Antiparkinsonian effects of the "Radiprodil and Tozadenant" combination in MPTP-treated marmosets

Investigate a combination of two clinically tested drugs, the NR2B antagonist Radiprodil and the A2A antagonist Tozadenant in the MPTP-treated marmoset model of Parkinson's Disease (PD). In PD, there remains a need for the development of non-dopaminergic drugs to effectively treat the motor sym...

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Veröffentlicht in:PloS one 2017-08, Vol.12 (8), p.e0182887-e0182887
Hauptverfasser: Michel, Anne, Nicolas, Jean-Marie, Rose, Sarah, Jackson, Michael, Colman, Peter, Briône, Willy, Sciberras, David, Muglia, Pierandrea, Scheller, Dieter K, Citron, Martin, Downey, Patrick
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container_issue 8
container_start_page e0182887
container_title PloS one
container_volume 12
creator Michel, Anne
Nicolas, Jean-Marie
Rose, Sarah
Jackson, Michael
Colman, Peter
Briône, Willy
Sciberras, David
Muglia, Pierandrea
Scheller, Dieter K
Citron, Martin
Downey, Patrick
description Investigate a combination of two clinically tested drugs, the NR2B antagonist Radiprodil and the A2A antagonist Tozadenant in the MPTP-treated marmoset model of Parkinson's Disease (PD). In PD, there remains a need for the development of non-dopaminergic drugs to effectively treat the motor symptoms without the induction of L-Dopa-induced motor complications. Clinically relevant doses of Radiprodil and Tozadenant were given both alone and in combination without the addition of L-Dopa, and the antiparkinsonian efficacy of the treatments was assessed in a primate model of PD. When compared to the drugs tested alone, the drug combination led to a significant increase of motor activity and an improvement of motor disability in MPTP-treated marmosets. In addition, the motor restoration brought about by the combination was almost completely devoid of dyskinesia. Interestingly, treated primates were not overstimulated, but were able to move normally when motivated by the exploration of novel objects. We have demonstrated in a primate model that, the "Radiprodil/Tozadenant" combination significantly improves motor activity, extending previous results obtained in unilaterally lesioned 6-OHDA-rats. The strength of the preclinical data accumulated so far suggests that the use of such an A2A and NR2B antagonist combination could bring significant motor improvement to PD patients, without inducing the motor complications induced by L-Dopa therapy. Although encouraging, these preclinical data need to be confirmed in the clinic.
doi_str_mv 10.1371/journal.pone.0182887
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apes</subject><subject>Motor activity</subject><subject>Motor Activity - drug effects</subject><subject>Motor Activity - physiology</subject><subject>Motor task performance</subject><subject>Movement disorders</subject><subject>MPTP</subject><subject>MPTP Poisoning - drug therapy</subject><subject>MPTP Poisoning - genetics</subject><subject>MPTP Poisoning - metabolism</subject><subject>MPTP Poisoning - physiopathology</subject><subject>Neurodegenerative diseases</subject><subject>Pain</subject><subject>Parkinson disease</subject><subject>Parkinson's disease</subject><subject>Parkinsons disease</subject><subject>Pharmaceutical sciences</subject><subject>Phosphorylation</subject><subject>Primates</subject><subject>Rats</subject><subject>Receptors, Adenosine A2 - genetics</subject><subject>Receptors, Adenosine A2 - metabolism</subject><subject>Receptors, N-Methyl-D-Aspartate - antagonists &amp; inhibitors</subject><subject>Receptors, N-Methyl-D-Aspartate - genetics</subject><subject>Receptors, N-Methyl-D-Aspartate - metabolism</subject><subject>Research and Analysis Methods</subject><subject>Restoration</subject><subject>Rodents</subject><subject>Treatment Outcome</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk1tv0zAUxyMEYqPwDRBEQ0Lw0JLEt-QFqZq4VBraNAqv1okvrUdid7aLgE-Pu2ZTg_aA_ODb7_xt_31Olj0vi1mJWPnuym29hW62cVbNirKu6po9yI7LBlVTWhXo4cH4KHsSwlVREFRT-jg7SizBFUbHGcxtNBvwP4wNzhqwudJaiRhyp_O4VvnJJUiz8U6aLgcr86X7A1JZsPEkF65vjYVonM2Nzb9cLC-m0SuISuY9-N4FFcPT7JGGLqhnQz_Jvn38sDz9PD07_7Q4nZ9NBW2qOCWkBpCSEaWA4laUmJaaKiEoYwohjTSUFJO2YIBwy2rSUAE1rlrdSIZEgybZy73upnOBD-4EnjxADWkYoolY7Anp4IpvvEl3_M0dGH6z4PyKg49GdIoLXLBCN3WrgWFCCRSUIah1mjao0TJpvR9O27a9kkLZ6KEbiY53rFnzlfvJCWGUJrFJ9mYQ8O56q0LkvQlCdR1Y5bY398ZVTdNPJfTVP-j9rxuoFaQHGKtdOlfsRPmcFBXGyTKcqNk9VGpS9UakVNImrY8C3o4CEhPVr7iCbQh88fXy_9nz72P29QG7VtDFdXDddpdMYQziPSi8C8ErfWdyWfBdJdy6wXeVwIdKSGEvDj_oLug29dFfJ7ID6Q</recordid><startdate>20170830</startdate><enddate>20170830</enddate><creator>Michel, Anne</creator><creator>Nicolas, Jean-Marie</creator><creator>Rose, Sarah</creator><creator>Jackson, Michael</creator><creator>Colman, Peter</creator><creator>Briône, Willy</creator><creator>Sciberras, David</creator><creator>Muglia, Pierandrea</creator><creator>Scheller, Dieter