Effect of copper on extracellular levels of key pro-inflammatory molecules in hypothalamic GN11 and primary neurons
Copper dyshomeostasis is responsible for the neurological symptoms observed in the genetically inherited copper-dependent disorders (e.g., Menkes’ and Wilson's diseases), but it has been also shown to have an important role in neurodegenerative diseases such as Alzheimer disease, prion diseases...
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Veröffentlicht in: | Neurotoxicology (Park Forest South) 2009-07, Vol.30 (4), p.605-612 |
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description | Copper dyshomeostasis is responsible for the neurological symptoms observed in the genetically inherited copper-dependent disorders (e.g., Menkes’ and Wilson's diseases), but it has been also shown to have an important role in neurodegenerative diseases such as Alzheimer disease, prion diseases, Parkinson's disease and amyotrophic lateral sclerosis. It is widely accepted that increased extracellular copper levels contribute to neuronal pathogenic process by increasing the production of dangerous radical oxygen species, but the existence of other molecular mechanisms explaining copper neurotoxicity has not been investigated yet. By using a cellular model based on hypothalamic GN11 cultured neurons exposed to copper supplementation and by analysing the cell conditioned media, we try here to identify new molecular events explaining the association between extracellular copper accumulation and neuronal damages. We show here that increased extracellular copper levels produce a wide complex of alterations in the neuronal extracellular environment. In particular, copper affects the secretion of molecules involved in the protection of neurons against oxidative stress, such as cyclophilin A (CypA), or of molecules capable of shifting neuronal cells towards a pro-inflammatory state, such as IL-1α, IL-12, Rantes, neutrophil gelatinase-associated lipocalin (NGAL) and secreted protein acidic and rich in cysteine (SPARC). Copper pro-inflammatory properties have been confirmed by using primary neurons. |
doi_str_mv | 10.1016/j.neuro.2009.03.005 |
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It is widely accepted that increased extracellular copper levels contribute to neuronal pathogenic process by increasing the production of dangerous radical oxygen species, but the existence of other molecular mechanisms explaining copper neurotoxicity has not been investigated yet. By using a cellular model based on hypothalamic GN11 cultured neurons exposed to copper supplementation and by analysing the cell conditioned media, we try here to identify new molecular events explaining the association between extracellular copper accumulation and neuronal damages. We show here that increased extracellular copper levels produce a wide complex of alterations in the neuronal extracellular environment. In particular, copper affects the secretion of molecules involved in the protection of neurons against oxidative stress, such as cyclophilin A (CypA), or of molecules capable of shifting neuronal cells towards a pro-inflammatory state, such as IL-1α, IL-12, Rantes, neutrophil gelatinase-associated lipocalin (NGAL) and secreted protein acidic and rich in cysteine (SPARC). Copper pro-inflammatory properties have been confirmed by using primary neurons.</description><identifier>ISSN: 0161-813X</identifier><identifier>EISSN: 1872-9711</identifier><identifier>DOI: 10.1016/j.neuro.2009.03.005</identifier><identifier>PMID: 19635393</identifier><language>eng</language><publisher>Amsterdam: Elsevier B.V</publisher><subject>Acute-Phase Proteins - metabolism ; Analysis of Variance ; Animals ; Animals, Newborn ; Biological and medical sciences ; Cells, Cultured ; Cerebral Cortex - cytology ; Chemical and industrial products toxicology. 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It is widely accepted that increased extracellular copper levels contribute to neuronal pathogenic process by increasing the production of dangerous radical oxygen species, but the existence of other molecular mechanisms explaining copper neurotoxicity has not been investigated yet. By using a cellular model based on hypothalamic GN11 cultured neurons exposed to copper supplementation and by analysing the cell conditioned media, we try here to identify new molecular events explaining the association between extracellular copper accumulation and neuronal damages. We show here that increased extracellular copper levels produce a wide complex of alterations in the neuronal extracellular environment. In particular, copper affects the secretion of molecules involved in the protection of neurons against oxidative stress, such as cyclophilin A (CypA), or of molecules capable of shifting neuronal cells towards a pro-inflammatory state, such as IL-1α, IL-12, Rantes, neutrophil gelatinase-associated lipocalin (NGAL) and secreted protein acidic and rich in cysteine (SPARC). Copper pro-inflammatory properties have been confirmed by using primary neurons.