Inhibition of the High Affinity Myo-Inositol Transport System: A Common Mechanism of Action of Antibipolar Drugs?
The mechanism of action of antibipolar drugs like lithium, carbamazepine, and valproate that are used in the treatment of manic-depressive illness, is unknown. Lithium is believed to act through uncompetitive inhibition of inositolmonophosphatase, which results in a depletion of neural cells of inos...
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| Veröffentlicht in: | Neuropsychopharmacology (New York, N.Y.) N.Y.), 1999-10, Vol.21 (4), p.519-529 |
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| creator | Lubrich, Beate van Calker, Dietrich |
| description | The mechanism of action of antibipolar drugs like lithium, carbamazepine, and valproate that are used in the treatment of manic-depressive illness, is unknown. Lithium is believed to act through uncompetitive inhibition of inositolmonophosphatase, which results in a depletion of neural cells of inositol and a concomitant modulation of phosphoinositol signaling. Here, we show that lithium ions, carbamazepine, and valproate, but not the tricyclic antidepressant amitriptyline, inhibit at therapeutically relevant concentrations and with a time course similar to their clinical actions the high affinity myo-inositol transport in astrocyte-like cells and downregulate the level of the respective mRNA. Inhibition of inositol uptake could thus represent an additional pathway for inositol depletion, which might be relevant in the mechanism of action of all three antibipolar drugs. |
| doi_str_mv | 10.1016/S0893-133X(99)00037-8 |
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Lithium is believed to act through uncompetitive inhibition of inositolmonophosphatase, which results in a depletion of neural cells of inositol and a concomitant modulation of phosphoinositol signaling. Here, we show that lithium ions, carbamazepine, and valproate, but not the tricyclic antidepressant amitriptyline, inhibit at therapeutically relevant concentrations and with a time course similar to their clinical actions the high affinity myo-inositol transport in astrocyte-like cells and downregulate the level of the respective mRNA. Inhibition of inositol uptake could thus represent an additional pathway for inositol depletion, which might be relevant in the mechanism of action of all three antibipolar drugs.</description><identifier>ISSN: 0893-133X</identifier><identifier>EISSN: 1740-634X</identifier><identifier>DOI: 10.1016/S0893-133X(99)00037-8</identifier><identifier>PMID: 10481836</identifier><identifier>CODEN: NEROEW</identifier><language>eng</language><publisher>New York, NY: Elsevier Inc</publisher><subject>Adrenergic Uptake Inhibitors - pharmacology ; Affective disorders ; Amitriptyline - pharmacology ; Animals ; Antimanic Agents - pharmacology ; Astrocytes - drug effects ; Astrocytes - metabolism ; Biological and medical sciences ; Biological Transport - drug effects ; Brain - cytology ; Brain - drug effects ; Carbamazepine - pharmacology ; Carrier Proteins - drug effects ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Heat-Shock Proteins - drug effects ; Heat-Shock Proteins - genetics ; Heat-Shock Proteins - metabolism ; Humans ; Inositol - metabolism ; Lithium - pharmacology ; Medical sciences ; Membrane Proteins ; Mood stabilizer ; Neuropharmacology ; Pharmacology. Drug treatments ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) ; Psychology. Psychoanalysis. 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Lithium is believed to act through uncompetitive inhibition of inositolmonophosphatase, which results in a depletion of neural cells of inositol and a concomitant modulation of phosphoinositol signaling. Here, we show that lithium ions, carbamazepine, and valproate, but not the tricyclic antidepressant amitriptyline, inhibit at therapeutically relevant concentrations and with a time course similar to their clinical actions the high affinity myo-inositol transport in astrocyte-like cells and downregulate the level of the respective mRNA. Inhibition of inositol uptake could thus represent an additional pathway for inositol depletion, which might be relevant in the mechanism of action of all three antibipolar drugs.</description><subject>Adrenergic Uptake Inhibitors - pharmacology</subject><subject>Affective disorders</subject><subject>Amitriptyline - pharmacology</subject><subject>Animals</subject><subject>Antimanic Agents - pharmacology</subject><subject>Astrocytes - drug effects</subject><subject>Astrocytes - metabolism</subject><subject>Biological and medical sciences</subject><subject>Biological Transport - drug effects</subject><subject>Brain - cytology</subject><subject>Brain - drug effects</subject><subject>Carbamazepine - pharmacology</subject><subject>Carrier Proteins - drug effects</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Heat-Shock Proteins - drug effects</subject><subject>Heat-Shock Proteins - genetics</subject><subject>Heat-Shock Proteins - metabolism</subject><subject>Humans</subject><subject>Inositol - metabolism</subject><subject>Lithium - pharmacology</subject><subject>Medical sciences</subject><subject>Membrane Proteins</subject><subject>Mood stabilizer</subject><subject>Neuropharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopharmacology</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>RNA, Messenger - drug effects</subject><subject>RNA, Messenger - metabolism</subject><subject>SMIT</subject><subject>Symporters</subject><subject>Time