Clinical response to Nabiximols correlates with the downregulation of immune pathways in multiple sclerosis
Background and purpose Nabiximols (Sativex®) is a cannabinoid‐based compound used for the treatment of moderate to severe spasticity in multiple sclerosis (MS). The aim of the study was to investigate the effect of the administration of Nabiximols on blood transcriptome profile of patients with MS a...
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| Veröffentlicht in: | European journal of neurology 2018-07, Vol.25 (7), p.934-e70 |
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| container_title | European journal of neurology |
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| creator | Sorosina, M. Clarelli, F. Ferrè, L. Osiceanu, A. M. Unal, N. T. Mascia, E. Martinelli, V. Comi, G. Benigni, F. Esposito, F. Martinelli Boneschi, F. |
| description | Background and purpose
Nabiximols (Sativex®) is a cannabinoid‐based compound used for the treatment of moderate to severe spasticity in multiple sclerosis (MS). The aim of the study was to investigate the effect of the administration of Nabiximols on blood transcriptome profile of patients with MS and to interpret it in the context of pathways and networks.
Methods
Whole‐genome expression profiling was performed in whole blood of 33 subjects with MS at baseline and after 4 weeks of drug treatment. Patients were classified as responders (n = 19) and non‐responders (n = 14). Pathway and network analyses on genes modulated by the drug were performed, followed by in vitro stimulation of peripheral blood mononuclear cells with pro‐inflammatory agents to support the immunomodulatory properties of the drug.
Results
Individual effect size was modest; however, we observed a downregulation of several immune‐related pathways after 4 weeks of treatment, which was more pronounced when restricting analyses to responders. Interesting hub molecules functionally related to the immune system emerged from network analysis, including NFKB1, FYN, MAP14 and TP53. The immunomodulatory properties of the drug were confirmed through in vitro assays in peripheral blood mononuclear cells collected from patients with MS.
Conclusions
Our findings support the immunomodulatory activity of cannabinoids in patients with MS. Further studies in more specific cell types are needed to refine these results. |
| doi_str_mv | 10.1111/ene.13623 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2013104362</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2056434418</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3533-619a33cadc5613077dbbfe02819a4969132926cd39cc5f55a5c1401f766a136c3</originalsourceid><addsrcrecordid>eNp1kU9rGzEQxUVpiB03h3yBIuilOayjkVay91iM8wdMcmnPi6ydreVqpa20i-tvX6VOcgh0LjMMPx4z7xFyBWwOuW7Q4xyE4uIDmUKplgUIAR_zLCQUEhhMyEVKe8YYX3B2Tia8knwpy2pKfq2c9dZoRyOmPviEdAj0UW_tH9sFl6gJMaLTAyZ6sMOODjukTTj4iD_HvLbB09BS23WjR9rrYXfQx0Stp93oBts7pMk4jCHZ9ImctdolvHzpM_Ljdv19dV9snu4eVt82hRFSiEJBpYUwujFSgWCLRbPdtsj4Mu_LSlUgeMWVaURljGyl1NJAyaBdKKWzC0bMyNeTbh_D7xHTUHc2GXROewxjqjkDAax8NmxGvrxD92GMPl-XKalKUZawzNT1iTL5jxSxrftoOx2PNbD6OYE6J1D_SyCzn18Ux22HzRv5ankGbk7AwTo8_l-pXj-uT5J_Abz7kAA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2056434418</pqid></control><display><type>article</type><title>Clinical response to Nabiximols correlates with the downregulation of immune pathways in multiple sclerosis</title><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><creator>Sorosina, M. ; Clarelli, F. ; Ferrè, L. ; Osiceanu, A. M. ; Unal, N. T. ; Mascia, E. ; Martinelli, V. ; Comi, G. ; Benigni, F. ; Esposito, F. ; Martinelli Boneschi, F.</creator><creatorcontrib>Sorosina, M. ; Clarelli, F. ; Ferrè, L. ; Osiceanu, A. M. ; Unal, N. T. ; Mascia, E. ; Martinelli, V. ; Comi, G. ; Benigni, F. ; Esposito, F. ; Martinelli Boneschi, F.</creatorcontrib><description>Background and purpose
Nabiximols (Sativex®) is a cannabinoid‐based compound used for the treatment of moderate to severe spasticity in multiple sclerosis (MS). The aim of the study was to investigate the effect of the administration of Nabiximols on blood transcriptome profile of patients with MS and to interpret it in the context of pathways and networks.
