L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors

Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a welltolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic gluta...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2013-03, Vol.110 (12), p.4804-4809
Hauptverfasser: Nasca, Carla, Xenos, Dionysios, Barone, Ylenia, Caruso, Alessandra, Scaccianoce, Sergio, Matrisciano, Francesco, Battaglia, Giuseppe, Mathé, Aleksander A., Pittaluga, Anna, Lionetto, Luana, Simmaco, Maurizio, Nicoletti, Ferdinando
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 4809
container_issue 12
container_start_page 4804
container_title Proceedings of the National Academy of Sciences - PNAS
container_volume 110
creator Nasca, Carla
Xenos, Dionysios
Barone, Ylenia
Caruso, Alessandra
Scaccianoce, Sergio
Matrisciano, Francesco
Battaglia, Giuseppe
Mathé, Aleksander A.
Pittaluga, Anna
Lionetto, Luana
Simmaco, Maurizio
Nicoletti, Ferdinando
description Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a welltolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-KB-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. Moreover, there was no tolerance to the action of LAC, and the antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-κB inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.
doi_str_mv 10.1073/pnas.1216100110
format Article
fullrecord <record><control><sourceid>jstor_pnas_</sourceid><recordid>TN_cdi_pnas_primary_110_12_4804</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><jstor_id>42583349</jstor_id><sourcerecordid>42583349</sourcerecordid><originalsourceid>FETCH-LOGICAL-c621t-4f1ce778465d39dcef1888a5084e5db5dc4d2a9cdd6e60bdb59c3fa5147330ae3</originalsourceid><addsrcrecordid>eNp1kk1vEzEQhi0EoiFw5gRY4rzt-GvXe0FCFRSkSlzgbDn2bOKQeBfbC-q_x1HSlB44zWj8vK_HniHkNYNLBp24mqLNl4yzlgEwBk_IgkHPmlb28JQsAHjXaMnlBXmR8xYAeqXhObngQmjOFSxIuG2sw3K3czbFUEJE6uycMdNkp-CpjSV4nBLmXFOKw4CuZFo2aZzXmxqR4hTWGLEER0P0sythjHQc6P5mN3Oa0OFUxpRfkmeD3WV8dYpL8uPzp-_XX5rbbzdfrz_eNq7lrDRyYA67TstWedF7hwPTWlsFWqLyK-Wd9Nz2zvsWW1jVSu_EYBWTnRBgUSxJc_TNf3CaV2ZKYW_TnRltMKfSz5qhUaJ-W1f5_r_8lEb_ILoXMt4qzTqAqv1w1FZgj7XZWJLdPbZ4dBLDxqzH30a00EHLqsH7k0Eaf82Yi9mOc4r1fwwT9eFK9fVZS3J1pFwac044nG9gYA57YA57YB72oCre_tvYmb8ffAXenYCD8mx38ONGapCVeHMktrmO74xIrrQQshd_AXXjxzg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1318855973</pqid></control><display><type>article</type><title>L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors</title><source>MEDLINE</source><source>SWEPUB Freely available online</source><source>JSTOR Archive Collection A-Z Listing</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><creator>Nasca, Carla ; Xenos, Dionysios ; Barone, Ylenia ; Caruso, Alessandra ; Scaccianoce, Sergio ; Matrisciano, Francesco ; Battaglia, Giuseppe ; Mathé, Aleksander A. ; Pittaluga, Anna ; Lionetto, Luana ; Simmaco, Maurizio ; Nicoletti, Ferdinando</creator><creatorcontrib>Nasca, Carla ; Xenos, Dionysios ; Barone, Ylenia ; Caruso, Alessandra ; Scaccianoce, Sergio ; Matrisciano, Francesco ; Battaglia, Giuseppe ; Mathé, Aleksander A. ; Pittaluga, Anna ; Lionetto, Luana ; Simmaco, Maurizio ; Nicoletti, Ferdinando</creatorcontrib><description>Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a welltolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-KB-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. Moreover, there was no tolerance to the action of LAC, and the antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-κB inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.</description><identifier>ISSN: 0027-8424</identifier><identifier>ISSN: 1091-6490</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1216100110</identifier><identifier>PMID: 23382250</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Acetylation ; Acetylation - drug effects ; Acetylcarnitine - pharmacology ; Amino Acids ; Animals ; Antidepressants ; Antidepressive Agents - pharmacology ; Biological Sciences ; Clomipramine - pharmacology ; Depressive disorders ; Epigenesis, Genetic - drug effects ; Epigenetics ; Excitatory Amino Acid Antagonists - pharmacology ; Farmakologi och toxikologi ; Gene expression ; Genetic variation ; Hippocampus ; Hippocampus - metabolism ; Hippocampus - pathology ; Histone Deacetylases - genetics ; Histone Deacetylases - metabolism ; Histones ; Histones - genetics ; Histones - metabolism ; Humans ; Klinisk medicin ; Major depressive disorder ; Male ; Medicin och hälsovetenskap ; Medicinska och farmaceutiska grundvetenskaper ; Mice ; Mice, Knockout ; Nerve Tissue Proteins - biosynthesis ; Nerve Tissue Proteins - genetics ; Neurologi ; NF-kappa B - genetics ; NF-kappa B - metabolism ; Nootropic Agents - pharmacology ; Prefrontal cortex ; Prefrontal Cortex - metabolism ; Prefrontal Cortex - pathology ; Rats ; Receptors ; Receptors, Metabotropic Glutamate - biosynthesis ; Receptors, Metabotropic Glutamate - genetics ; Rodents ; Serotonin Uptake Inhibitors - pharmacology ; Stress, Psychological - drug therapy ; Stress, Psychological - metabolism ; Stress, Psychological - pathology ; T cell receptors ; Time Factors ; Xanthenes</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2013-03, Vol.110 (12), p.4804-4809</ispartof><rights>copyright © 1993-2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Mar 19, 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c621t-4f1ce778465d39dcef1888a5084e5db5dc4d2a9cdd6e60bdb59c3fa5147330ae3</citedby><cites>FETCH-LOGICAL-c621t-4f1ce778465d39dcef1888a5084e5db5dc4d2a9cdd6e60bdb59c3fa5147330ae3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/110/12.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/42583349$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/42583349$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,552,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23382250$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:126581700$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Nasca, Carla</creatorcontrib><creatorcontrib>Xenos, Dionysios</creatorcontrib><creatorcontrib>Barone, Ylenia</creatorcontrib><creatorcontrib>Caruso, Alessandra</creatorcontrib><creatorcontrib>Scaccianoce, Sergio</creatorcontrib><creatorcontrib>Matrisciano, Francesco</creatorcontrib><creatorcontrib>Battaglia, Giuseppe</creatorcontrib><creatorcontrib>Mathé, Aleksander A.</creatorcontrib><creatorcontrib>Pittaluga, Anna</creatorcontrib><creatorcontrib>Lionetto, Luana</creatorcontrib><creatorcontrib>Simmaco, Maurizio</creatorcontrib><creatorcontrib>Nicoletti, Ferdinando</creatorcontrib><title>L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a welltolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-KB-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. Moreover, there was no tolerance to the action of LAC, and the antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-κB inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.</description><subject>Acetylation</subject><subject>Acetylation - drug effects</subject><subject>Acetylcarnitine - pharmacology</subject><subject>Amino Acids</subject><subject>Animals</subject><subject>Antidepressants</subject><subject>Antidepressive Agents - pharmacology</subject><subject>Biological Sciences</subject><subject>Clomipramine - pharmacology</subject><subject>Depressive disorders</subject><subject>Epigenesis, Genetic - drug effects</subject><subject>Epigenetics</subject><subject>Excitatory Amino Acid Antagonists - pharmacology</subject><subject>Farmakologi och toxikologi</subject><subject>Gene expression</subject><subject>Genetic variation</subject><subject>Hippocampus</subject><subject>Hippocampus - metabolism</subject><subject>Hippocampus - pathology</subject><subject>Histone Deacetylases - genetics</subject><subject>Histone Deacetylases - metabolism</subject><subject>Histones</subject><subject>Histones - genetics</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Klinisk medicin</subject><subject>Major depressive disorder</subject><subject>Male</subject><subject>Medicin och hälsovetenskap</subject><subject>Medicinska och farmaceutiska grundvetenskaper</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Nerve Tissue Proteins - biosynthesis</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Neurologi</subject><subject>NF-kappa B - genetics</subject><subject>NF-kappa B - metabolism</subject><subject>Nootropic Agents - pharmacology</subject><subject>Prefrontal