BN82451 attenuates l-dopa-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson’s disease
The development of l-dopa-induced dyskinesia (LID) remains a major problem in the long-term treatment of Parkinson’s disease (PD). This study aimed to assess the effect of the multitargeting molecule BN82451 on LID and to measure striatal mRNA expression of several genes in a rat model of PD. Rats w...
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| Veröffentlicht in: | Neuropharmacology 2011-03, Vol.60 (4), p.692-700 |
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| creator | Spinnewyn, Brigitte Mautino, Gisele Marin, Jean-Gregoire Rocher, Marie Noëlle Grandoulier, Anne Sophie Ferrandis, Eric Auguet, Michel Chabrier, Pierre-Etienne |
| description | The development of
l-dopa-induced dyskinesia (LID) remains a major problem in the long-term treatment of Parkinson’s disease (PD). This study aimed to assess the effect of the multitargeting molecule BN82451 on LID and to measure striatal mRNA expression of several genes in a rat model of PD.
Rats were administered two unilateral injections of 6-OHDA in the striatum. After four weeks, the animals started a chronic daily treatment with increasing doses of
l-dopa over a further four-week period. Over the course of
l-dopa treatment, the rats developed abnormal involuntary movements (AIMs) classified as locomotive, axial, orolingual and forelimb dyskinesia.
In animals rendered dyskinetic by
l-dopa, administration of BN82451 at doses ranging from 1 to 10 mg/kg p.o. attenuated the severity of fully-established AIMs in a dose-related manner. This anti-dyskinetic effect could be achieved with lower doses of BN82451 administered sub chronically vs. acute single treatment. The improvement of AIMs is not due to a reduction in the general motor activity of dyskinetic rats. BN82451 treatment significantly reversed the overexpression of c-Fos, FosB and Arc mRNA associated with the dyskinesiogenic action of
l-dopa. A significant correlation between the degree of overexpression of c-Fos, FosB and Arc mRNA and the dyskinesiogenic action of
l-dopa was observed. The data demonstrate that BN82451 effectively attenuates LID and the associated molecular alterations in an animal model of PD and may represent a treatment option for managing dyskinesia.
► BN82451, a multitargeting molecule, reduces dyskinesia in 6-OHDA-lesioned rat model. ► BN82451 attenuates abnormal involuntary movements in a dose-related manner. ► BN82451 attenuates the associated molecular alterations: c-Fos, FosB and Arc mRNA. ► A significant correlation between these effects is observed. |
| doi_str_mv | 10.1016/j.neuropharm.2010.11.019 |
| format | Article |
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l-dopa-induced dyskinesia (LID) remains a major problem in the long-term treatment of Parkinson’s disease (PD). This study aimed to assess the effect of the multitargeting molecule BN82451 on LID and to measure striatal mRNA expression of several genes in a rat model of PD.
Rats were administered two unilateral injections of 6-OHDA in the striatum. After four weeks, the animals started a chronic daily treatment with increasing doses of
l-dopa over a further four-week period. Over the course of
l-dopa treatment, the rats developed abnormal involuntary movements (AIMs) classified as locomotive, axial, orolingual and forelimb dyskinesia.
In animals rendered dyskinetic by
l-dopa, administration of BN82451 at doses ranging from 1 to 10 mg/kg p.o. attenuated the severity of fully-established AIMs in a dose-related manner. This anti-dyskinetic effect could be achieved with lower doses of BN82451 administered sub chronically vs. acute single treatment. The improvement of AIMs is not due to a reduction in the general motor activity of dyskinetic rats. BN82451 treatment significantly reversed the overexpression of c-Fos, FosB and Arc mRNA associated with the dyskinesiogenic action of
l-dopa. A significant correlation between the degree of overexpression of c-Fos, FosB and Arc mRNA and the dyskinesiogenic action of
l-dopa was observed. The data demonstrate that BN82451 effectively attenuates LID and the associated molecular alterations in an animal model of PD and may represent a treatment option for managing dyskinesia.
