regarding the efficacy of minocycline. ► Using live imaging of neuroinflammation we analyzed in real time the effects of minocycline. ► Treatment with minocycline initiated after disease onset exaggerated neuroinflammation.</description><subject>ALS</subject><subject>Amyotrophic Lateral Sclerosis - drug therapy</subject><subject>Amyotrophic Lateral Sclerosis - enzymology</subject><subject>Amyotrophic Lateral Sclerosis - genetics</subject><subject>Animals</subject><subject>Astrocytes - drug effects</subject><subject>Astrocytes - metabolism</subject><subject>Biological and medical sciences</subject><subject>Bioluminescence/biophotonic imaging</subject><subject>CD68</subject><subject>Connexin-43</subject><subject>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</subject><subject>Female</subject><subject>GFAP-reporter mouse</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Neurologic Mutants</subject><subject>Mice, Transgenic</subject><subject>Microglia - drug effects</subject><subject>Microglia - metabolism</subject><subject>Minocycline - pharmacology</subject><subject>Minocycline - therapeutic use</subject><subject>Neurology</subject><subject>Random Allocation</subject><subject>Superoxide Dismutase - genetics</subject><subject>Superoxide Dismutase-1</subject><subject>Treatment Outcome</subject><issn>0014-4886</issn><issn>1090-2430</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU1v1DAQhi0EotuWvwC-IE7Z-msT51i1fEmVeqA9W8Yeg1eJs3iclv33ONqlHOlppNfPOzOel5B3nK054-3Fdg2_dwnmPA1rwRZVrGt5QVac9awRSrKXZMUYV43Suj0hp4hbxlivRPeanAjOW62YXpH9XQZbRkiFPsbyk44xTW7vhpiA2lAgUx8RLAKdEkKhdqgaUoslV64ArXZX4kMse2qTpzG5vOBYO7k8_RjihBGrTL_dXnM6zsXWUfUNzsmrYAeEN8d6Ru4_fby7-tLc3H7-enV50zglRWlC23svJe9UUFwz7junXQ-gQrvRFfFcSW2tlV6p0LvlOsrprne9gCC8kmfkw6HvLk-_ZsBixogOhsEmmGY0eqOVYIJtnkHyXiq9WcjuQNYvImYIZpfjaPPecGaWFczWPAVkloAMF6aW6nx7nDF_H8E_-f4mUoH3R8Cis0PINrmI_zjZq67GW7nLAwf1dg8RskEXITnwMYMrxk_xv8v8AWqntSU</recordid><startdate>20110301</startdate><enddate>20110301</enddate><creator>Keller, A. Florence</creator><creator>Gravel, Mathieu</creator><creator>Kriz, Jasna</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>IQODW</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>7X8</scope><scope>7TK</scope></search><sort><creationdate>20110301</creationdate><title>Treatment with minocycline after disease onset alters astrocyte reactivity and increases microgliosis in SOD1 mutant mice</title><author>Keller, A. Florence ; Gravel, Mathieu ; Kriz, Jasna</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c432t-f69dd33174f41801d7c8c9ee4f658c43d1438aaa3d44f9c10164c879c92ef2d43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>ALS</topic><topic>Amyotrophic Lateral Sclerosis - drug therapy</topic><topic>Amyotrophic Lateral Sclerosis - enzymology</topic><topic>Amyotrophic Lateral Sclerosis - genetics</topic><topic>Animals</topic><topic>Astrocytes - drug effects</topic><topic>Astrocytes - metabolism</topic><topic>Biological and medical sciences</topic><topic>Bioluminescence/biophotonic imaging</topic><topic>CD68</topic><topic>Connexin-43</topic><topic>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</topic><topic>Female</topic><topic>GFAP-reporter mouse</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Neurologic Mutants</topic><topic>Mice, Transgenic</topic><topic>Microglia - drug effects</topic><topic>Microglia - metabolism</topic><topic>Minocycline - pharmacology</topic><topic>Minocycline - therapeutic use</topic><topic>Neurology</topic><topic>Random Allocation</topic><topic>Superoxide Dismutase - genetics</topic><topic>Superoxide Dismutase-1</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Keller, A. Florence</creatorcontrib><creatorcontrib>Gravel, Mathieu</creatorcontrib><creatorcontrib>Kriz, Jasna</creatorcontrib><collection>Pascal-Francis</collection><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>Neurosciences Abstracts</collection><jtitle>Experimental neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Keller, A. Florence</au><au>Gravel, Mathieu</au><au>Kriz, Jasna</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Treatment with minocycline after disease onset alters astrocyte reactivity and increases microgliosis in SOD1 mutant mice</atitle><jtitle>Experimental neurology</jtitle><addtitle>Exp Neurol</addtitle><date>2011-03-01</date><risdate>2011</risdate><volume>228</volume><issue>1</issue><spage>69</spage><epage>79</epage><pages>69-79</pages><issn>0014-4886</issn><eissn>1090-2430</eissn><coden>EXNEAC</coden><abstract>Several reports have demonstrated that attenuation of microglial activation by minocycline, an antimicrobial drug with anti-inflammatory properties, delays disease progression in a mouse model of ALS. However, the negative results obtained in recent clinical trials raised some questions regarding the role of inflammatory response and glial cells as a therapeutic target in ALS. To investigate this controversy we took advantage of a mouse model for live imaging of neuroinflammatory responses in ALS (GFAP-luc/ SOD1
G93A reporter mouse) and analyzed in real time the effects of minocycline treatment initiated at different stages of the disease. To our surprise, unlike neuroprotection that is conferred when minocycline is administered pre-symptomatically, treatment with minocycline initiated after the disease onset significantly altered glial responses and exaggerated neuroinflammation. Further analysis revealed that the late minocycline treatment was associated with significant induction of the end-stage GFAP-biophotonic signals, expression levels of connexin 43, a major protein of astrocytic gap junction and markers of microglial activation, such as Iba1 and CD68. The results of our study suggest that when administered at later stages of disease, once microglial cells are chronically reactive, minocycline may not have anti-inflammatory properties, and contrary to expectations, may alter astrocyte reactivity and increase microgliosis. Finally, our results further suggest the existence of close interactions/communication between activated microglia and astrocytes in late stage ALS.
► Previous reports showed that minocycline is neuroprotective in a mouse model of ALS. ► Recent clinical trials raised some questions regarding the efficacy of minocycline. ► Using live imaging of neuroinflammation we analyzed in real time the effects of minocycline. ► Treatment with minocycline initiated after disease onset exaggerated neuroinflammation.</abstract><cop>Amsterdam</cop><pub>Elsevier Inc</pub><pmid>21168408</pmid><doi>10.1016/j.expneurol.2010.12.010</doi><tpages>11</tpages></addata></record> |
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| subjects | ALS Amyotrophic Lateral Sclerosis - drug therapy Amyotrophic Lateral Sclerosis - enzymology Amyotrophic Lateral Sclerosis - genetics Animals Astrocytes - drug effects Astrocytes - metabolism Biological and medical sciences Bioluminescence/biophotonic imaging CD68 Connexin-43 Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Female GFAP-reporter mouse Male Medical sciences Mice Mice, Inbred C57BL Mice, Neurologic Mutants Mice, Transgenic Microglia - drug effects Microglia - metabolism Minocycline - pharmacology Minocycline - therapeutic use Neurology Random Allocation Superoxide Dismutase - genetics Superoxide Dismutase-1 Treatment Outcome |
| title | Treatment with minocycline after disease onset alters astrocyte reactivity and increases microgliosis in SOD1 mutant mice |
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