Minocycline upregulates pro-survival genes and downregulates pro-apoptotic genes in experimental glaucoma
Purpose Minocycline, a second-generation tetracycline with anti-inflammatory and anti-apoptotic properties, was reported to be neuroprotective in experimental glaucoma and optic nerve transection as well as in other neurodegenerative diseases. The purpose of this study was to investigate the mechani...
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| Veröffentlicht in: | Graefe's archive for clinical and experimental ophthalmology 2014-05, Vol.252 (5), p.761-772 |
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| creator | Levkovitch-Verbin, Hani Waserzoog, Yael Vander, Shelly Makarovsky, Daria Piven, Ilia |
| description | Purpose
Minocycline, a second-generation tetracycline with anti-inflammatory and anti-apoptotic properties, was reported to be neuroprotective in experimental glaucoma and optic nerve transection as well as in other neurodegenerative diseases. The purpose of this study was to investigate the mechanism underlying that neuroprotective effect in murine glaucoma.
Methods
Elevated intraocular pressure was induced in 159 rats by the translimbal photocoagulation laser model. Minocycline 22 mg/kg or saline was injected intraperitoneally starting 3 days before the induction of glaucoma, and continued daily until the animals were sacrificed. The effect of minocycline on gene expression was evaluated using a quantitative polymerase chain reaction (PCR) array for apoptosis. The involvement of selected pro-apoptotic, pro-survival, and inflammatory genes was further analyzed by quantitative real-time PCR at multiple time points. Immunohistochemistry was used to study the effect of minocycline on microglial activation and to localize Bcl-2 changes.
Results
Minocycline significantly increased the anti-apoptotic gene Bcl-2 expression at day 8 and day 14 after the induction of glaucoma (
p
= 0.04 and
p
= 0.03 respectively), and decreased IL-18 expression in the retina at day 14 and day 30 (
p
= 0.04 and
p
|
| doi_str_mv | 10.1007/s00417-014-2588-4 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1687661263</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3291349491</sourcerecordid><originalsourceid>FETCH-LOGICAL-c405t-852a686f0d3efd25e830bc5b537fad30405aaefe0a5d9edcee6ef56497ce93a03</originalsourceid><addsrcrecordid>eNp1kc1q3DAUhUVp6EySPkA3xdBNNkquJEuylyHkD1KySSA7oZGvBweP5Ej2JHn7avC0NIWuLuh-5-hIh5BvDE4ZgD5LACXTFFhJuawqWn4iS1YKSTXwp89kCZozWgn-tCCHKT1DxoVkX8iCl1KpGtiSdD87H9y76zuPxTREXE-9HTEVQww0TXHbbW1frNHnI-ubogmv_iNkhzCMYezcnup8gW8Dxm6Dftxpezu5sLHH5KC1fcKv-3lEHq8uHy5u6N399e3F-R11JciRVpJbVakWGoFtwyVWAlZOrqTQrW0EZMhabBGsbGpsHKLCVqqy1g5rYUEckZPZN4d7mTCNZtMlh31vPYYpGaYqrRTjSmT0xz_oc5iiz-kMkxx4VWutMsVmysWQUsTWDPlxNr4bBmbXg5l7MLkHs-vBlFnzfe88rTbY_FH8_vgM8BlIeeXXGP-6-r-uvwDiHZXR</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1520289776</pqid></control><display><type>article</type><title>Minocycline upregulates pro-survival genes and downregulates pro-apoptotic genes in experimental glaucoma</title><source>MEDLINE</source><source>Springer Journals</source><creator>Levkovitch-Verbin, Hani ; Waserzoog, Yael ; Vander, Shelly ; Makarovsky, Daria ; Piven, Ilia</creator><creatorcontrib>Levkovitch-Verbin, Hani ; Waserzoog, Yael ; Vander, Shelly ; Makarovsky, Daria ; Piven, Ilia</creatorcontrib><description>Purpose
Minocycline, a second-generation tetracycline with anti-inflammatory and anti-apoptotic properties, was reported to be neuroprotective in experimental glaucoma and optic nerve transection as well as in other neurodegenerative diseases. The purpose of this study was to investigate the mechanism underlying that neuroprotective effect in murine glaucoma.
Methods
Elevated intraocular pressure was induced in 159 rats by the translimbal photocoagulation laser model. Minocycline 22 mg/kg or saline was injected intraperitoneally starting 3 days before the induction of glaucoma, and continued daily until the animals were sacrificed. The effect of minocycline on gene expression was evaluated using a quantitative polymerase chain reaction (PCR) array for apoptosis. The involvement of selected pro-apoptotic, pro-survival, and inflammatory genes was further analyzed by quantitative real-time PCR at multiple time points. Immunohistochemistry was used to study the effect of minocycline on microglial activation and to localize Bcl-2 changes.
