Co-administration of adenosine kinase and deaminase inhibitors produces supra-additive potentiation of N -methyl-d-aspartate-evoked adenosine formation in cortex
Identifieur interne : 000A51 ( Istex/Corpus ); précédent : 000A50; suivant : 000A52Co-administration of adenosine kinase and deaminase inhibitors produces supra-additive potentiation of N -methyl-d-aspartate-evoked adenosine formation in cortex
Auteurs : Matthew O. Hebb ; Thomas D. WhiteSource :
- European Journal of Pharmacology [ 0014-2999 ] ; 1998.
Abstract
Activation of glutamate receptors triggers the release of adenosine, which exerts important inhibitory actions in the brain. Evoked adenosine release is potentiated when either adenosine kinase or adenosine deaminase are inhibited. We studied the effects of concurrent inhibition of adenosine kinase and adenosine deaminase on N-methyl-d-aspartate (NMDA)-evoked formation of extracellular adenosine in slices of rat parietal cortex, to determine if combinations of inhibitors of adenosine kinase and adenosine deaminase can produce supra-additive potentiation of this adenosine formation. Combinations of low concentrations of the adenosine kinase inhibitors 5′-amino-5′-deoxyadenosine (0.2 μM) or 5′-iodotubercidin (0.01 μM) with a low concentration of the adenosine deaminase inhibitor 2′-deoxycoformycin (0.2 μM) produced additive potentiations of NMDA-evoked adenosine release from slices of rat parietal cortex. However, combinations of low concentrations of 5′-amino-5′-deoxyadenosine (0.2 μM) or 5′-iodotubercidin (0.01 μM) with a maximal concentration of 2′-deoxycoformycin (200 μM) produced supra-additive potentiation of NMDA-evoked adenosine release. These findings suggest that such combinations of adenosine kinase inhibitors with adenosine deaminase inhibitors may provide useful strategies for developing therapies to treat disorders associated with excessive NMDA receptor activation, such as seizures, ischemic damage and neurodegenerative diseases.
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DOI: 10.1016/S0014-2999(97)01582-3
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>Co-administration of adenosine kinase and deaminase inhibitors produces supra-additive potentiation of N -methyl-d-aspartate-evoked adenosine formation in cortex</title><author><name sortKey="Hebb, Matthew O" sort="Hebb, Matthew O" uniqKey="Hebb M" first="Matthew O" last="Hebb">Matthew O. Hebb</name><affiliation><mods:affiliation>Department of Pharmacology, Dalhousie University, Halifax, NS, Canada B3H 4H7</mods:affiliation></affiliation></author><author><name sortKey="White, Thomas D" sort="White, Thomas D" uniqKey="White T" first="Thomas D" last="White">Thomas D. White</name><affiliation><mods:affiliation>Department of Pharmacology, Dalhousie University, Halifax, NS, Canada B3H 4H7</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:28B92C05BC1BD4A63B6E53626695D088AAFB178D</idno><date when="1998" year="1998">1998</date><idno type="doi">10.1016/S0014-2999(97)01582-3</idno><idno type="url">https://api-v5.istex.fr/document/28B92C05BC1BD4A63B6E53626695D088AAFB178D/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000A51</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">000A51</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Co-administration of adenosine kinase and deaminase inhibitors produces supra-additive potentiation of N -methyl-d-aspartate-evoked adenosine formation in cortex</title><author><name sortKey="Hebb, Matthew O" sort="Hebb, Matthew O" uniqKey="Hebb M" first="Matthew O" last="Hebb">Matthew O. Hebb</name><affiliation><mods:affiliation>Department of Pharmacology, Dalhousie University, Halifax, NS, Canada B3H 4H7</mods:affiliation></affiliation></author><author><name sortKey="White, Thomas D" sort="White, Thomas D" uniqKey="White T" first="Thomas D" last="White">Thomas D. White</name><affiliation><mods:affiliation>Department of Pharmacology, Dalhousie University, Halifax, NS, Canada B3H 4H7</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">European Journal of Pharmacology</title><title level="j" type="abbrev">EJP</title><idno type="ISSN">0014-2999</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1998">1998</date><biblScope unit="volume">344</biblScope><biblScope unit="issue">2–3</biblScope><biblScope unit="page" from="121">121</biblScope><biblScope unit="page" to="125">125</biblScope></imprint><idno