► BN82451, a multitargeting molecule, reduces dyskinesia in 6-OHDA-lesioned rat model. ► BN82451 attenuates abnormal involuntary movements in a dose-related manner. ► BN82451 attenuates the associated molecular alterations: c-Fos, FosB and Arc mRNA. ► A significant correlation between these effects is observed.</description><identifier>ISSN: 0028-3908</identifier><identifier>EISSN: 1873-7064</identifier><identifier>DOI: 10.1016/j.neuropharm.2010.11.019</identifier><identifier>PMID: 21129389</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>6-OHDA ; Animals ; Area Under Curve ; Behavior, Animal - drug effects ; BN82451 ; c-Fos ; Chromatography, High Pressure Liquid ; Corpus Striatum - drug effects ; Corpus Striatum - metabolism ; Dose-Response Relationship, Drug ; Dyskinesia ; Dyskinesia, Drug-Induced - drug therapy ; Dyskinesia, Drug-Induced - metabolism ; FosB ; Gene Expression ; l-dopa ; Levodopa - adverse effects ; Male ; Neuroprotective Agents - metabolism ; Neuroprotective Agents - pharmacology ; Neuroprotective Agents - therapeutic use ; Oxidopamine - pharmacology ; Parkinsonian Disorders - drug therapy ; Parkinsonian Disorders - metabolism ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - metabolism ; Thiazoles - metabolism ; Thiazoles - pharmacology ; Thiazoles - therapeutic use</subject><ispartof>Neuropharmacology, 2011-03, Vol.60 (4), p.692-700</ispartof><rights>2010 Elsevier Ltd</rights><rights>Copyright © 2010 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c373t-4ecfb0129e74d2a6e99c65f0f0701c5e9fdb8b4eabf3d7fbe40aef9f8aec1e653</citedby><cites>FETCH-LOGICAL-c373t-4ecfb0129e74d2a6e99c65f0f0701c5e9fdb8b4eabf3d7fbe40aef9f8aec1e653</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0028390810003187$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21129389$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Spinnewyn, Brigitte</creatorcontrib><creatorcontrib>Mautino, Gisele</creatorcontrib><creatorcontrib>Marin, Jean-Gregoire</creatorcontrib><creatorcontrib>Rocher, Marie Noëlle</creatorcontrib><creatorcontrib>Grandoulier, Anne Sophie</creatorcontrib><creatorcontrib>Ferrandis, Eric</creatorcontrib><creatorcontrib>Auguet, Michel</creatorcontrib><creatorcontrib>Chabrier, Pierre-Etienne</creatorcontrib><title>BN82451 attenuates l-dopa-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson’s disease</title><title>Neuropharmacology</title><addtitle>Neuropharmacology</addtitle><description>The development of
l-dopa-induced dyskinesia (LID) remains a major problem in the long-term treatment of Parkinson’s disease (PD). This study aimed to assess the effect of the multitargeting molecule BN82451 on LID and to measure striatal mRNA expression of several genes in a rat model of PD.
Rats were administered two unilateral injections of 6-OHDA in the striatum. After four weeks, the animals started a chronic daily treatment with increasing doses of
l-dopa over a further four-week period. Over the course of
l-dopa treatment, the rats developed abnormal involuntary movements (AIMs) classified as locomotive, axial, orolingual and forelimb dyskinesia.
In animals rendered dyskinetic by
l-dopa, administration of BN82451 at doses ranging from 1 to 10 mg/kg p.o. attenuated the severity of fully-established AIMs in a dose-related manner. This anti-dyskinetic effect could be achieved with lower doses of BN82451 administered sub chronically vs. acute single treatment. The improvement of AIMs is not due to a reduction in the general motor activity of dyskinetic rats. BN82451 treatment significantly reversed the overexpression of c-Fos, FosB and Arc mRNA associated with the dyskinesiogenic action of
l-dopa. A significant correlation between the degree of overexpression of c-Fos, FosB and Arc mRNA and the dyskinesiogenic action of
l-dopa was observed. The data demonstrate that BN82451 effectively attenuates LID and the associated molecular alterations in an animal model of PD and may represent a treatment option for managing dyskinesia.