Methods
Whole‐genome expression profiling was performed in whole blood of 33 subjects with MS at baseline and after 4 weeks of drug treatment. Patients were classified as responders (n = 19) and non‐responders (n = 14). Pathway and network analyses on genes modulated by the drug were performed, followed by in vitro stimulation of peripheral blood mononuclear cells with pro‐inflammatory agents to support the immunomodulatory properties of the drug.
Results
Individual effect size was modest; however, we observed a downregulation of several immune‐related pathways after 4 weeks of treatment, which was more pronounced when restricting analyses to responders. Interesting hub molecules functionally related to the immune system emerged from network analysis, including NFKB1, FYN, MAP14 and TP53. The immunomodulatory properties of the drug were confirmed through in vitro assays in peripheral blood mononuclear cells collected from patients with MS.
Conclusions
Our findings support the immunomodulatory activity of cannabinoids in patients with MS. Further studies in more specific cell types are needed to refine these results.</description><identifier>ISSN: 1351-5101</identifier><identifier>EISSN: 1468-1331</identifier><identifier>DOI: 10.1111/ene.13623</identifier><identifier>PMID: 29528549</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Adult ; Blood ; Cannabidiol - pharmacology ; Cannabidiol - therapeutic use ; Cannabinoids ; Down-Regulation ; Dronabinol - pharmacology ; Dronabinol - therapeutic use ; Drug Combinations ; Female ; Fyn protein ; Gene expression ; Genomes ; Humans ; Immune system ; Immunomodulation ; Inflammation ; Interferon ; Leukocytes (mononuclear) ; Leukocytes, Mononuclear - drug effects ; Leukocytes, Mononuclear - immunology ; Male ; Middle Aged ; Molecular chains ; Multiple sclerosis ; Multiple Sclerosis - drug therapy ; Multiple Sclerosis - immunology ; Nabiximols ; Network analysis ; p53 Protein ; Patients ; Peripheral blood mononuclear cells ; Sativex ; Spasticity ; transcriptomics</subject><ispartof>European journal of neurology, 2018-07, Vol.25 (7), p.934-e70</ispartof><rights>2018 EAN</rights><rights>2018 EAN.</rights><rights>Copyright © 2018 European Academy of Neurology</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3533-619a33cadc5613077dbbfe02819a4969132926cd39cc5f55a5c1401f766a136c3</citedby><cites>FETCH-LOGICAL-c3533-619a33cadc5613077dbbfe02819a4969132926cd39cc5f55a5c1401f766a136c3</cites><orcidid>0000-0003-4376-2550 ; 0000-0003-2550-0805</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fene.13623$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fene.13623$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29528549$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sorosina, M.</creatorcontrib><creatorcontrib>Clarelli, F.</creatorcontrib><creatorcontrib>Ferrè, L.</creatorcontrib><creatorcontrib>Osiceanu, A. M.</creatorcontrib><creatorcontrib>Unal, N. T.</creatorcontrib><creatorcontrib>Mascia, E.</creatorcontrib><creatorcontrib>Martinelli, V.</creatorcontrib><creatorcontrib>Comi, G.</creatorcontrib><creatorcontrib>Benigni, F.</creatorcontrib><creatorcontrib>Esposito, F.</creatorcontrib><creatorcontrib>Martinelli Boneschi, F.</creatorcontrib><title>Clinical response to Nabiximols correlates with the downregulation of immune pathways in multiple sclerosis</title><title>European journal of neurology</title><addtitle>Eur J Neurol</addtitle><description>Background and purpose
Nabiximols (Sativex®) is a cannabinoid‐based compound used for the treatment of moderate to severe spasticity in multiple sclerosis (MS). The aim of the study was to investigate the effect of the administration of Nabiximols on blood transcriptome profile of patients with MS and to interpret it in the context of pathways and networks.
Methods
Whole‐genome expression profiling was performed in whole blood of 33 subjects with MS at baseline and after 4 weeks of drug treatment. Patients were classified as responders (n = 19) and non‐responders (n = 14). Pathway and network analyses on genes modulated by the drug were performed, followed by in vitro stimulation of peripheral blood mononuclear cells with pro‐inflammatory agents to support the immunomodulatory properties of the drug.