type="ISSN">0014-2999</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0014-2999</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Activation of glutamate receptors triggers the release of adenosine, which exerts important inhibitory actions in the brain. Evoked adenosine release is potentiated when either adenosine kinase or adenosine deaminase are inhibited. We studied the effects of concurrent inhibition of adenosine kinase and adenosine deaminase on N-methyl-d-aspartate (NMDA)-evoked formation of extracellular adenosine in slices of rat parietal cortex, to determine if combinations of inhibitors of adenosine kinase and adenosine deaminase can produce supra-additive potentiation of this adenosine formation. Combinations of low concentrations of the adenosine kinase inhibitors 5′-amino-5′-deoxyadenosine (0.2 μM) or 5′-iodotubercidin (0.01 μM) with a low concentration of the adenosine deaminase inhibitor 2′-deoxycoformycin (0.2 μM) produced additive potentiations of NMDA-evoked adenosine release from slices of rat parietal cortex. However, combinations of low concentrations of 5′-amino-5′-deoxyadenosine (0.2 μM) or 5′-iodotubercidin (0.01 μM) with a maximal concentration of 2′-deoxycoformycin (200 μM) produced supra-additive potentiation of NMDA-evoked adenosine release. These findings suggest that such combinations of adenosine kinase inhibitors with adenosine deaminase inhibitors may provide useful strategies for developing therapies to treat disorders associated with excessive NMDA receptor activation, such as seizures, ischemic damage and neurodegenerative diseases.</div></front></TEI><istex><corpusName>elsevier</corpusName><author><json:item><name>Matthew O Hebb</name><affiliations><json:string>Department of Pharmacology, Dalhousie University, Halifax, NS, Canada B3H 4H7</json:string></affiliations></json:item><json:item><name>Thomas D White</name><affiliations><json:string>Department of Pharmacology, Dalhousie University, Halifax, NS, Canada B3H 4H7</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>2′-Deoxycoformycin</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>5′-Amino-5′-deoxyadenosine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>5′-Iodotubercidin</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Adenosine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>NMDA (N-methyl-d-aspartate)</value></json:item></subject><language><json:string>eng</json:string></language><originalGenre><json:string>Full-length article</json:string></originalGenre><abstract>Activation of glutamate receptors triggers the release of adenosine, which exerts important inhibitory actions in the brain. Evoked adenosine release is potentiated when either adenosine kinase or adenosine deaminase are inhibited. We studied the effects of concurrent inhibition of adenosine kinase and adenosine deaminase on N-methyl-d-aspartate (NMDA)-evoked formation of extracellular adenosine in slices of rat parietal cortex, to determine if combinations of inhibitors of adenosine kinase and adenosine deaminase can produce supra-additive potentiation of this adenosine formation. Combinations of low concentrations of the adenosine kinase inhibitors 5′-amino-5′-deoxyadenosine (0.2 μM) or 5′-iodotubercidin (0.01 μM) with a low concentration of the adenosine deaminase inhibitor 2′-deoxycoformycin (0.2 μM) produced additive potentiations of NMDA-evoked adenosine release from slices of rat parietal cortex. However, combinations of low concentrations of 5′-amino-5′-deoxyadenosine (0.2 μM) or 5′-iodotubercidin (0.01 μM) with a maximal concentration of 2′-deoxycoformycin (200 μM) produced supra-additive potentiation of NMDA-evoked adenosine release. These findings suggest that such combinations of adenosine kinase inhibitors with adenosine deaminase inhibitors may provide useful strategies for developing therapies to treat disorders associated with excessive NMDA receptor activation, such as seizures, ischemic damage and neurodegenerative diseases.