► BN82451, a multitargeting molecule, reduces dyskinesia in 6-OHDA-lesioned rat model. ► BN82451 attenuates abnormal involuntary movements in a dose-related manner. ► BN82451 attenuates the associated molecular alterations: c-Fos, FosB and Arc mRNA. ► A significant correlation between these effects is observed.</description><subject>6-OHDA</subject><subject>Animals</subject><subject>Area Under Curve</subject><subject>Behavior, Animal - drug effects</subject><subject>BN82451</subject><subject>c-Fos</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Corpus Striatum - drug effects</subject><subject>Corpus Striatum - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Dyskinesia</subject><subject>Dyskinesia, Drug-Induced - drug therapy</subject><subject>Dyskinesia, Drug-Induced - metabolism</subject><subject>FosB</subject><subject>Gene Expression</subject><subject>l-dopa</subject><subject>Levodopa - adverse effects</subject><subject>Male</subject><subject>Neuroprotective Agents - metabolism</subject><subject>Neuroprotective Agents - pharmacology</subject><subject>Neuroprotective Agents - therapeutic use</subject><subject>Oxidopamine - pharmacology</subject><subject>Parkinsonian Disorders - drug therapy</subject><subject>Parkinsonian Disorders - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - metabolism</subject><subject>Thiazoles - metabolism</subject><subject>Thiazoles - pharmacology</subject><subject>Thiazoles - therapeutic use</subject><issn>0028-3908</issn><issn>1873-7064</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkM1uFDEMgCNERZfCK6DcOGVxJvOTHNvyU6Sq5QDnKJM4IstMsiQzlXrjNXg9nqRZbYFjT1bsz7H9EUI5bDnw_t1uG3HNaf_d5HnbwCHNt8DVM7LhchBsgL59TjYAjWRCgTwlL0vZAUAruXxBThvOGyWk2pDx4kY2bcepWRaMq1mw0Im5tDcsRLdadNTdlx8hYgmGhkh7dnv1_pxN9Z1irWaz0Dk5nGjy9IvJFS0p_vn1u1AXCpqCr8iJN1PB14_xjHz7-OHr5RW7vv30-fL8mlkxiIW1aP0IdS8cWteYHpWyfefBwwDcdqi8G-XYohm9cIMfsQWDXnlp0HLsO3FG3h7_3ef0c8Wy6DkUi9NkIqa1aAUD7wSAqKQ8kjanUjJ6vc9hNvlec9AHwXqn_wvWB8Gac10F19Y3j0PWcUb3r_Gv0QpcHAGsp94FzLrYgLGKDBntol0KT095AOX6k6M</recordid><startdate>20110301</startdate><enddate>20110301</enddate><creator>Spinnewyn, Brigitte</creator><creator>Mautino, Gisele</creator><creator>Marin, Jean-Gregoire</creator><creator>Rocher, Marie Noëlle</creator><creator>Grandoulier, Anne Sophie</creator><creator>Ferrandis, Eric</creator><creator>Auguet, Michel</creator><creator>Chabrier, Pierre-Etienne</creator><general>Elsevier Ltd</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>7TK</scope></search><sort><creationdate>20110301</creationdate><title>BN82451 attenuates l-dopa-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson’s disease</title><author>Spinnewyn, Brigitte ; Mautino, Gisele ; Marin, Jean-Gregoire ; Rocher, Marie Noëlle ; Grandoulier, Anne Sophie ; Ferrandis, Eric ; Auguet, Michel ; Chabrier, Pierre-Etienne</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c373t-4ecfb0129e74d2a6e99c65f0f0701c5e9fdb8b4eabf3d7fbe40aef9f8aec1e653</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>6-OHDA</topic><topic>Animals</topic><topic>Area Under Curve</topic><topic>Behavior, Animal - drug effects</topic><topic>BN82451</topic><topic>c-Fos</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Corpus Striatum - drug effects</topic><topic>Corpus Striatum - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Dyskinesia</topic><topic>Dyskinesia, Drug-Induced - drug therapy</topic><topic>Dyskinesia, Drug-Induced - metabolism</topic><topic>FosB</topic><topic>Gene Expression</topic><topic>l-dopa</topic><topic>Levodopa - adverse effects</topic><topic>Male</topic><topic>Neuroprotective Agents - metabolism</topic><topic>Neuroprotective Agents - pharmacology</topic><topic>Neuroprotective Agents - therapeutic use</topic><topic>Oxidopamine - pharmacology</topic><topic>Parkinsonian Disorders - drug therapy</topic><topic>Parkinsonian Disorders - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - metabolism</topic><topic>Thiazoles - metabolism</topic><topic>Thiazoles - pharmacology</topic><topic>Thiazoles - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Spinnewyn, Brigitte</creatorcontrib><creatorcontrib>Mautino, Gisele</creatorcontrib><creatorcontrib>Marin, Jean-Gregoire</creatorcontrib><creatorcontrib>Rocher, Marie