K</creator><creator>Citron, Martin</creator><creator>Downey, Patrick</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-7271-7903</orcidid></search><sort><creationdate>20170830</creationdate><title>Antiparkinsonian effects of the "Radiprodil and Tozadenant" combination in MPTP-treated marmosets</title><author>Michel, Anne ; 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Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing &amp; Allied Health Database (Alumni Edition)</collection><collection>Meteorological &amp; Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>Advanced Technologies &amp; Aerospace Database</collection><collection>ProQuest Advanced Technologies &amp; Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Michel, Anne</au><au>Nicolas, Jean-Marie</au><au>Rose, Sarah</au><au>Jackson, Michael</au><au>Colman, Peter</au><au>Briône, Willy</au><au>Sciberras, David</au><au>Muglia, Pierandrea</au><au>Scheller, Dieter K</au><au>Citron, Martin</au><au>Downey, Patrick</au><au>Boraud, Thomas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antiparkinsonian effects of the "Radiprodil and Tozadenant" combination in MPTP-treated marmosets</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-08-30</date><risdate>2017</risdate><volume>12</volume><issue>8</issue><spage>e0182887</spage><epage>e0182887</epage><pages>e0182887-e0182887</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Investigate a combination of two clinically tested drugs, the NR2B antagonist Radiprodil and the A2A antagonist Tozadenant in the MPTP-treated marmoset model of Parkinson's Disease (PD). In PD, there remains a need for the development of non-dopaminergic drugs to effectively treat the motor symptoms without the induction of L-Dopa-induced motor complications. Clinically relevant doses of Radiprodil and Tozadenant were given both alone and in combination without the addition of L-Dopa, and the antiparkinsonian efficacy of the treatments was assessed in a primate model of PD. When compared to the drugs tested alone, the drug combination led to a significant increase of motor activity and an improvement of motor disability in MPTP-treated marmosets. In addition, the motor restoration brought about by the combination was almost completely devoid of dyskinesia. Interestingly, treated primates were not overstimulated, but were able to move normally when motivated by the exploration of novel objects. We have demonstrated in a primate model that, the "Radiprodil/Tozadenant" combination significantly improves motor activity, extending previous results obtained in unilaterally lesioned 6-OHDA-rats. The strength of the preclinical data accumulated so far suggests that the use of such an A2A and NR2B antagonist combination could bring significant motor improvement to PD patients, without inducing the motor complications induced by L-Dopa therapy. Although encouraging, these preclinical data need to be confirmed in the clinic.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28854243</pmid><doi>10.1371/journal.pone.0182887</doi><tpages>e0182887</tpages><orcidid>https://orcid.org/0000-0002-7271-7903</orcidid><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1932-6203
ispartof PloS one, 2017-08, Vol.12 (8), p.e0182887-e0182887
issn 1932-6203
1932-6203
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source MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central; Free Full-Text Journals in Chemistry
subjects Adenosine
Animals
Antiparkinson agents
Antiparkinson Agents - pharmacology
Benzothiazoles - pharmacology
Biology and Life Sciences
Callithrix
Care and treatment
Cocaine
Complications
Dihydroxyphenylalanine
Dopa
Dopamine
Dopamine receptors
Dosage and administration
Drug Administration Schedule
Drug Combinations
Drug development
Drug dosages
Drug Evaluation, Preclinical
Drug Synergism
Drugs
Dyskinesia
Dyskinesia, Drug-Induced - prevention & control
Female
Gene Expression
Kinases
Levodopa
Male
Marmosets
Medicine and Health Sciences
Monkeys & apes
Motor activity
Motor Activity - drug effects
Motor Activity - physiology
Motor task performance
Movement disorders
MPTP
MPTP Poisoning - drug therapy
MPTP Poisoning - genetics
MPTP Poisoning - metabolism
MPTP Poisoning - physiopathology
Neurodegenerative diseases
Pain
Parkinson disease
Parkinson's disease
Parkinsons disease
Pharmaceutical sciences
Phosphorylation
Primates
Rats
Receptors, Adenosine A2 - genetics
Receptors, Adenosine A2 - metabolism
Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors
Receptors, N-Methyl-D-Aspartate - genetics
Receptors, N-Methyl-D-Aspartate - metabolism
Research and Analysis Methods
Restoration
Rodents
Treatment Outcome
title Antiparkinsonian effects of the "Radiprodil and Tozadenant" combination in MPTP-treated marmosets
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