</abstract><qualityIndicators><score>5.26</score><pdfWordCount>3052</pdfWordCount><pdfCharCount>20990</pdfCharCount><pdfVersion>1.2</pdfVersion><pdfPageCount>5</pdfPageCount><pdfPageSize>595 x 738 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractWordCount>184</abstractWordCount><abstractCharCount>1466</abstractCharCount><keywordCount>5</keywordCount></qualityIndicators><title>Co-administration of adenosine kinase and deaminase inhibitors produces supra-additive potentiation of N -methyl-d-aspartate-evoked adenosine formation in cortex</title><pii><json:string>S0014-2999(97)01582-3</json:string></pii><genre><json:string>research-article</json:string></genre><host><title>European Journal of Pharmacology</title><language><json:string>unknown</json:string></language><publicationDate>1998</publicationDate><issn><json:string>0014-2999</json:string></issn><pii><json:string>S0014-2999(00)X0136-7</json:string></pii><volume>344</volume><issue>2–3</issue><pages><first>121</first><last>125</last></pages><genre><json:string>journal</json:string></genre></host><categories><wos><json:string>science</json:string><json:string>pharmacology & pharmacy</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>clinical medicine</json:string><json:string>pharmacology & pharmacy</json:string></scienceMetrix><inist><json:string>sciences appliquees, technologies et medecines</json:string><json:string>sciences biologiques et medicales</json:string><json:string>sciences medicales</json:string><json:string>cardiologie. appareil circulatoire</json:string></inist></categories><publicationDate>1998</publicationDate><copyrightDate>1998</copyrightDate><doi><json:string>10.1016/S0014-2999(97)01582-3</json:string></doi><id>28B92C05BC1BD4A63B6E53626695D088AAFB178D</id><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api-v5.istex.fr/document/28B92C05BC1BD4A63B6E53626695D088AAFB178D/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api-v5.istex.fr/document/28B92C05BC1BD4A63B6E53626695D088AAFB178D/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api-v5.istex.fr/document/28B92C05BC1BD4A63B6E53626695D088AAFB178D/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Co-administration of adenosine kinase and deaminase inhibitors produces supra-additive potentiation of N -methyl-d-aspartate-evoked adenosine formation in cortex</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>ELSEVIER</publisher><availability><p>©1998 Elsevier Science B.V.</p></availability><date>1998</date></publicationStmt><notesStmt><note type="content">Fig. 1: Concentration–response relations for the potentiation of NMDA-evoked adenosine release by adenosine deaminase inhibitors and adenosine kinase inhibitors. Abbreviations: IOT, 5′-iodotubercidin; NH2dADO, 5′-amino-5′-deoxyadenosine; DCF, 2′-deoxycoformycin. The adenosine kinase inhibitors 5′-iodotubercidin and 5′-amino-5′-deoxyadenosine appeared to be more effective than the adenosine deaminase inhibitor 2′-deoxycoformycin in potentiating NMDA-evoked formation of extracellular adenosine. 5′-Iodotubercidin was more potent than 5′-amino-5′-deoxyadenosine in potentiating adenosine formation. Numbers in parentheses indicate the number of experiments.</note><note type="content">Fig. 2: Effects of combinations of 5′-amino-5′-deoxyadenosine with 2′-deoxycoformycin on NMDA-evoked formation of extracellular adenosine. Abbreviations: NH2dADO, 5′-amino-5′-deoxyadenosine; DCF, 2′-deoxycoformycin. The effect of a combination of 0.2 μM 5′-amino-5′-deoxyadenosine with 0.2 μM 2′-deoxycoformycin on NMDA-evoked formation of extracellular adenosine was not statistically different than the effect of 0.2 μM 2′-deoxycoformycin alone (P>0.05). However, the effect of the combination of 0.2 μM 5′-amino-5′-deoxyadenosine with 200 μM 2′-deoxycoformycin on NMDA-evoked adenosine formation was significantly greater than the effect of 200 μM 2′-deoxycoformycin alone (P<0.05). Numbers in parentheses indicate the number of experiments.</note><note type="content">Fig. 3: Effects of combinations of 5′-iodotubercidin with 2′-deoxycoformycin on NMDA-evoked formation of extracellular adenosine. Abbreviations: IOT, 5′-iodotubercidin; DCF, 2′-deoxycoformycin. The effect of a combination of 0.01 μM 5′-iodotubercidin with 0.2 μM 2′-deoxycoformycin on NMDA-evoked formation of extracellular adenosine was not statistically different than the effect of 0.2 μM 2′-deoxycoformycin alone (P>0.05). However, the effect of a combination of 0.01 μM 5′-iodotubercidin with 200 μM 2′-deoxycoformycin was significantly greater than 200 μM 2′-deoxycoformycin alone (P<0.05). Numbers in parentheses indicate the number of experiments.