Results
Individual effect size was modest; however, we observed a downregulation of several immune‐related pathways after 4 weeks of treatment, which was more pronounced when restricting analyses to responders. Interesting hub molecules functionally related to the immune system emerged from network analysis, including NFKB1, FYN, MAP14 and TP53. The immunomodulatory properties of the drug were confirmed through in vitro assays in peripheral blood mononuclear cells collected from patients with MS.
Conclusions
Our findings support the immunomodulatory activity of cannabinoids in patients with MS. Further studies in more specific cell types are needed to refine these results.</description><subject>Adult</subject><subject>Blood</subject><subject>Cannabidiol - pharmacology</subject><subject>Cannabidiol - therapeutic use</subject><subject>Cannabinoids</subject><subject>Down-Regulation</subject><subject>Dronabinol - pharmacology</subject><subject>Dronabinol - therapeutic use</subject><subject>Drug Combinations</subject><subject>Female</subject><subject>Fyn protein</subject><subject>Gene expression</subject><subject>Genomes</subject><subject>Humans</subject><subject>Immune system</subject><subject>Immunomodulation</subject><subject>Inflammation</subject><subject>Interferon</subject><subject>Leukocytes (mononuclear)</subject><subject>Leukocytes, Mononuclear - drug effects</subject><subject>Leukocytes, Mononuclear - immunology</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Molecular chains</subject><subject>Multiple sclerosis</subject><subject>Multiple Sclerosis - drug therapy</subject><subject>Multiple Sclerosis - immunology</subject><subject>Nabiximols</subject><subject>Network analysis</subject><subject>p53 Protein</subject><subject>Patients</subject><subject>Peripheral blood mononuclear cells</subject><subject>Sativex</subject><subject>Spasticity</subject><subject>transcriptomics</subject><issn>1351-5101</issn><issn>1468-1331</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kU9rGzEQxUVpiB03h3yBIuilOayjkVay91iM8wdMcmnPi6ydreVqpa20i-tvX6VOcgh0LjMMPx4z7xFyBWwOuW7Q4xyE4uIDmUKplgUIAR_zLCQUEhhMyEVKe8YYX3B2Tia8knwpy2pKfq2c9dZoRyOmPviEdAj0UW_tH9sFl6gJMaLTAyZ6sMOODjukTTj4iD_HvLbB09BS23WjR9rrYXfQx0Stp93oBts7pMk4jCHZ9ImctdolvHzpM_Ljdv19dV9snu4eVt82hRFSiEJBpYUwujFSgWCLRbPdtsj4Mu_LSlUgeMWVaURljGyl1NJAyaBdKKWzC0bMyNeTbh_D7xHTUHc2GXROewxjqjkDAax8NmxGvrxD92GMPl-XKalKUZawzNT1iTL5jxSxrftoOx2PNbD6OYE6J1D_SyCzn18Ux22HzRv5ankGbk7AwTo8_l-pXj-uT5J_Abz7kAA</recordid><startdate>201807</startdate><enddate>201807</enddate><creator>Sorosina, M.</creator><creator>Clarelli, F.</creator><creator>Ferrè, L.</creator><creator>Osiceanu, A. M.</creator><creator>Unal, N. T.</creator><creator>Mascia, E.</creator><creator>Martinelli, V.</creator><creator>Comi, G.</creator><creator>Benigni, F.</creator><creator>Esposito, F.</creator><creator>Martinelli Boneschi, F.</creator><general>John Wiley & Sons, Inc</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>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-4376-2550</orcidid><orcidid>https://orcid.org/0000-0003-2550-0805</orcidid></search><sort><creationdate>201807</creationdate><title>Clinical response to Nabiximols correlates with the downregulation of immune pathways in multiple sclerosis</title><author>Sorosina, M. ; Clarelli, F. ; Ferrè, L. ; Osiceanu, A. M. ; Unal, N. T. ; Mascia, E. ; Martinelli, V. ; Comi, G. ; Benigni, F. ; Esposito, F. ; Martinelli Boneschi, F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3533-619a33cadc5613077dbbfe02819a4969132926cd39cc5f55a5c1401f766a136c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adult</topic><topic>Blood</topic><topic>Cannabidiol - pharmacology</topic><topic>Cannabidiol - therapeutic use</topic><topic>Cannabinoids</topic><topic>Down-Regulation</topic><topic>Dronabinol - pharmacology</topic><topic>Dronabinol - therapeutic use</topic><topic>Drug Combinations</topic><topic>Female</topic><topic>Fyn protein</topic><topic>Gene expression</topic><topic>Genomes</topic><topic>Humans</topic><topic>Immune system</topic><topic>Immunomodulation</topic><topic>Inflammation</topic><topic>Interferon</topic><topic>Leukocytes (mononuclear)</topic><topic>Leukocytes, Mononuclear - drug effects</topic><topic>Leukocytes, Mononuclear - immunology</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Molecular chains</topic><topic>Multiple sclerosis</topic><topic>Multiple Sclerosis - drug therapy</topic><topic>Multiple Sclerosis - immunology</topic><topic>Nabiximols</topic><topic>Network analysis</topic><topic>p53 Protein</topic><topic>Patients</topic><topic>Peripheral blood mononuclear cells</topic><topic>Sativex</topic><topic>Spasticity</topic><topic>transcriptomics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sorosina, M.