Olesoxime protects embryonic cortical neurons from camptothecin intoxication by a mechanism distinct from BDNF
Identifieur interne : 001041 ( Ncbi/Merge ); précédent : 001040; suivant : 001042Olesoxime protects embryonic cortical neurons from camptothecin intoxication by a mechanism distinct from BDNF
Auteurs : Caroline Gouarné ; Marc Giraudon-Paoli ; Mathieu Seimandi ; Clotilde Biscarrat ; Gwenaëlle Tardif ; Rebecca M. Pruss ; Thierry BordetSource :
- British Journal of Pharmacology [ 0007-1188 ] ; 2013.
Abstract
Olesoxime is a small cholesterol–oxime promoting rat embryonic motor neurons survival in the absence of trophic factors. Because olesoxime can substitute for neurotrophic factors in many situations, and to gain further understanding of its mechanism of action, we wondered if it could prevent neuronal death induced by camptothecin (CPT) and compared its effects with those of brain-derived neurotrophic factor (BDNF).
E17 rat embryonic cortical neurons were treated with olesoxime, BDNF or vehicle and intoxicated with CPT. Caspase-dependent and caspase-independent death pathways along with pro-survival pathways activation were explored.
As previously reported for BDNF, olesoxime dose-dependently delayed CPT-induced cell death. Both compounds acted downstream of p53 activation preventing cytochrome c release and caspases activation. When caspase activation was blocked, both olesoxime and BDNF provided additional neuroprotective effect, potentially through the prevention of apoptosis-inducing factor release from mitochondria. While BDNF activates both the PI3K/Akt and the ERK pathway, olesoxime induced only a late activation of the ERK pathways, which did not seem to play a major role in its neuroprotection against CPT. Rather, our results favour preserved mitochondrial membrane integrity by olesoxime.
Albeit different, olesoxime and BDNF mechanisms for neuroprotection converge to preserve mitochondrial function. These findings emphasize the importance of targeting the mitochondria in the process of neurodegeneration. Importantly olesoxime, by mimicking neurotrophin pro-survival activities without impacting PI3K/Akt and ERK signalling, may have greater therapeutic potential in many diseases where neurotrophins were considered as a therapeutic solution.
Url:
DOI: 10.1111/bph.12094
PubMed: 23278424
PubMed Central: 3623066
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<author><name sortKey="Gouarne, Caroline" sort="Gouarne, Caroline" uniqKey="Gouarne C" first="Caroline" last="Gouarné">Caroline Gouarné</name>
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<author><name sortKey="Giraudon Paoli, Marc" sort="Giraudon Paoli, Marc" uniqKey="Giraudon Paoli M" first="Marc" last="Giraudon-Paoli">Marc Giraudon-Paoli</name>
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<author><name sortKey="Tardif, Gwenaelle" sort="Tardif, Gwenaelle" uniqKey="Tardif G" first="Gwenaëlle" last="Tardif">Gwenaëlle Tardif</name>
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<author><name sortKey="Pruss, Rebecca M" sort="Pruss, Rebecca M" uniqKey="Pruss R" first="Rebecca M" last="Pruss">Rebecca M. Pruss</name>
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<author><name sortKey="Bordet, Thierry" sort="Bordet, Thierry" uniqKey="Bordet T" first="Thierry" last="Bordet">Thierry Bordet</name>
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<author><name sortKey="Giraudon Paoli, Marc" sort="Giraudon Paoli, Marc" uniqKey="Giraudon Paoli M" first="Marc" last="Giraudon-Paoli">Marc Giraudon-Paoli</name>
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<front><div type="abstract" xml:lang="en"><sec><title>Background and Purpose</title>
<p>Olesoxime is a small cholesterol–oxime promoting rat embryonic motor neurons survival in the absence of trophic factors. Because olesoxime can substitute for neurotrophic factors in many situations, and to gain further understanding of its mechanism of action, we wondered if it could prevent neuronal death induced by camptothecin (CPT) and compared its effects with those of brain-derived neurotrophic factor (BDNF).</p>