cortex</subject><subject>Prefrontal Cortex - metabolism</subject><subject>Prefrontal Cortex - pathology</subject><subject>Rats</subject><subject>Receptors</subject><subject>Receptors, Metabotropic Glutamate - biosynthesis</subject><subject>Receptors, Metabotropic Glutamate - genetics</subject><subject>Rodents</subject><subject>Serotonin Uptake Inhibitors - pharmacology</subject><subject>Stress, Psychological - drug therapy</subject><subject>Stress, Psychological - metabolism</subject><subject>Stress, Psychological - pathology</subject><subject>T cell receptors</subject><subject>Time Factors</subject><subject>Xanthenes</subject><issn>0027-8424</issn><issn>1091-6490</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>D8T</sourceid><recordid>eNp1kk1vEzEQhi0EoiFw5gRY4rzt-GvXe0FCFRSkSlzgbDn2bOKQeBfbC-q_x1HSlB44zWj8vK_HniHkNYNLBp24mqLNl4yzlgEwBk_IgkHPmlb28JQsAHjXaMnlBXmR8xYAeqXhObngQmjOFSxIuG2sw3K3czbFUEJE6uycMdNkp-CpjSV4nBLmXFOKw4CuZFo2aZzXmxqR4hTWGLEER0P0sythjHQc6P5mN3Oa0OFUxpRfkmeD3WV8dYpL8uPzp-_XX5rbbzdfrz_eNq7lrDRyYA67TstWedF7hwPTWlsFWqLyK-Wd9Nz2zvsWW1jVSu_EYBWTnRBgUSxJc_TNf3CaV2ZKYW_TnRltMKfSz5qhUaJ-W1f5_r_8lEb_ILoXMt4qzTqAqv1w1FZgj7XZWJLdPbZ4dBLDxqzH30a00EHLqsH7k0Eaf82Yi9mOc4r1fwwT9eFK9fVZS3J1pFwac044nG9gYA57YA57YB72oCre_tvYmb8ffAXenYCD8mx38ONGapCVeHMktrmO74xIrrQQshd_AXXjxzg</recordid><startdate>20130319</startdate><enddate>20130319</enddate><creator>Nasca, Carla</creator><creator>Xenos, Dionysios</creator><creator>Barone, Ylenia</creator><creator>Caruso, Alessandra</creator><creator>Scaccianoce, Sergio</creator><creator>Matrisciano, Francesco</creator><creator>Battaglia, Giuseppe</creator><creator>Mathé, Aleksander A.</creator><creator>Pittaluga, Anna</creator><creator>Lionetto, Luana</creator><creator>Simmaco, Maurizio</creator><creator>Nicoletti, Ferdinando</creator><general>National Academy of Sciences</general><general>National Acad Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope></search><sort><creationdate>20130319</creationdate><title>L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors</title><author>Nasca, Carla ; Xenos, Dionysios ; Barone, Ylenia ; Caruso, Alessandra ; Scaccianoce, Sergio ; Matrisciano, Francesco ; Battaglia, Giuseppe ; Mathé, Aleksander A. ; Pittaluga, Anna ; Lionetto, Luana ; Simmaco, Maurizio ; Nicoletti, Ferdinando</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c621t-4f1ce778465d39dcef1888a5084e5db5dc4d2a9cdd6e60bdb59c3fa5147330ae3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Acetylation</topic><topic>Acetylation - drug effects</topic><topic>Acetylcarnitine - pharmacology</topic><topic>Amino Acids</topic><topic>Animals</topic><topic>Antidepressants</topic><topic>Antidepressive Agents - pharmacology</topic><topic>Biological Sciences</topic><topic>Clomipramine - pharmacology</topic><topic>Depressive disorders</topic><topic>Epigenesis, Genetic - drug effects</topic><topic>Epigenetics</topic><topic>Excitatory Amino Acid Antagonists - pharmacology</topic><topic>Farmakologi och toxikologi</topic><topic>Gene expression</topic><topic>Genetic variation</topic><topic>Hippocampus</topic><topic>Hippocampus - metabolism</topic><topic>Hippocampus - pathology</topic><topic>Histone Deacetylases - genetics</topic><topic>Histone Deacetylases - metabolism</topic><topic>Histones</topic><topic>Histones - genetics</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>Klinisk medicin</topic><topic>Major depressive disorder</topic><topic>Male</topic><topic>Medicin och hälsovetenskap</topic><topic>Medicinska och farmaceutiska grundvetenskaper</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Nerve Tissue Proteins - biosynthesis</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Neurologi</topic><topic>NF-kappa B - genetics</topic><topic>NF-kappa B - metabolism</topic><topic>Nootropic Agents - pharmacology</topic><topic>Prefrontal cortex</topic><topic>Prefrontal Cortex - metabolism</topic><topic>Prefrontal Cortex - pathology</topic><topic>Rats</topic><topic>Receptors</topic><topic>Receptors, Metabotropic Glutamate - biosynthesis</topic><topic>Receptors, Metabotropic Glutamate - genetics</topic><topic>Rodents</topic><topic>Serotonin Uptake Inhibitors - pharmacology</topic><topic>Stress, Psychological - drug therapy</topic><topic>Stress, Psychological - metabolism</topic><topic>Stress, Psychological - pathology</topic><topic>T cell receptors</topic><topic>Time Factors</topic><topic>Xanthenes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nasca, Carla</creatorcontrib><creatorcontrib>Xenos, Dionysios</creatorcontrib><creatorcontrib>Barone, Ylenia</creatorcontrib><creatorcontrib>Caruso, Alessandra</creatorcontrib><creatorcontrib>Scaccianoce, Sergio</creatorcontrib><creatorcontrib>Matrisciano, Francesco</creatorcontrib><creatorcontrib>Battaglia, Giuseppe</creatorcontrib><creatorcontrib>Mathé, Aleksander A.