</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Co-administration of adenosine kinase and deaminase inhibitors produces supra-additive potentiation of N -methyl-d-aspartate-evoked adenosine formation in cortex</title><author xml:id="author-0000"><persName><forename type="first">Matthew O</forename><surname>Hebb</surname></persName><affiliation>Department of Pharmacology, Dalhousie University, Halifax, NS, Canada B3H 4H7</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Thomas D</forename><surname>White</surname></persName><note type="correspondence"><p>Corresponding author. Tel.: +1-902-4943462; fax: +1-902-4941388; e-mail: tdwhite@is.dal.ca</p></note><affiliation>Department of Pharmacology, Dalhousie University, Halifax, NS, Canada B3H 4H7</affiliation></author><idno type="istex">28B92C05BC1BD4A63B6E53626695D088AAFB178D</idno><idno type="DOI">10.1016/S0014-2999(97)01582-3</idno><idno type="PII">S0014-2999(97)01582-3</idno></analytic><monogr><title level="j">European Journal of Pharmacology</title><title level="j" type="abbrev">EJP</title><idno type="pISSN">0014-2999</idno><idno type="PII">S0014-2999(00)X0136-7</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1998"></date><biblScope unit="volume">344</biblScope><biblScope unit="issue">2–3</biblScope><biblScope unit="page" from="121">121</biblScope><biblScope unit="page" to="125">125</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1998</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Activation of glutamate receptors triggers the release of adenosine, which exerts important inhibitory actions in the brain. Evoked adenosine release is potentiated when either adenosine kinase or adenosine deaminase are inhibited. We studied the effects of concurrent inhibition of adenosine kinase and adenosine deaminase on N-methyl-d-aspartate (NMDA)-evoked formation of extracellular adenosine in slices of rat parietal cortex, to determine if combinations of inhibitors of adenosine kinase and adenosine deaminase can produce supra-additive potentiation of this adenosine formation. Combinations of low concentrations of the adenosine kinase inhibitors 5′-amino-5′-deoxyadenosine (0.2 μM) or 5′-iodotubercidin (0.01 μM) with a low concentration of the adenosine deaminase inhibitor 2′-deoxycoformycin (0.2 μM) produced additive potentiations of NMDA-evoked adenosine release from slices of rat parietal cortex. However, combinations of low concentrations of 5′-amino-5′-deoxyadenosine (0.2 μM) or 5′-iodotubercidin (0.01 μM) with a maximal concentration of 2′-deoxycoformycin (200 μM) produced supra-additive potentiation of NMDA-evoked adenosine release. These findings suggest that such combinations of adenosine kinase inhibitors with adenosine deaminase inhibitors may provide useful strategies for developing therapies to treat disorders associated with excessive NMDA receptor activation, such as seizures, ischemic damage and neurodegenerative diseases.</p></abstract><textClass><keywords scheme="keyword"><list><head>Keywords</head><item><term>2′-Deoxycoformycin</term></item><item><term>5′-Amino-5′-deoxyadenosine</term></item><item><term>5′-Iodotubercidin</term></item><item><term>Adenosine</term></item><item><term>NMDA (N-methyl-d-aspartate)</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1997-12-01">Modified</change><change when="1998">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api-v5.istex.fr/document/28B92C05BC1BD4A63B6E53626695D088AAFB178D/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier, elements deleted: ce:floats; body; tail"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 4.5.2//EN//XML" URI="art452.dtd" name="istex:docType"><istex:entity SYSTEM="gr1" NDATA="IMAGE" name="gr1"></istex:entity><istex:entity SYSTEM="gr2" NDATA="IMAGE" name="gr2"></istex:entity><istex:entity SYSTEM="gr3" NDATA="IMAGE" name="gr3"></istex:entity></istex:docType><istex:document><converted-article version="4.5.2" docsubtype="fla"><item-info><jid>EJP</jid><aid>56683</aid><ce:pii>S0014-2999(97)01582-3</ce:pii><ce:doi>10.1016/S0014-2999(97)01582-3</ce:doi><ce:copyright year="1998" type="full-transfer">Elsevier Science B.V.