</sec>
<sec><title>Experimental Approach</title>
<p>E17 rat embryonic cortical neurons were treated with olesoxime, BDNF or vehicle and intoxicated with CPT. Caspase-dependent and caspase-independent death pathways along with pro-survival pathways activation were explored.</p>
</sec>
<sec><title>Key Results</title>
<p>As previously reported for BDNF, olesoxime dose-dependently delayed CPT-induced cell death. Both compounds acted downstream of p53 activation preventing cytochrome c release and caspases activation. When caspase activation was blocked, both olesoxime and BDNF provided additional neuroprotective effect, potentially through the prevention of apoptosis-inducing factor release from mitochondria. While BDNF activates both the PI3K/Akt and the ERK pathway, olesoxime induced only a late activation of the ERK pathways, which did not seem to play a major role in its neuroprotection against CPT. Rather, our results favour preserved mitochondrial membrane integrity by olesoxime.</p>
</sec>
<sec><title>Conclusions and Implications</title>
<p>Albeit different, olesoxime and BDNF mechanisms for neuroprotection converge to preserve mitochondrial function. These findings emphasize the importance of targeting the mitochondria in the process of neurodegeneration. Importantly olesoxime, by mimicking neurotrophin pro-survival activities without impacting PI3K/Akt and ERK signalling, may have greater therapeutic potential in many diseases where neurotrophins were considered as a therapeutic solution.</p>
</sec>
</div>
</front>
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<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Br J Pharmacol</journal-id>
<journal-id journal-id-type="iso-abbrev">Br. J. Pharmacol</journal-id>
<journal-id journal-id-type="publisher-id">bph</journal-id>
<journal-title-group><journal-title>British Journal of Pharmacology</journal-title>
</journal-title-group>
<issn pub-type="ppub">0007-1188</issn>
<issn pub-type="epub">1476-5381</issn>
<publisher><publisher-name>Blackwell Publishing Ltd</publisher-name>
</publisher>
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<article-meta><article-id pub-id-type="pmid">23278424</article-id>
<article-id pub-id-type="pmc">3623066</article-id>
<article-id pub-id-type="doi">10.1111/bph.12094</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Papers</subject>
</subj-group>
</article-categories>
<title-group><article-title>Olesoxime protects embryonic cortical neurons from camptothecin intoxication by a mechanism distinct from BDNF</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Gouarné</surname>
<given-names>Caroline</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Giraudon-Paoli</surname>
<given-names>Marc</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Seimandi</surname>
<given-names>Mathieu</given-names>
</name>
<xref ref-type="author-notes" rid="fn1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Biscarrat</surname>
<given-names>Clotilde</given-names>
</name>
<xref ref-type="author-notes" rid="fn2">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tardif</surname>
<given-names>Gwenaëlle</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Pruss</surname>
<given-names>Rebecca M</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Bordet</surname>
<given-names>Thierry</given-names>
</name>
</contrib>
<aff><institution>Trophos</institution>
<addr-line>Marseille, France</addr-line>
</aff>
</contrib-group>
<author-notes><corresp id="cor1">Thierry Bordet, Trophos, Parc Scientifique de Luminy, Luminy Biotech Entreprises, Case 931, 13288 Marseille Cedex 9, France. E-mail: <email>tbordet@trophos.com</email>
</corresp>
<fn id="fn1" fn-type="present-address"><label>*</label>
<p>Present address: NEUROSERVICE, Aix-en-Provence, France.</p>
</fn>
<fn id="fn2" fn-type="present-address"><label>†</label>
<p>Present address: ICDD, Meyreuil, France.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><month>4</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>25</day>
