Plasmalogen precursor analog treatment reduces levodopa-induced dyskinesias in parkinsonian monkeys.
Identifieur interne : 000580 ( Main/Exploration ); précédent : 000579; suivant : 000581Plasmalogen precursor analog treatment reduces levodopa-induced dyskinesias in parkinsonian monkeys.
Auteurs : Laurent Grégoire [Canada] ; Tara Smith [Canada] ; Vijitha Senanayake [Canada] ; Asuka Mochizuki [Japon] ; Edith Miville-Godbout [Canada] ; Dayan Goodenowe [Canada] ; Thérèse Di Paolo [Canada]Source :
- Behavioural brain research [ 1872-7549 ] ; 2015.
English descriptors
- KwdEn :
- Animals, Anti-Dyskinesia Agents (blood), Anti-Dyskinesia Agents (pharmacology), Anti-Dyskinesia Agents (toxicity), Docosahexaenoic Acids (blood), Docosahexaenoic Acids (pharmacology), Dose-Response Relationship, Drug, Dyskinesia, Drug-Induced (drug therapy), Female, Levodopa (pharmacology), Levodopa (toxicity), Macaca fascicularis, Ovariectomy, Parkinsonian Disorders (drug therapy), Phosphatidylethanolamines (blood), Phosphatidylethanolamines (pharmacology), Plasmalogens (blood), Plasmalogens (pharmacology).
- MESH :
- chemical , blood : Anti-Dyskinesia Agents, Docosahexaenoic Acids, Phosphatidylethanolamines, Plasmalogens.
- chemical , pharmacology : Anti-Dyskinesia Agents, Docosahexaenoic Acids, Levodopa, Phosphatidylethanolamines, Plasmalogens.
- chemical , toxicity : Anti-Dyskinesia Agents, Levodopa.
- drug therapy : Dyskinesia, Drug-Induced, Parkinsonian Disorders.
- Animals, Dose-Response Relationship, Drug, Female, Macaca fascicularis, Ovariectomy.
Abstract
L-DOPA-induced dyskinesias (LID) remain a serious obstacle in the treatment of Parkinson's disease (PD). The objective of this study was to test a new target for treatment of dyskinesias, ethanolamine plasmalogens (PlsEtn). PlsEtn play critical roles in membrane structure mediated functions and as a storage depot of polyunsaturated fatty acids such as docosahexaenoic acid (DHA, omega-3) known to reduce dyskinesias. The motor effect of a daily treatment for 12 days of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Macaca fascicularis monkeys with DHA (100mg/kg) was compared to the DHA-PlsEtn precursor PPI-1011 (50mg/kg). PPI-1011 and DHA reduced LID while maintaining the antiparkinsonian activity of l-DOPA, however the PPI-1011 effect was observed at the first behavioral time point analyzed following drug administration (day 2) whereas the effect of DHA was not observed until after 10 days of administration. DHA treatment increased plasma DHA levels 2-3× whereas PPI-1011 had no effect. DHA and PPI-1011 increased DHA-PlsEtn levels by 1.5-2× while DHA-phosphatidylethanolamine (PtdEtn) levels remained unaffected. DHA treatment also elevated very long chain fatty acid containing PtdEtn and reduced non-DHA containing PtdEtn and PlsEtn levels. PPI-1011 had no effect on these systems. LID scores were inversely correlated with serum DHA-PlsEtn/total PlsEtn ratios levels in DHA and PPI-1011 treated monkeys. Hence, the antidyskinetic activity of DHA and PPI-1011 in MPTP monkeys appears to be associated with the increase of serum DHA-PlsEtn concentrations. This is the first study reporting an antidyskinetic response to augmentation of DHA-PlsEtn using a plasmalogen precursor thus providing a novel drug target for dyskinesias.