</description><subject>Acute-Phase Proteins - metabolism</subject><subject>Analysis of Variance</subject><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Biological and medical sciences</subject><subject>Cells, Cultured</subject><subject>Cerebral Cortex - cytology</subject><subject>Chemical and industrial products toxicology. Toxic occupational diseases</subject><subject>Copper</subject><subject>Copper - metabolism</subject><subject>Copper - pharmacology</subject><subject>Culture Media, Conditioned - chemistry</subject><subject>Cyclophilin A</subject><subject>Cyclophilin A - metabolism</subject><subject>Cytokines - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Extracellular Fluid - drug effects</subject><subject>Extracellular Fluid - metabolism</subject><subject>Hypothalamus - cytology</subject><subject>Inflammation</subject><subject>Lipocalins - metabolism</subject><subject>Medical sciences</subject><subject>Metals and various inorganic compounds</subject><subject>Mice</subject><subject>Neurons - drug effects</subject><subject>Neutrophil gelatinase-associated lipocalin (NGAL)</subject><subject>Osteonectin - metabolism</subject><subject>Peptide Mapping</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Secreted protein acidic and rich in cysteine (SPARC)</subject><subject>Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization - methods</subject><subject>Spectrophotometry, Atomic</subject><subject>Toxicology</subject><subject>Trace Elements - metabolism</subject><subject>Trace Elements - pharmacology</subject><issn>0161-813X</issn><issn>1872-9711</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1v1DAQhi0EokvhFyAhX-CW4InzYR84oKoUpAouIHGzvM5Y9eLYi51U3X-P043gxskHP-_omXcIeQ2sBgb9-0MdcEmxbhiTNeM1Y90TsgMxNJUcAJ6SXaGgEsB_XpAXOR8Yg27o5XNyAbLnHZd8R_K1tWhmGi018XjERGOg-DAnbdD7xetEPd6jzyvxC0_0mGLlgvV6mvQc04lO0aNZPGbqAr07HeN8p8uvM_TmKwDVYSwZN-mCPvqG_JI8s9pnfLW9l-THp-vvV5-r2283X64-3lamBTFXYNHurREaOmHBiFGbVnRy38phkMUehEGme7DMCMtZU_ZoZIey248CBg38krw7zy3OvxfMs5pcXtfSAeOSVcOGvu35CvIzaFLMOaFVm7ECptau1UE9uqu1a8W4Kl2X1Jtt_LKfcPyX2cotwNsN0Nlob5MOxuW_XAOioO1QuA9nrtSM9w6TysZhMDi6VG6jxuj-K_IHsa6gRA</recordid><startdate>20090701</startdate><enddate>20090701</enddate><creator>Spisni, Enzo</creator><creator>Valerii, Maria Chiara</creator><creator>Manerba, Marcella</creator><creator>Strillacci, Antonio</creator><creator>Polazzi, Elisabetta</creator><creator>Mattia, Toni</creator><creator>Griffoni, Cristiana</creator><creator>Tomasi, Vittorio</creator><general>Elsevier B.V</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>7ST</scope><scope>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>SOI</scope></search><sort><creationdate>20090701</creationdate><title>Effect of copper on extracellular levels of key pro-inflammatory molecules in hypothalamic GN11 and primary neurons</title><author>Spisni, Enzo ; Valerii, Maria Chiara ; Manerba, Marcella ; Strillacci, Antonio ; Polazzi, Elisabetta ; Mattia, Toni ; Griffoni, Cristiana ; Tomasi, Vittorio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c418t-1fefbfc8a158f1c8dac4859b4977953918ce0a61f0c8f302fec295e95bd817a13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Acute-Phase Proteins - metabolism</topic><topic>Analysis of Variance</topic><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Biological and medical sciences</topic><topic>Cells, Cultured</topic><topic>Cerebral Cortex - cytology</topic><topic>Chemical and industrial products toxicology. Toxic occupational diseases</topic><topic>Copper</topic><topic>Copper - metabolism</topic><topic>Copper - pharmacology</topic><topic>Culture Media, Conditioned - chemistry</topic><topic>Cyclophilin A</topic><topic>Cyclophilin A - metabolism</topic><topic>Cytokines - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Extracellular Fluid - drug effects</topic><topic>Extracellular Fluid - metabolism</topic><topic>Hypothalamus - cytology</topic><topic>Inflammation</topic><topic>Lipocalins - metabolism</topic><topic>Medical sciences</topic><topic>Metals and various inorganic compounds</topic><topic>Mice</topic><topic>Neurons - drug effects</topic><topic>Neutrophil gelatinase-associated lipocalin (NGAL)</topic><topic>Osteonectin - metabolism</topic><topic>Peptide Mapping</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Secreted protein acidic and rich in cysteine (SPARC)</topic><topic>Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization - methods</topic><topic>Spectrophotometry, Atomic</topic><topic>Toxicology</topic><topic>Trace Elements - metabolism</topic><topic>Trace Elements - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Spisni, Enzo</creatorcontrib><creatorcontrib>Valerii, Maria Chiara</creatorcontrib><creatorcontrib>Manerba, Marcella</creatorcontrib><creatorcontrib>Strillacci, Antonio</creatorcontrib><creatorcontrib>Polazzi, Elisabetta</creatorcontrib><creatorcontrib>Mattia, Toni</creatorcontrib><creatorcontrib>Griffoni, Cristiana</creatorcontrib><creatorcontrib>Tomasi, Vittorio</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>Environment Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Environment Abstracts</collection><jtitle>Neurotoxicology (Park Forest South)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Spisni, Enzo</au><au>Valerii, Maria Chiara</au><au>Manerba, Marcella</au><au>Strillacci, Antonio</au><au>Polazzi, Elisabetta</au><au>Mattia, Toni</au><au>Griffoni, Cristiana</au><au>Tomasi, Vittorio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of copper on extracellular levels of key pro-inflammatory molecules in hypothalamic GN11 and primary neurons</atitle><jtitle>Neurotoxicology (Park Forest South)</jtitle><addtitle>Neurotoxicology</addtitle><date>2009-07-01</date><risdate>2009</risdate><volume>30</volume><issue>4</issue><spage>605</spage><epage>612</epage><pages>605-612</pages><issn>0161-813X</issn><eissn>1872-9711</eissn><abstract>Copper dyshomeostasis is responsible for the neurological symptoms observed in the genetically inherited copper-dependent disorders (e.g., Menkes’ and Wilson's diseases), but it has been also shown to have an important role in neurodegenerative diseases such as Alzheimer disease, prion diseases, Parkinson's disease and amyotrophic lateral sclerosis. It is widely accepted that increased extracellular copper levels contribute to neuronal pathogenic process by increasing the production of dangerous radical oxygen species, but the existence of other molecular mechanisms explaining copper neurotoxicity has not been investigated yet. By using a cellular model based on hypothalamic GN11 cultured neurons exposed to copper supplementation and by analysing the cell conditioned media, we try here to identify new molecular events explaining the association between extracellular copper accumulation and neuronal damages. We show here that increased extracellular copper levels produce a wide complex of alterations in the neuronal extracellular environment. In particular, copper affects the secretion of molecules involved in the protection of neurons against oxidative stress, such as cyclophilin A (CypA), or of molecules capable of shifting neuronal cells towards a pro-inflammatory state, such as IL-1α, IL-12, Rantes, neutrophil gelatinase-associated lipocalin (NGAL) and secreted protein acidic and rich in cysteine (SPARC). Copper pro-inflammatory properties have been confirmed by using primary neurons.</abstract><cop>Amsterdam</cop><pub>Elsevier B.V</pub><pmid>19635393</pmid><doi>10.1016/j.neuro.2009.03.005</doi><tpages>8</tpages></addata></record> |
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subjects | Acute-Phase Proteins - metabolism Analysis of Variance Animals Animals, Newborn Biological and medical sciences Cells, Cultured Cerebral Cortex - cytology Chemical and industrial products toxicology. Toxic occupational diseases Copper Copper - metabolism Copper - pharmacology Culture Media, Conditioned - chemistry Cyclophilin A Cyclophilin A - metabolism Cytokines - metabolism Dose-Response Relationship, Drug Extracellular Fluid - drug effects Extracellular Fluid - metabolism Hypothalamus - cytology Inflammation Lipocalins - metabolism Medical sciences Metals and various inorganic compounds Mice Neurons - drug effects Neutrophil gelatinase-associated lipocalin (NGAL) Osteonectin - metabolism Peptide Mapping Proto-Oncogene Proteins - metabolism Rats Rats, Wistar Secreted protein acidic and rich in cysteine (SPARC) Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization - methods Spectrophotometry, Atomic Toxicology Trace Elements - metabolism Trace Elements - pharmacology |
title | Effect of copper on extracellular levels of key pro-inflammatory molecules in hypothalamic GN11 and primary neurons |
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