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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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 |
format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0182887</identifier><identifier>PMID: 28854243</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>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</subject><ispartof>PloS one, 2017-08, Vol.12 (8), p.e0182887-e0182887</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Michel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Michel et al 2017 Michel et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-558aadd75eea64bc1461f6ecc677e33f3fa1645b07a34b78596ca842bf9d73c93</citedby><cites>FETCH-LOGICAL-c692t-558aadd75eea64bc1461f6ecc677e33f3fa1645b07a34b78596ca842bf9d73c93</cites><orcidid>0000-0002-7271-7903</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576667/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576667/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28854243$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Boraud, Thomas</contributor><creatorcontrib>Michel, Anne</creatorcontrib><creatorcontrib>Nicolas, Jean-Marie</creatorcontrib><creatorcontrib>Rose, Sarah</creatorcontrib><creatorcontrib>Jackson, Michael</creatorcontrib><creatorcontrib>Colman, Peter</creatorcontrib><creatorcontrib>Briône, Willy</creatorcontrib><creatorcontrib>Sciberras, David</creatorcontrib><creatorcontrib>Muglia, Pierandrea</creatorcontrib><creatorcontrib>Scheller, Dieter K</creatorcontrib><creatorcontrib>Citron, Martin</creatorcontrib><creatorcontrib>Downey, Patrick</creatorcontrib><title>Antiparkinsonian effects of the "Radiprodil and Tozadenant" combination in MPTP-treated marmosets</title><title>PloS one</title><addtitle>PLoS One</addtitle><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.</description><subject>Adenosine</subject><subject>Animals</subject><subject>Antiparkinson agents</subject><subject>Antiparkinson Agents - pharmacology</subject><subject>Benzothiazoles - pharmacology</subject><subject>Biology and Life Sciences</subject><subject>Callithrix</subject><subject>Care and treatment</subject><subject>Cocaine</subject><subject>Complications</subject><subject>Dihydroxyphenylalanine</subject><subject>Dopa</subject><subject>Dopamine</subject><subject>Dopamine receptors</subject><subject>Dosage and administration</subject><subject>Drug Administration Schedule</subject><subject>Drug Combinations</subject><subject>Drug development</subject><subject>Drug dosages</subject><subject>Drug Evaluation, Preclinical</subject><subject>Drug Synergism</subject><subject>Drugs</subject><subject>Dyskinesia</subject><subject>Dyskinesia, Drug-Induced - prevention & control</subject><subject>Female</subject><subject>Gene Expression</subject><subject>Kinases</subject><subject>Levodopa</subject><subject>Male</subject><subject>Marmosets</subject><subject>Medicine and Health Sciences</subject><subject>Monkeys & 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 & 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 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effects of the "Radiprodil and Tozadenant" combination in MPTP-treated marmosets</title><author>Michel, Anne ; Nicolas, Jean-Marie ; Rose, Sarah ; Jackson, Michael ; Colman, Peter ; Briône, Willy ; Sciberras, David ; Muglia, Pierandrea ; Scheller, Dieter K ; Citron, Martin ; Downey, Patrick</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-558aadd75eea64bc1461f6ecc677e33f3fa1645b07a34b78596ca842bf9d73c93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Adenosine</topic><topic>Animals</topic><topic>Antiparkinson agents</topic><topic>Antiparkinson Agents - pharmacology</topic><topic>Benzothiazoles - pharmacology</topic><topic>Biology and Life Sciences</topic><topic>Callithrix</topic><topic>Care and treatment</topic><topic>Cocaine</topic><topic>Complications</topic><topic>Dihydroxyphenylalanine</topic><topic>Dopa</topic><topic>Dopamine</topic><topic>Dopamine receptors</topic><topic>Dosage and administration</topic><topic>Drug Administration Schedule</topic><topic>Drug Combinations</topic><topic>Drug development</topic><topic>Drug dosages</topic><topic>Drug Evaluation, Preclinical</topic><topic>Drug Synergism</topic><topic>Drugs</topic><topic>Dyskinesia</topic><topic>Dyskinesia, Drug-Induced - prevention & control</topic><topic>Female</topic><topic>Gene Expression</topic><topic>Kinases</topic><topic>Levodopa</topic><topic>Male</topic><topic>Marmosets</topic><topic>Medicine and Health Sciences</topic><topic>Monkeys & apes</topic><topic>Motor activity</topic><topic>Motor Activity - drug effects</topic><topic>Motor Activity - physiology</topic><topic>Motor task performance</topic><topic>Movement disorders</topic><topic>MPTP</topic><topic>MPTP Poisoning - drug therapy</topic><topic>MPTP Poisoning - genetics</topic><topic>MPTP Poisoning - metabolism</topic><topic>MPTP Poisoning - physiopathology</topic><topic>Neurodegenerative diseases</topic><topic>Pain</topic><topic>Parkinson disease</topic><topic>Parkinson's disease</topic><topic>Parkinsons disease</topic><topic>Pharmaceutical sciences</topic><topic>Phosphorylation</topic><topic>Primates</topic><topic>Rats</topic><topic>Receptors, Adenosine A2 - genetics</topic><topic>Receptors, Adenosine A2 - metabolism</topic><topic>Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors</topic><topic>Receptors, N-Methyl-D-Aspartate - genetics</topic><topic>Receptors, N-Methyl-D-Aspartate - metabolism</topic><topic>Research and Analysis Methods</topic><topic>Restoration</topic><topic>Rodents</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Michel, Anne</creatorcontrib><creatorcontrib>Nicolas, Jean-Marie</creatorcontrib><creatorcontrib>Rose, Sarah</creatorcontrib><creatorcontrib>Jackson, Michael</creatorcontrib><creatorcontrib>Colman, Peter</creatorcontrib><creatorcontrib>Briône, 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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> |
fulltext | fulltext |
identifier | ISSN: 1932-6203 |
ispartof | PloS one, 2017-08, Vol.12 (8), p.e0182887-e0182887 |
issn | 1932-6203 1932-6203 |
language | eng |
recordid | cdi_plos_journals_1933959736 |
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 |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-23T13%3A41%3A33IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Antiparkinsonian%20effects%20of%20the%20%22Radiprodil%20and%20Tozadenant%22%20combination%20in%20MPTP-treated%20marmosets&rft.jtitle=PloS%20one&rft.au=Michel,%20Anne&rft.date=2017-08-30&rft.volume=12&rft.issue=8&rft.spage=e0182887&rft.epage=e0182887&rft.pages=e0182887-e0182887&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0182887&rft_dat=%3Cgale_plos_%3EA502448594%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1933959736&rft_id=info:pmid/28854243&rft_galeid=A502448594&rft_doaj_id=oai_doaj_org_article_c4070f98bfa74565a0673a8ffa7939fd&rfr_iscdi=true |