Results
Minocycline significantly increased the anti-apoptotic gene Bcl-2 expression at day 8 and day 14 after the induction of glaucoma (
p
= 0.04 and
p
= 0.03 respectively), and decreased IL-18 expression in the retina at day 14 and day 30 (
p
= 0.04 and
p
< 0.001 respectively). PCR arrays suggested that additional genes were affected by minocycline, including Tp53bp2, TRAF4, osteoprotegerin, caspase 1 and 4, and members of the tumor necrosis factor superfamily. Additionally, minocycline decreased the amount of activated microglia in glaucomatous eyes.
Conclusions
These results suggest that minocycline upregulates pro-survival genes and downregulates apoptotic genes, thus shifting the balance toward the anti-apoptotic side in experimental glaucoma.</description><identifier>ISSN: 0721-832X</identifier><identifier>EISSN: 1435-702X</identifier><identifier>DOI: 10.1007/s00417-014-2588-4</identifier><identifier>PMID: 24566901</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Animals ; Anti-Bacterial Agents - therapeutic use ; Apoptosis Regulatory Proteins - genetics ; Basic Science ; bcl-2-Associated X Protein - genetics ; bcl-2-Associated X Protein - metabolism ; bcl-Associated Death Protein - genetics ; bcl-Associated Death Protein - metabolism ; Disease Models, Animal ; Gene Expression Regulation - drug effects ; Glaucoma ; Glaucoma - genetics ; Glaucoma - metabolism ; Glaucoma - prevention & control ; Injections, Intraperitoneal ; Interleukin-18 - genetics ; Interleukin-18 - metabolism ; Medicine ; Medicine & Public Health ; Microglia - drug effects ; Minocycline - therapeutic use ; Ophthalmology ; Optic Nerve Diseases - genetics ; Optic Nerve Diseases - metabolism ; Optic Nerve Diseases - prevention & control ; Proto-Oncogene Proteins c-bcl-2 - genetics ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; Rats ; Rats, Wistar ; Real-Time Polymerase Chain Reaction ; Retinal Ganglion Cells - metabolism ; Up-Regulation</subject><ispartof>Graefe's archive for clinical and experimental ophthalmology, 2014-05, Vol.252 (5), p.761-772</ispartof><rights>Springer-Verlag Berlin Heidelberg 2014</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c405t-852a686f0d3efd25e830bc5b537fad30405aaefe0a5d9edcee6ef56497ce93a03</citedby><cites>FETCH-LOGICAL-c405t-852a686f0d3efd25e830bc5b537fad30405aaefe0a5d9edcee6ef56497ce93a03</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/s00417-014-2588-4$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00417-014-2588-4$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24566901$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Levkovitch-Verbin, Hani</creatorcontrib><creatorcontrib>Waserzoog, Yael</creatorcontrib><creatorcontrib>Vander, Shelly</creatorcontrib><creatorcontrib>Makarovsky, Daria</creatorcontrib><creatorcontrib>Piven, Ilia</creatorcontrib><title>Minocycline upregulates pro-survival genes and downregulates pro-apoptotic genes in experimental glaucoma</title><title>Graefe's archive for clinical and experimental ophthalmology</title><addtitle>Graefes Arch Clin Exp Ophthalmol</addtitle><addtitle>Graefes Arch Clin Exp Ophthalmol</addtitle><description>Purpose
Minocycline, a second-generation tetracycline with anti-inflammatory and anti-apoptotic properties, was reported to be neuroprotective in experimental glaucoma and optic nerve transection as well as in other neurodegenerative diseases. The purpose of this study was to investigate the mechanism underlying that neuroprotective effect in murine glaucoma.
Methods
Elevated intraocular pressure was induced in 159 rats by the translimbal photocoagulation laser model. Minocycline 22 mg/kg or saline was injected intraperitoneally starting 3 days before the induction of glaucoma, and continued daily until the animals were sacrificed. The effect of minocycline on gene expression was evaluated using a quantitative polymerase chain reaction (PCR) array for apoptosis. The involvement of selected pro-apoptotic, pro-survival, and inflammatory genes was further analyzed by quantitative real-time PCR at multiple time points. Immunohistochemistry was used to study the effect of minocycline on microglial activation and to localize Bcl-2 changes.