</ce:copyright></item-info><head><ce:title>Co-administration of adenosine kinase and deaminase inhibitors produces supra-additive potentiation of <ce:italic>N</ce:italic>-methyl-<ce:small-caps>d</ce:small-caps>-aspartate-evoked adenosine formation in cortex</ce:title><ce:author-group><ce:author><ce:given-name>Matthew O</ce:given-name><ce:surname>Hebb</ce:surname></ce:author><ce:author><ce:given-name>Thomas D</ce:given-name><ce:surname>White</ce:surname><ce:cross-ref refid="CORR1">*</ce:cross-ref></ce:author><ce:affiliation><ce:textfn>Department of Pharmacology, Dalhousie University, Halifax, NS, Canada B3H 4H7</ce:textfn></ce:affiliation><ce:correspondence id="CORR1"><ce:label>*</ce:label><ce:text>Corresponding author. Tel.: +1-902-4943462; fax: +1-902-4941388; e-mail: tdwhite@is.dal.ca</ce:text></ce:correspondence></ce:author-group><ce:date-received day="4" month="9" year="1997"></ce:date-received><ce:date-revised day="1" month="12" year="1997"></ce:date-revised><ce:date-accepted day="9" month="12" year="1997"></ce:date-accepted><ce:abstract><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para>Activation of glutamate receptors triggers the release of adenosine, which exerts important inhibitory actions in the brain. Evoked adenosine release is potentiated when either adenosine kinase or adenosine deaminase are inhibited. We studied the effects of concurrent inhibition of adenosine kinase and adenosine deaminase on <ce:italic>N</ce:italic>-methyl-<ce:small-caps>d</ce:small-caps>-aspartate (NMDA)-evoked formation of extracellular adenosine in slices of rat parietal cortex, to determine if combinations of inhibitors of adenosine kinase and adenosine deaminase can produce supra-additive potentiation of this adenosine formation. Combinations of low concentrations of the adenosine kinase inhibitors 5′-amino-5′-deoxyadenosine (0.2 <ce:italic>μ</ce:italic>M) or 5′-iodotubercidin (0.01 <ce:italic>μ</ce:italic>M) with a low concentration of the adenosine deaminase inhibitor 2′-deoxycoformycin (0.2 <ce:italic>μ</ce:italic>M) produced additive potentiations of NMDA-evoked adenosine release from slices of rat parietal cortex. However, combinations of low concentrations of 5′-amino-5′-deoxyadenosine (0.2 <ce:italic>μ</ce:italic>M) or 5′-iodotubercidin (0.01 <ce:italic>μ</ce:italic>M) with a maximal concentration of 2′-deoxycoformycin (200 <ce:italic>μ</ce:italic>M) produced supra-additive potentiation of NMDA-evoked adenosine release. These findings suggest that such combinations of adenosine kinase inhibitors with adenosine deaminase inhibitors may provide useful strategies for developing therapies to treat disorders associated with excessive NMDA receptor activation, such as seizures, ischemic damage and neurodegenerative diseases.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:keywords class="keyword"><ce:section-title>Keywords</ce:section-title><ce:keyword><ce:text>2′-Deoxycoformycin</ce:text></ce:keyword><ce:keyword><ce:text>5′-Amino-5′-deoxyadenosine</ce:text></ce:keyword><ce:keyword><ce:text>5′-Iodotubercidin</ce:text></ce:keyword><ce:keyword><ce:text>Adenosine</ce:text></ce:keyword><ce:keyword><ce:text>NMDA (<ce:italic>N</ce:italic>-methyl-<ce:small-caps>d</ce:small-caps>-aspartate)</ce:text></ce:keyword></ce:keywords></head></converted-article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Co-administration of adenosine kinase and deaminase inhibitors produces supra-additive potentiation of N -methyl-d-aspartate-evoked adenosine formation in cortex</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Co-administration of adenosine kinase and deaminase inhibitors produces supra-additive potentiation of</title></titleInfo><name type="personal"><namePart type="given">Matthew O</namePart><namePart type="family">Hebb</namePart><affiliation>Department of Pharmacology, Dalhousie University, Halifax, NS, Canada B3H 4H7</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thomas D</namePart><namePart type="family">White</namePart><affiliation>Department of Pharmacology, Dalhousie University, Halifax, NS, Canada B3H 4H7</affiliation><description>Corresponding author. Tel.: +1-902-4943462; fax: +1-902-4941388; e-mail: tdwhite@is.dal.ca</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Full-length article"></genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1998</dateIssued><dateModified encoding="w3cdtf">1997-12-01</dateModified><copyrightDate encoding="w3cdtf">1998</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">Activation of glutamate receptors triggers the release of adenosine, which exerts important inhibitory actions in the brain. Evoked adenosine release is potentiated when either adenosine kinase or adenosine deaminase are inhibited. We studied the effects of concurrent inhibition of adenosine kinase and adenosine deaminase on N-methyl-d-aspartate (NMDA)-evoked formation of extracellular adenosine in slices of rat parietal cortex, to determine if combinations of inhibitors of adenosine kinase and adenosine deaminase can produce supra-additive potentiation of this adenosine