Noëlle</creatorcontrib><creatorcontrib>Grandoulier, Anne Sophie</creatorcontrib><creatorcontrib>Ferrandis, Eric</creatorcontrib><creatorcontrib>Auguet, Michel</creatorcontrib><creatorcontrib>Chabrier, Pierre-Etienne</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><jtitle>Neuropharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Spinnewyn, Brigitte</au><au>Mautino, Gisele</au><au>Marin, Jean-Gregoire</au><au>Rocher, Marie Noëlle</au><au>Grandoulier, Anne Sophie</au><au>Ferrandis, Eric</au><au>Auguet, Michel</au><au>Chabrier, Pierre-Etienne</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>BN82451 attenuates l-dopa-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson’s disease</atitle><jtitle>Neuropharmacology</jtitle><addtitle>Neuropharmacology</addtitle><date>2011-03-01</date><risdate>2011</risdate><volume>60</volume><issue>4</issue><spage>692</spage><epage>700</epage><pages>692-700</pages><issn>0028-3908</issn><eissn>1873-7064</eissn><abstract>The development of
l-dopa-induced dyskinesia (LID) remains a major problem in the long-term treatment of Parkinson’s disease (PD). This study aimed to assess the effect of the multitargeting molecule BN82451 on LID and to measure striatal mRNA expression of several genes in a rat model of PD.
Rats were administered two unilateral injections of 6-OHDA in the striatum. After four weeks, the animals started a chronic daily treatment with increasing doses of
l-dopa over a further four-week period. Over the course of
l-dopa treatment, the rats developed abnormal involuntary movements (AIMs) classified as locomotive, axial, orolingual and forelimb dyskinesia.
In animals rendered dyskinetic by
l-dopa, administration of BN82451 at doses ranging from 1 to 10 mg/kg p.o. attenuated the severity of fully-established AIMs in a dose-related manner. This anti-dyskinetic effect could be achieved with lower doses of BN82451 administered sub chronically vs. acute single treatment. The improvement of AIMs is not due to a reduction in the general motor activity of dyskinetic rats. BN82451 treatment significantly reversed the overexpression of c-Fos, FosB and Arc mRNA associated with the dyskinesiogenic action of
l-dopa. A significant correlation between the degree of overexpression of c-Fos, FosB and Arc mRNA and the dyskinesiogenic action of
l-dopa was observed. The data demonstrate that BN82451 effectively attenuates LID and the associated molecular alterations in an animal model of PD and may represent a treatment option for managing dyskinesia.
► BN82451, a multitargeting molecule, reduces dyskinesia in 6-OHDA-lesioned rat model. ► BN82451 attenuates abnormal involuntary movements in a dose-related manner. ► BN82451 attenuates the associated molecular alterations: c-Fos, FosB and Arc mRNA. ► A significant correlation between these effects is observed.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>21129389</pmid><doi>10.1016/j.neuropharm.2010.11.019</doi><tpages>9</tpages></addata></record> |
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| ispartof | Neuropharmacology, 2011-03, Vol.60 (4), p.692-700 |
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| subjects | 6-OHDA Animals Area Under Curve Behavior, Animal - drug effects BN82451 c-Fos Chromatography, High Pressure Liquid Corpus Striatum - drug effects Corpus Striatum - metabolism Dose-Response Relationship, Drug Dyskinesia Dyskinesia, Drug-Induced - drug therapy Dyskinesia, Drug-Induced - metabolism FosB Gene Expression l-dopa Levodopa - adverse effects Male Neuroprotective Agents - metabolism Neuroprotective Agents - pharmacology Neuroprotective Agents - therapeutic use Oxidopamine - pharmacology Parkinsonian Disorders - drug therapy Parkinsonian Disorders - metabolism Rats Rats, Sprague-Dawley Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - metabolism Thiazoles - metabolism Thiazoles - pharmacology Thiazoles - therapeutic use |
| title | BN82451 attenuates l-dopa-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson’s disease |
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