DOI: 10.1016/j.bbr.2015.03.012
PubMed: 25771209
Affiliations:
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Le document en format XML
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Electronic address: therese.dipaolo@crchul.ulaval.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Neuroscience Research Unit, Centre de Recherche du CHU de Québec, Québec, QC, Canada; Faculty of Pharmacy, Laval University, Quebec, QC</wicri:regionArea><wicri:noRegion>QC</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2015">2015</date><idno type="RBID">pubmed:25771209</idno><idno type="pmid">25771209</idno><idno type="doi">10.1016/j.bbr.2015.03.012</idno><idno type="wicri:Area/PubMed/Corpus">000482</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000482</idno><idno type="wicri:Area/PubMed/Curation">000482</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000482</idno><idno type="wicri:Area/PubMed/Checkpoint">000482</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000482</idno><idno type="wicri:Area/Ncbi/Merge">001A99</idno><idno type="wicri:Area/Ncbi/Curation">001A99</idno><idno type="wicri:Area/Ncbi/Checkpoint">001A99</idno><idno type="wicri:Area/Main/Merge">000581</idno><idno type="wicri:Area/Main/Curation">000580</idno><idno type="wicri:Area/Main/Exploration">000580</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Plasmalogen precursor analog treatment reduces levodopa-induced dyskinesias in parkinsonian monkeys.</title><author><name sortKey="Gregoire, Laurent" sort="Gregoire, Laurent" uniqKey="Gregoire L" first="Laurent" last="Grégoire">Laurent Grégoire</name><affiliation wicri:level="1"><nlm:affiliation>Neuroscience Research Unit, Centre de Recherche du CHU de Québec, Québec, QC, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Neuroscience Research Unit, Centre de Recherche du CHU de Québec, Québec, QC</wicri:regionArea><wicri:noRegion>QC</wicri:noRegion></affiliation></author><author><name sortKey="Smith, Tara" sort="Smith, Tara" uniqKey="Smith T" first="Tara" last="Smith">Tara Smith</name><affiliation wicri:level="1"><nlm:affiliation>Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, SK, Canada S7N 4L8.</nlm:affiliation><country>Canada</country><wicri:regionArea>Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, SK</wicri:regionArea><wicri:noRegion>SK</wicri:noRegion></affiliation></author><author><name sortKey="Senanayake, Vijitha" sort="Senanayake, Vijitha" uniqKey="Senanayake V" first="Vijitha" last="Senanayake">Vijitha Senanayake</name><affiliation wicri:level="1"><nlm:affiliation>Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, SK, Canada S7N 4L8.</nlm:affiliation><country>Canada</country><wicri:regionArea>Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, SK</wicri:regionArea><wicri:noRegion>SK</wicri:noRegion></affiliation></author><author><name sortKey="Mochizuki, Asuka" sort="Mochizuki, Asuka" uniqKey="Mochizuki A" first="Asuka" last="Mochizuki">Asuka Mochizuki</name><affiliation wicri:level="1"><nlm:affiliation>Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, SK, Canada S7N 4L8; Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, SK, Canada S7N 4L8; Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba</wicri:regionArea><wicri:noRegion>Chiba</wicri:noRegion></affiliation></author><author><name sortKey="Miville Godbout, Edith" sort="Miville Godbout, Edith" uniqKey="Miville Godbout E" first="Edith" last="Miville-Godbout">Edith Miville-Godbout</name><affiliation wicri:level="1"><nlm:affiliation>Neuroscience Research Unit, Centre de Recherche du CHU de Québec, Québec, QC, Canada; Faculty of Pharmacy, Laval University, Quebec, QC, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Neuroscience Research Unit, Centre de Recherche du CHU de Québec, Québec, QC, Canada; Faculty of Pharmacy, Laval University, Quebec, QC</wicri:regionArea><wicri:noRegion>QC</wicri:noRegion></affiliation></author><author><name sortKey="Goodenowe, Dayan" sort="Goodenowe, Dayan" uniqKey="Goodenowe D" first="Dayan" last="Goodenowe">Dayan Goodenowe</name><affiliation wicri:level="1"><nlm:affiliation>Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, SK, Canada S7N 4L8.</nlm:affiliation><country>Canada</country><wicri:regionArea>Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, SK</wicri:regionArea><wicri:noRegion>SK</wicri:noRegion></affiliation></author><author><name sortKey="Di Paolo, Therese" sort="Di Paolo, Therese" uniqKey="Di Paolo T" first="Thérèse" last="Di Paolo">Thérèse Di Paolo</name><affiliation wicri:level="1"><nlm:affiliation>Neuroscience Research Unit, Centre de Recherche du CHU de Québec, Québec, QC, Canada; Faculty of Pharmacy, Laval University, Quebec, QC, Canada. Electronic address: therese.dipaolo@crchul.ulaval.