</creatorcontrib><creatorcontrib>Clarelli, F.</creatorcontrib><creatorcontrib>Ferrè, L.</creatorcontrib><creatorcontrib>Osiceanu, A. M.</creatorcontrib><creatorcontrib>Unal, N. T.</creatorcontrib><creatorcontrib>Mascia, E.</creatorcontrib><creatorcontrib>Martinelli, V.</creatorcontrib><creatorcontrib>Comi, G.</creatorcontrib><creatorcontrib>Benigni, F.</creatorcontrib><creatorcontrib>Esposito, F.</creatorcontrib><creatorcontrib>Martinelli Boneschi, F.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sorosina, M.</au><au>Clarelli, F.</au><au>Ferrè, L.</au><au>Osiceanu, A. M.</au><au>Unal, N. T.</au><au>Mascia, E.</au><au>Martinelli, V.</au><au>Comi, G.</au><au>Benigni, F.</au><au>Esposito, F.</au><au>Martinelli Boneschi, F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Clinical response to Nabiximols correlates with the downregulation of immune pathways in multiple sclerosis</atitle><jtitle>European journal of neurology</jtitle><addtitle>Eur J Neurol</addtitle><date>2018-07</date><risdate>2018</risdate><volume>25</volume><issue>7</issue><spage>934</spage><epage>e70</epage><pages>934-e70</pages><issn>1351-5101</issn><eissn>1468-1331</eissn><abstract>Background and purpose
Nabiximols (Sativex®) is a cannabinoid‐based compound used for the treatment of moderate to severe spasticity in multiple sclerosis (MS). The aim of the study was to investigate the effect of the administration of Nabiximols on blood transcriptome profile of patients with MS and to interpret it in the context of pathways and networks.
Methods
Whole‐genome expression profiling was performed in whole blood of 33 subjects with MS at baseline and after 4 weeks of drug treatment. Patients were classified as responders (n = 19) and non‐responders (n = 14). Pathway and network analyses on genes modulated by the drug were performed, followed by in vitro stimulation of peripheral blood mononuclear cells with pro‐inflammatory agents to support the immunomodulatory properties of the drug.
Results
Individual effect size was modest; however, we observed a downregulation of several immune‐related pathways after 4 weeks of treatment, which was more pronounced when restricting analyses to responders. Interesting hub molecules functionally related to the immune system emerged from network analysis, including NFKB1, FYN, MAP14 and TP53. The immunomodulatory properties of the drug were confirmed through in vitro assays in peripheral blood mononuclear cells collected from patients with MS.
Conclusions
Our findings support the immunomodulatory activity of cannabinoids in patients with MS. Further studies in more specific cell types are needed to refine these results.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>29528549</pmid><doi>10.1111/ene.13623</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-4376-2550</orcidid><orcidid>https://orcid.org/0000-0003-2550-0805</orcidid></addata></record> |
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| language | eng |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Adult Blood Cannabidiol - pharmacology Cannabidiol - therapeutic use Cannabinoids Down-Regulation Dronabinol - pharmacology Dronabinol - therapeutic use Drug Combinations Female Fyn protein Gene expression Genomes Humans Immune system Immunomodulation Inflammation Interferon Leukocytes (mononuclear) Leukocytes, Mononuclear - drug effects Leukocytes, Mononuclear - immunology Male Middle Aged Molecular chains Multiple sclerosis Multiple Sclerosis - drug therapy Multiple Sclerosis - immunology Nabiximols Network analysis p53 Protein Patients Peripheral blood mononuclear cells Sativex Spasticity transcriptomics |
| title | Clinical response to Nabiximols correlates with the downregulation of immune pathways in multiple sclerosis |
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