Results
Minocycline significantly increased the anti-apoptotic gene Bcl-2 expression at day 8 and day 14 after the induction of glaucoma (
p
= 0.04 and
p
= 0.03 respectively), and decreased IL-18 expression in the retina at day 14 and day 30 (
p
= 0.04 and
p
< 0.001 respectively). PCR arrays suggested that additional genes were affected by minocycline, including Tp53bp2, TRAF4, osteoprotegerin, caspase 1 and 4, and members of the tumor necrosis factor superfamily. Additionally, minocycline decreased the amount of activated microglia in glaucomatous eyes.
Conclusions
These results suggest that minocycline upregulates pro-survival genes and downregulates apoptotic genes, thus shifting the balance toward the anti-apoptotic side in experimental glaucoma.</description><subject>Animals</subject><subject>Anti-Bacterial Agents - therapeutic use</subject><subject>Apoptosis Regulatory Proteins - genetics</subject><subject>Basic Science</subject><subject>bcl-2-Associated X Protein - genetics</subject><subject>bcl-2-Associated X Protein - metabolism</subject><subject>bcl-Associated Death Protein - genetics</subject><subject>bcl-Associated Death Protein - metabolism</subject><subject>Disease Models, Animal</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Glaucoma</subject><subject>Glaucoma - genetics</subject><subject>Glaucoma - metabolism</subject><subject>Glaucoma - prevention & control</subject><subject>Injections, Intraperitoneal</subject><subject>Interleukin-18 - genetics</subject><subject>Interleukin-18 - metabolism</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Microglia - drug effects</subject><subject>Minocycline - therapeutic use</subject><subject>Ophthalmology</subject><subject>Optic Nerve Diseases - genetics</subject><subject>Optic Nerve Diseases - metabolism</subject><subject>Optic Nerve Diseases - prevention & control</subject><subject>Proto-Oncogene Proteins c-bcl-2 - genetics</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Retinal Ganglion Cells - metabolism</subject><subject>Up-Regulation</subject><issn>0721-832X</issn><issn>1435-702X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kc1q3DAUhUVp6EySPkA3xdBNNkquJEuylyHkD1KySSA7oZGvBweP5Ej2JHn7avC0NIWuLuh-5-hIh5BvDE4ZgD5LACXTFFhJuawqWn4iS1YKSTXwp89kCZozWgn-tCCHKT1DxoVkX8iCl1KpGtiSdD87H9y76zuPxTREXE-9HTEVQww0TXHbbW1frNHnI-ubogmv_iNkhzCMYezcnup8gW8Dxm6Dftxpezu5sLHH5KC1fcKv-3lEHq8uHy5u6N399e3F-R11JciRVpJbVakWGoFtwyVWAlZOrqTQrW0EZMhabBGsbGpsHKLCVqqy1g5rYUEckZPZN4d7mTCNZtMlh31vPYYpGaYqrRTjSmT0xz_oc5iiz-kMkxx4VWutMsVmysWQUsTWDPlxNr4bBmbXg5l7MLkHs-vBlFnzfe88rTbY_FH8_vgM8BlIeeXXGP-6-r-uvwDiHZXR</recordid><startdate>20140501</startdate><enddate>20140501</enddate><creator>Levkovitch-Verbin, Hani</creator><creator>Waserzoog, Yael</creator><creator>Vander, Shelly</creator><creator>Makarovsky, Daria</creator><creator>Piven, Ilia</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</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>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20140501</creationdate><title>Minocycline upregulates pro-survival genes and downregulates pro-apoptotic genes in experimental glaucoma</title><author>Levkovitch-Verbin, Hani ; Waserzoog, Yael ; Vander, Shelly ; Makarovsky, Daria ; Piven, Ilia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c405t-852a686f0d3efd25e830bc5b537fad30405aaefe0a5d9edcee6ef56497ce93a03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Anti-Bacterial Agents - therapeutic use</topic><topic>Apoptosis Regulatory Proteins - genetics</topic><topic>Basic Science</topic><topic>bcl-2-Associated X Protein - genetics</topic><topic>bcl-2-Associated X Protein - metabolism</topic><topic>bcl-Associated Death Protein - genetics</topic><topic>bcl-Associated Death Protein - metabolism</topic><topic>Disease Models, Animal</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Glaucoma</topic><topic>Glaucoma - genetics</topic><topic>Glaucoma - metabolism</topic><topic>Glaucoma - prevention & control</topic><topic>Injections, Intraperitoneal</topic><topic>Interleukin-18 - genetics</topic><topic>Interleukin-18 - metabolism</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Microglia - drug effects</topic><topic>Minocycline - therapeutic use</topic><topic>Ophthalmology</topic><topic>Optic Nerve Diseases - genetics</topic><topic>Optic Nerve Diseases - metabolism</topic><topic>Optic Nerve Diseases - prevention & control</topic><topic>Proto-Oncogene Proteins c-bcl-2 - genetics</topic><topic>Proto-Oncogene Proteins c-bcl-2 - metabolism</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Retinal Ganglion Cells - metabolism</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Levkovitch-Verbin, Hani</creatorcontrib><creatorcontrib>Waserzoog, Yael</creatorcontrib><creatorcontrib>Vander, Shelly</creatorcontrib><creatorcontrib>Makarovsky, Daria</creatorcontrib><creatorcontrib>Piven, Ilia</creatorcontrib><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>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma 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)</collection><collection>ProQuest Central UK/Ireland</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</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>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Graefe's archive for clinical and experimental ophthalmology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Levkovitch-Verbin, Hani</au><au>Waserzoog, Yael</au><au>Vander, Shelly</au><au>Makarovsky, Daria</au><au>Piven, Ilia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Minocycline upregulates pro-survival genes and downregulates pro-apoptotic genes in experimental glaucoma</atitle><jtitle>Graefe's archive for clinical and experimental ophthalmology</jtitle><stitle>Graefes Arch Clin Exp Ophthalmol</stitle><addtitle>Graefes Arch Clin Exp Ophthalmol</addtitle><date>2014-05-01</date><risdate>2014</risdate><volume>252</volume><issue>5</issue><spage>761</spage><epage>772</epage><pages>761-772</pages><issn>0721-832X</issn><eissn>1435-702X</eissn><abstract>Purpose
Minocycline, a second-generation tetracycline with anti-inflammatory and anti-apoptotic properties, was reported to be neuroprotective in experimental glaucoma and optic nerve transection as well as in other neurodegenerative diseases. The purpose of this study was to investigate the mechanism underlying that neuroprotective effect in murine glaucoma.
Methods
Elevated intraocular pressure was induced in 159 rats by the translimbal photocoagulation laser model. Minocycline 22 mg/kg or saline was injected intraperitoneally starting 3 days before the induction of glaucoma, and continued daily until the animals were sacrificed. The effect of minocycline on gene expression was evaluated using a quantitative polymerase chain reaction (PCR) array for apoptosis. The involvement of selected pro-apoptotic, pro-survival, and inflammatory genes was further analyzed by quantitative real-time PCR at multiple time points. Immunohistochemistry was used to study the effect of minocycline on microglial activation and to localize Bcl-2 changes.
Results
Minocycline significantly increased the anti-apoptotic gene Bcl-2 expression at day 8 and day 14 after the induction of glaucoma (
p
= 0.04 and
p
= 0.03 respectively), and decreased IL-18 expression in the retina at day 14 and day 30 (
p
= 0.04 and
p
< 0.001 respectively). PCR arrays suggested that additional genes were affected by minocycline, including Tp53bp2, TRAF4, osteoprotegerin, caspase 1 and 4, and members of the tumor necrosis factor superfamily. Additionally, minocycline decreased the amount of activated microglia in glaucomatous eyes.
Conclusions
These results suggest that minocycline upregulates pro-survival genes and downregulates apoptotic genes, thus shifting the balance toward the anti-apoptotic side in experimental glaucoma.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>24566901</pmid><doi>10.1007/s00417-014-2588-4</doi><tpages>12</tpages></addata></record> |
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| identifier | ISSN: 0721-832X |
| ispartof | Graefe's archive for clinical and experimental ophthalmology, 2014-05, Vol.252 (5), p.761-772 |
| issn | 0721-832X 1435-702X |
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| subjects | Animals Anti-Bacterial Agents - therapeutic use Apoptosis Regulatory Proteins - genetics Basic Science bcl-2-Associated X Protein - genetics bcl-2-Associated X Protein - metabolism bcl-Associated Death Protein - genetics bcl-Associated Death Protein - metabolism Disease Models, Animal Gene Expression Regulation - drug effects Glaucoma Glaucoma - genetics Glaucoma - metabolism Glaucoma - prevention & control Injections, Intraperitoneal Interleukin-18 - genetics Interleukin-18 - metabolism Medicine Medicine & Public Health Microglia - drug effects Minocycline - therapeutic use Ophthalmology Optic Nerve Diseases - genetics Optic Nerve Diseases - metabolism Optic Nerve Diseases - prevention & control Proto-Oncogene Proteins c-bcl-2 - genetics Proto-Oncogene Proteins c-bcl-2 - metabolism Rats Rats, Wistar Real-Time Polymerase Chain Reaction Retinal Ganglion Cells - metabolism Up-Regulation |
| title | Minocycline upregulates pro-survival genes and downregulates pro-apoptotic genes in experimental glaucoma |
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