Factors</subject><subject>Tumor Cells, Cultured</subject><subject>Valproic Acid - pharmacology</subject><issn>0893-133X</issn><issn>1740-634X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkEFP2zAYhq1p0yhsP4HJh2naDoHPsZPYu6CosFEJtANM4mY5jk09JXax3Un996S0wG47-fK8z2c9CB0TOCFA6tMb4IIWhNK7r0J8AwDaFPwNmpGGQVFTdvcWzV6QA3SY0h8AUjU1f48OCDBOOK1n6GHhl65z2QWPg8V5afClu1_i1lrnXd7g600oFj4kl8OAb6PyaRVixjeblM34Hbd4HsZxGl8bvVTepXGrafWzsPV50q_CoCI-j-v7dPYBvbNqSObj_j1Cv39c3M4vi6tfPxfz9qrQFS1zoUjV2Up3NeOq1A1vOmJBqBIY67U2JShrwfQdJUIoMaFEga543aialp0W9Ah92XlXMTysTcpydEmbYVDehHWSDUDZMEYmsNqBOoaUorFyFd2o4kYSkNvW8qm13IaUQsin1pJPu0_7A-tuNP0_q13cCfi8B1TSarBTPO3SKycYq-nWc7bDzFTjrzNRJu2M16Z30egs--D-85NHfF6cfA</recordid><startdate>19991001</startdate><enddate>19991001</enddate><creator>Lubrich, Beate</creator><creator>van Calker, Dietrich</creator><general>Elsevier Inc</general><general>Nature Publishing</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></search><sort><creationdate>19991001</creationdate><title>Inhibition of the High Affinity Myo-Inositol Transport System: A Common Mechanism of Action of Antibipolar Drugs?</title><author>Lubrich, Beate ; van Calker, Dietrich</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c532t-a15bf5cb648a2c787b1f09a2044dcce20aff0edb3199a9bf51a0c5867a632bc93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Adrenergic Uptake Inhibitors - pharmacology</topic><topic>Affective disorders</topic><topic>Amitriptyline - pharmacology</topic><topic>Animals</topic><topic>Antimanic Agents - pharmacology</topic><topic>Astrocytes - drug effects</topic><topic>Astrocytes - metabolism</topic><topic>Biological and medical sciences</topic><topic>Biological Transport - drug effects</topic><topic>Brain - cytology</topic><topic>Brain - drug effects</topic><topic>Carbamazepine - pharmacology</topic><topic>Carrier Proteins - drug effects</topic><topic>Carrier Proteins - genetics</topic><topic>Carrier Proteins - metabolism</topic><topic>Heat-Shock Proteins - drug effects</topic><topic>Heat-Shock Proteins - genetics</topic><topic>Heat-Shock Proteins - metabolism</topic><topic>Humans</topic><topic>Inositol - metabolism</topic><topic>Lithium - pharmacology</topic><topic>Medical sciences</topic><topic>Membrane Proteins</topic><topic>Mood stabilizer</topic><topic>Neuropharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</topic><topic>Psychology. Psychoanalysis. Psychiatry</topic><topic>Psychopharmacology</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>RNA, Messenger - drug effects</topic><topic>RNA, Messenger - metabolism</topic><topic>SMIT</topic><topic>Symporters</topic><topic>Time Factors</topic><topic>Tumor Cells, Cultured</topic><topic>Valproic Acid - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lubrich, Beate</creatorcontrib><creatorcontrib>van Calker, Dietrich</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><jtitle>Neuropsychopharmacology (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lubrich, Beate</au><au>van Calker, Dietrich</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of the High Affinity Myo-Inositol Transport System: A Common Mechanism of Action of Antibipolar Drugs?</atitle><jtitle>Neuropsychopharmacology (New York, N.Y.)</jtitle><addtitle>Neuropsychopharmacology</addtitle><date>1999-10-01</date><risdate>1999</risdate><volume>21</volume><issue>4</issue><spage>519</spage><epage>529</epage><pages>519-529</pages><issn>0893-133X</issn><eissn>1740-634X</eissn><coden>NEROEW</coden><abstract>The mechanism of action of antibipolar drugs like lithium, carbamazepine, and valproate that are used in the treatment of manic-depressive illness, is unknown. Lithium is believed to act through uncompetitive inhibition of inositolmonophosphatase, which results in a depletion of neural cells of inositol and a concomitant modulation of phosphoinositol signaling. Here, we show that lithium ions, carbamazepine, and valproate, but not the tricyclic antidepressant amitriptyline, inhibit at therapeutically relevant concentrations and with a time course similar to their clinical actions the high affinity myo-inositol transport in astrocyte-like cells and downregulate the level of the respective mRNA. Inhibition of inositol uptake could thus represent an additional pathway for inositol depletion, which might be relevant in the mechanism of action of all three antibipolar drugs.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>10481836</pmid><doi>10.1016/S0893-133X(99)00037-8</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adrenergic Uptake Inhibitors - pharmacology Affective disorders Amitriptyline - pharmacology Animals Antimanic Agents - pharmacology Astrocytes - drug effects Astrocytes - metabolism Biological and medical sciences Biological Transport - drug effects Brain - cytology Brain - drug effects Carbamazepine - pharmacology Carrier Proteins - drug effects Carrier Proteins - genetics Carrier Proteins - metabolism Heat-Shock Proteins - drug effects Heat-Shock Proteins - genetics Heat-Shock Proteins - metabolism Humans Inositol - metabolism Lithium - pharmacology Medical sciences Membrane Proteins Mood stabilizer Neuropharmacology Pharmacology. Drug treatments Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Rats Rats, Wistar RNA, Messenger - drug effects RNA, Messenger - metabolism SMIT Symporters Time Factors Tumor Cells, Cultured Valproic Acid - pharmacology |
| title | Inhibition of the High Affinity Myo-Inositol Transport System: A Common Mechanism of Action of Antibipolar Drugs? |
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