</creatorcontrib><creatorcontrib>Pittaluga, Anna</creatorcontrib><creatorcontrib>Lionetto, Luana</creatorcontrib><creatorcontrib>Simmaco, Maurizio</creatorcontrib><creatorcontrib>Nicoletti, Ferdinando</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nasca, Carla</au><au>Xenos, Dionysios</au><au>Barone, Ylenia</au><au>Caruso, Alessandra</au><au>Scaccianoce, Sergio</au><au>Matrisciano, Francesco</au><au>Battaglia, Giuseppe</au><au>Mathé, Aleksander A.</au><au>Pittaluga, Anna</au><au>Lionetto, Luana</au><au>Simmaco, Maurizio</au><au>Nicoletti, Ferdinando</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2013-03-19</date><risdate>2013</risdate><volume>110</volume><issue>12</issue><spage>4804</spage><epage>4809</epage><pages>4804-4809</pages><issn>0027-8424</issn><issn>1091-6490</issn><eissn>1091-6490</eissn><abstract>Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a welltolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-KB-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. Moreover, there was no tolerance to the action of LAC, and the antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-κB inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>23382250</pmid><doi>10.1073/pnas.1216100110</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0027-8424
ispartof Proceedings of the National Academy of Sciences - PNAS, 2013-03, Vol.110 (12), p.4804-4809
issn 0027-8424
1091-6490
1091-6490
language eng
recordid cdi_pnas_primary_110_12_4804
source MEDLINE; SWEPUB Freely available online; JSTOR Archive Collection A-Z Listing; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry
subjects Acetylation
Acetylation - drug effects
Acetylcarnitine - pharmacology
Amino Acids
Animals
Antidepressants
Antidepressive Agents - pharmacology
Biological Sciences
Clomipramine - pharmacology
Depressive disorders
Epigenesis, Genetic - drug effects
Epigenetics
Excitatory Amino Acid Antagonists - pharmacology
Farmakologi och toxikologi
Gene expression
Genetic variation
Hippocampus
Hippocampus - metabolism
Hippocampus - pathology
Histone Deacetylases - genetics
Histone Deacetylases - metabolism
Histones
Histones - genetics
Histones - metabolism
Humans
Klinisk medicin
Major depressive disorder
Male
Medicin och hälsovetenskap
Medicinska och farmaceutiska grundvetenskaper
Mice
Mice, Knockout
Nerve Tissue Proteins - biosynthesis
Nerve Tissue Proteins - genetics
Neurologi
NF-kappa B - genetics
NF-kappa B - metabolism
Nootropic Agents - pharmacology
Prefrontal cortex
Prefrontal Cortex - metabolism
Prefrontal Cortex - pathology
Rats
Receptors
Receptors, Metabotropic Glutamate - biosynthesis
Receptors, Metabotropic Glutamate - genetics
Rodents
Serotonin Uptake Inhibitors - pharmacology
Stress, Psychological - drug therapy
Stress, Psychological - metabolism
Stress, Psychological - pathology
T cell receptors
Time Factors
Xanthenes
title L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T18%3A19%3A04IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_pnas_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=L-acetylcarnitine%20causes%20rapid%20antidepressant%20effects%20through%20the%20epigenetic%20induction%20of%20mGlu2%20receptors&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Nasca,%20Carla&rft.date=2013-03-19&rft.volume=110&rft.issue=12&rft.spage=4804&rft.epage=4809&rft.pages=4804-4809&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.1216100110&rft_dat=%3Cjstor_pnas_%3E42583349%3C/jstor_pnas_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1318855973&rft_id=info:pmid/23382250&rft_jstor_id=42583349&rfr_iscdi=true