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Neuroscience Research Unit, Centre de Recherche du CHU de Québec, Québec, QC, Canada; Faculty of Pharmacy, Laval University, Quebec, QC</wicri:regionArea><wicri:noRegion>QC</wicri:noRegion></affiliation></author></analytic><series><title level="j">Behavioural brain research</title><idno type="eISSN">1872-7549</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Anti-Dyskinesia Agents (blood)</term><term>Anti-Dyskinesia Agents (pharmacology)</term><term>Anti-Dyskinesia Agents (toxicity)</term><term>Docosahexaenoic Acids (blood)</term><term>Docosahexaenoic Acids (pharmacology)</term><term>Dose-Response Relationship, Drug</term><term>Dyskinesia, Drug-Induced (drug therapy)</term><term>Female</term><term>Levodopa (pharmacology)</term><term>Levodopa (toxicity)</term><term>Macaca fascicularis</term><term>Ovariectomy</term><term>Parkinsonian Disorders (drug therapy)</term><term>Phosphatidylethanolamines (blood)</term><term>Phosphatidylethanolamines (pharmacology)</term><term>Plasmalogens (blood)</term><term>Plasmalogens (pharmacology)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="blood" xml:lang="en"><term>Anti-Dyskinesia Agents</term><term>Docosahexaenoic Acids</term><term>Phosphatidylethanolamines</term><term>Plasmalogens</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Anti-Dyskinesia Agents</term><term>Docosahexaenoic Acids</term><term>Levodopa</term><term>Phosphatidylethanolamines</term><term>Plasmalogens</term></keywords><keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en"><term>Anti-Dyskinesia Agents</term><term>Levodopa</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Dyskinesia, Drug-Induced</term><term>Parkinsonian Disorders</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Dose-Response Relationship, Drug</term><term>Female</term><term>Macaca fascicularis</term><term>Ovariectomy</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">L-DOPA-induced dyskinesias (LID) remain a serious obstacle in the treatment of Parkinson's disease (PD). The objective of this study was to test a new target for treatment of dyskinesias, ethanolamine plasmalogens (PlsEtn). PlsEtn play critical roles in membrane structure mediated functions and as a storage depot of polyunsaturated fatty acids such as docosahexaenoic acid (DHA, omega-3) known to reduce dyskinesias. The motor effect of a daily treatment for 12 days of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Macaca fascicularis monkeys with DHA (100mg/kg) was compared to the DHA-PlsEtn precursor PPI-1011 (50mg/kg). PPI-1011 and DHA reduced LID while maintaining the antiparkinsonian activity of l-DOPA, however the PPI-1011 effect was observed at the first behavioral time point analyzed following drug administration (day 2) whereas the effect of DHA was not observed until after 10 days of administration. DHA treatment increased plasma DHA levels 2-3× whereas PPI-1011 had no effect. DHA and PPI-1011 increased DHA-PlsEtn levels by 1.5-2× while DHA-phosphatidylethanolamine (PtdEtn) levels remained unaffected. DHA treatment also elevated very long chain fatty acid containing PtdEtn and reduced non-DHA containing PtdEtn and PlsEtn levels. PPI-1011 had no effect on these systems. LID scores were inversely correlated with serum DHA-PlsEtn/total PlsEtn ratios levels in DHA and PPI-1011 treated monkeys. Hence, the antidyskinetic activity of DHA and PPI-1011 in MPTP monkeys appears to be associated with the increase of serum DHA-PlsEtn concentrations. This is the first study reporting an antidyskinetic response to augmentation of DHA-PlsEtn using a plasmalogen precursor thus providing a novel drug target for dyskinesias.</div></front></TEI><affiliations><list><country><li>Canada</li><li>Japon</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Gregoire, Laurent" sort="Gregoire, Laurent" uniqKey="Gregoire L" first="Laurent" last="Grégoire">Laurent Grégoire</name></noRegion><name sortKey="Di Paolo, Therese" sort="Di Paolo, Therese" uniqKey="Di Paolo T" first="Thérèse" last="Di Paolo">Thérèse Di Paolo</name><name sortKey="Goodenowe, Dayan" sort="Goodenowe, Dayan" uniqKey="Goodenowe D" first="Dayan" last="Goodenowe">Dayan Goodenowe</name><name sortKey="Miville Godbout, Edith" sort="Miville Godbout, Edith" uniqKey="Miville Godbout E" first="Edith" last="Miville-Godbout">Edith Miville-Godbout</name><name sortKey="Senanayake, Vijitha" sort="Senanayake, Vijitha" uniqKey="Senanayake V" first="Vijitha" last="Senanayake">Vijitha Senanayake</name><name sortKey="Smith, Tara" sort="Smith, Tara" uniqKey="Smith T" first="Tara" last="Smith">Tara Smith</name></country><country name="Japon"><noRegion><name sortKey="Mochizuki, Asuka" sort="Mochizuki, Asuka" uniqKey="Mochizuki A" first="Asuka" last="Mochizuki">Asuka Mochizuki</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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