formation. Combinations of low concentrations of the adenosine kinase inhibitors 5′-amino-5′-deoxyadenosine (0.2 μM) or 5′-iodotubercidin (0.01 μM) with a low concentration of the adenosine deaminase inhibitor 2′-deoxycoformycin (0.2 μM) produced additive potentiations of NMDA-evoked adenosine release from slices of rat parietal cortex. However, combinations of low concentrations of 5′-amino-5′-deoxyadenosine (0.2 μM) or 5′-iodotubercidin (0.01 μM) with a maximal concentration of 2′-deoxycoformycin (200 μM) produced supra-additive potentiation of NMDA-evoked adenosine release. These findings suggest that such combinations of adenosine kinase inhibitors with adenosine deaminase inhibitors may provide useful strategies for developing therapies to treat disorders associated with excessive NMDA receptor activation, such as seizures, ischemic damage and neurodegenerative diseases.</abstract><note type="content">Fig. 1: Concentration–response relations for the potentiation of NMDA-evoked adenosine release by adenosine deaminase inhibitors and adenosine kinase inhibitors. Abbreviations: IOT, 5′-iodotubercidin; NH2dADO, 5′-amino-5′-deoxyadenosine; DCF, 2′-deoxycoformycin. The adenosine kinase inhibitors 5′-iodotubercidin and 5′-amino-5′-deoxyadenosine appeared to be more effective than the adenosine deaminase inhibitor 2′-deoxycoformycin in potentiating NMDA-evoked formation of extracellular adenosine. 5′-Iodotubercidin was more potent than 5′-amino-5′-deoxyadenosine in potentiating adenosine formation. Numbers in parentheses indicate the number of experiments.</note><note type="content">Fig. 2: Effects of combinations of 5′-amino-5′-deoxyadenosine with 2′-deoxycoformycin on NMDA-evoked formation of extracellular adenosine. Abbreviations: NH2dADO, 5′-amino-5′-deoxyadenosine; DCF, 2′-deoxycoformycin. The effect of a combination of 0.2 μM 5′-amino-5′-deoxyadenosine with 0.2 μM 2′-deoxycoformycin on NMDA-evoked formation of extracellular adenosine was not statistically different than the effect of 0.2 μM 2′-deoxycoformycin alone (P>0.05). However, the effect of the combination of 0.2 μM 5′-amino-5′-deoxyadenosine with 200 μM 2′-deoxycoformycin on NMDA-evoked adenosine formation was significantly greater than the effect of 200 μM 2′-deoxycoformycin alone (P<0.05). Numbers in parentheses indicate the number of experiments.</note><note type="content">Fig. 3: Effects of combinations of 5′-iodotubercidin with 2′-deoxycoformycin on NMDA-evoked formation of extracellular adenosine. Abbreviations: IOT, 5′-iodotubercidin; DCF, 2′-deoxycoformycin. The effect of a combination of 0.01 μM 5′-iodotubercidin with 0.2 μM 2′-deoxycoformycin on NMDA-evoked formation of extracellular adenosine was not statistically different than the effect of 0.2 μM 2′-deoxycoformycin alone (P>0.05). However, the effect of a combination of 0.01 μM 5′-iodotubercidin with 200 μM 2′-deoxycoformycin was significantly greater than 200 μM 2′-deoxycoformycin alone (P<0.05). Numbers in parentheses indicate the number of experiments.</note><subject><genre>Keywords</genre><topic>2′-Deoxycoformycin</topic><topic>5′-Amino-5′-deoxyadenosine</topic><topic>5′-Iodotubercidin</topic><topic>Adenosine</topic><topic>NMDA (N-methyl-d-aspartate)</topic></subject><relatedItem type="host"><titleInfo><title>European Journal of Pharmacology</title></titleInfo><titleInfo type="abbreviated"><title>EJP</title></titleInfo><genre type="journal">journal</genre><originInfo><dateIssued encoding="w3cdtf">19980305</dateIssued></originInfo><identifier type="ISSN">0014-2999</identifier><identifier type="PII">S0014-2999(00)X0136-7</identifier><part><date>19980305</date><detail type="volume"><number>344</number><caption>vol.</caption></detail><detail type="issue"><number>2–3</number><caption>no.</caption></detail><extent unit="issue pages"><start>115</start><end>344</end></extent><extent unit="pages"><start>121</start><end>125</end></extent></part></relatedItem><identifier type="istex">28B92C05BC1BD4A63B6E53626695D088AAFB178D</identifier><identifier type="DOI">10.1016/S0014-2999(97)01582-3</identifier><identifier type="PII">S0014-2999(97)01582-3</identifier><accessCondition type="use and reproduction" contentType="copyright">©1998 Elsevier Science B.V.</accessCondition><recordInfo><recordContentSource>ELSEVIER</recordContentSource><recordOrigin>Elsevier Science B.V., ©1998</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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