<month>3</month>
<year>2013</year>
</pub-date>
<volume>168</volume>
<issue>8</issue>
<fpage>1975</fpage>
<lpage>1988</lpage>
<history><date date-type="received"><day>29</day>
<month>8</month>
<year>2012</year>
</date>
<date date-type="rev-recd"><day>28</day>
<month>11</month>
<year>2012</year>
</date>
<date date-type="accepted"><day>10</day>
<month>12</month>
<year>2012</year>
</date>
</history>
<permissions><copyright-statement>British Journal of Pharmacology © 2013 The British Pharmacological Society</copyright-statement>
<copyright-year>2013</copyright-year>
</permissions>
<abstract><sec><title>Background and Purpose</title>
<p>Olesoxime is a small cholesterol–oxime promoting rat embryonic motor neurons survival in the absence of trophic factors. Because olesoxime can substitute for neurotrophic factors in many situations, and to gain further understanding of its mechanism of action, we wondered if it could prevent neuronal death induced by camptothecin (CPT) and compared its effects with those of brain-derived neurotrophic factor (BDNF).</p>
</sec>
<sec><title>Experimental Approach</title>
<p>E17 rat embryonic cortical neurons were treated with olesoxime, BDNF or vehicle and intoxicated with CPT. Caspase-dependent and caspase-independent death pathways along with pro-survival pathways activation were explored.</p>
</sec>
<sec><title>Key Results</title>
<p>As previously reported for BDNF, olesoxime dose-dependently delayed CPT-induced cell death. Both compounds acted downstream of p53 activation preventing cytochrome c release and caspases activation. When caspase activation was blocked, both olesoxime and BDNF provided additional neuroprotective effect, potentially through the prevention of apoptosis-inducing factor release from mitochondria. While BDNF activates both the PI3K/Akt and the ERK pathway, olesoxime induced only a late activation of the ERK pathways, which did not seem to play a major role in its neuroprotection against CPT. Rather, our results favour preserved mitochondrial membrane integrity by olesoxime.</p>
</sec>
<sec><title>Conclusions and Implications</title>
<p>Albeit different, olesoxime and BDNF mechanisms for neuroprotection converge to preserve mitochondrial function. These findings emphasize the importance of targeting the mitochondria in the process of neurodegeneration. Importantly olesoxime, by mimicking neurotrophin pro-survival activities without impacting PI3K/Akt and ERK signalling, may have greater therapeutic potential in many diseases where neurotrophins were considered as a therapeutic solution.</p>
</sec>
</abstract>
<kwd-group><kwd>olesoxime</kwd>
<kwd>TRO19622</kwd>
<kwd>BDNF</kwd>
<kwd>neurotrophic factors</kwd>
<kwd>camptothecin</kwd>
<kwd>mitochondria</kwd>
<kwd>apoptosis</kwd>
<kwd>MAPK/ERK</kwd>
<kwd>PI3K/Akt</kwd>
<kwd>neurodegenerative diseases</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
<affiliations><list></list>
<tree><noCountry><name sortKey="Biscarrat, Clotilde" sort="Biscarrat, Clotilde" uniqKey="Biscarrat C" first="Clotilde" last="Biscarrat">Clotilde Biscarrat</name>
<name sortKey="Bordet, Thierry" sort="Bordet, Thierry" uniqKey="Bordet T" first="Thierry" last="Bordet">Thierry Bordet</name>
<name sortKey="Giraudon Paoli, Marc" sort="Giraudon Paoli, Marc" uniqKey="Giraudon Paoli M" first="Marc" last="Giraudon-Paoli">Marc Giraudon-Paoli</name>
<name sortKey="Gouarne, Caroline" sort="Gouarne, Caroline" uniqKey="Gouarne C" first="Caroline" last="Gouarné">Caroline Gouarné</name>
<name sortKey="Pruss, Rebecca M" sort="Pruss, Rebecca M" uniqKey="Pruss R" first="Rebecca M" last="Pruss">Rebecca M. Pruss</name>
<name sortKey="Seimandi, Mathieu" sort="Seimandi, Mathieu" uniqKey="Seimandi M" first="Mathieu" last="Seimandi">Mathieu Seimandi</name>
<name sortKey="Tardif, Gwenaelle" sort="Tardif, Gwenaelle" uniqKey="Tardif G" first="Gwenaëlle" last="Tardif">Gwenaëlle Tardif</name>
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