Side effect profile of 5-HT treatments for Parkinson's disease and L-DOPA-induced dyskinesia in rats
Identifieur interne : 000465 ( Ncbi/Curation ); précédent : 000464; suivant : 000466Side effect profile of 5-HT treatments for Parkinson's disease and L-DOPA-induced dyskinesia in rats
Auteurs : D. Lindenbach ; N. Palumbo ; C Ostock ; N. Vilceus ; M Conti ; C. BishopSource :
- British Journal of Pharmacology [ 0007-1188 ] ; 2014.
Abstract
Treatment of Parkinson's disease (PD) with L-DOPA eventually causes abnormal involuntary movements known as dyskinesias in most patients. Dyskinesia can be reduced using compounds that act as direct or indirect agonists of the 5-HT1A receptor, but these drugs have been reported to worsen PD features and are known to produce ‘5-HT syndrome’, symptoms of which include tremor, myoclonus, rigidity and hyper-reflexia.
Sprague-Dawley rats were given unilateral nigrostriatal dopamine lesions with 6-hydroxydopamine. Each of the following three purportedly anti-dyskinetic 5-HT compounds were administered 15 min before L-DOPA: the full 5-HT1A agonist ±-8-hydroxy-2-dipropylaminotetralin (±8-OH-DPAT), the partial 5-HT1A agonist buspirone or the 5-HT transporter inhibitor citalopram. After these injections, animals were monitored for dyskinesia, 5-HT syndrome, motor activity and PD akinesia.
Each 5-HT drug dose-dependently reduced dyskinesia by relatively equal amounts (±8-OH-DPAT ≥ citalopram ≥ buspirone), but 5-HT syndrome was higher with ±8-OH-DPAT, lower with buspirone and not present with citalopram. Importantly, with or without L-DOPA, all three compounds provided an additional improvement of PD akinesia. All drugs tempered the locomotor response to L-DOPA suggesting dyskinesia reduction, but vertical rearing was reduced with 5-HT drugs, potentially reflecting features of 5-HT syndrome.
The results suggest that compounds that indirectly facilitate 5-HT1A receptor activation, such as citalopram, may be more effective therapeutics than direct 5-HT1A receptor agonists because they exhibit similar anti-dyskinesia efficacy, while possessing a reduced side effect profile.
Url:
DOI: 10.1111/bph.12894
PubMed: 25175895
PubMed Central: 4280972
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Side effect profile of 5-HT treatments for Parkinson's disease and L-DOPA-induced dyskinesia in rats</title><author><name sortKey="Lindenbach, D" sort="Lindenbach, D" uniqKey="Lindenbach D" first="D" last="Lindenbach">D. Lindenbach</name></author><author><name sortKey="Palumbo, N" sort="Palumbo, N" uniqKey="Palumbo N" first="N" last="Palumbo">N. Palumbo</name></author><author><name sortKey="Ostock, C Y" sort="Ostock, C Y" uniqKey="Ostock C" first="C" last="Ostock">C Ostock</name></author><author><name sortKey="Vilceus, N" sort="Vilceus, N" uniqKey="Vilceus N" first="N" last="Vilceus">N. Vilceus</name></author><author><name sortKey="Conti, M M" sort="Conti, M M" uniqKey="Conti M" first="M" last="Conti">M Conti</name></author><author><name sortKey="Bishop, C" sort="Bishop, C" uniqKey="Bishop C" first="C" last="Bishop">C. Bishop</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25175895</idno><idno type="pmc">4280972</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280972</idno><idno type="RBID">PMC:4280972</idno><idno type="doi">10.1111/bph.12894</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000225</idno><idno type="wicri:Area/Pmc/Curation">000225</idno><idno type="wicri:Area/Pmc/Checkpoint">000034</idno><idno type="wicri:Area/Ncbi/Merge">000465</idno><idno type="wicri:Area/Ncbi/Curation">000465</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Side effect profile of 5-HT treatments for Parkinson's disease and L-DOPA-induced dyskinesia in rats</title><author><name sortKey="Lindenbach, D" sort="Lindenbach, D" uniqKey="Lindenbach D" first="D" last="Lindenbach">D. Lindenbach</name></author><author><name sortKey="Palumbo, N" sort="Palumbo, N" uniqKey="Palumbo N" first="N" last="Palumbo">N. Palumbo</name></author><author><name sortKey="Ostock, C Y" sort="Ostock, C Y" uniqKey="Ostock C" first="C" last="Ostock">C Ostock</name></author><author><name sortKey="Vilceus, N" sort="Vilceus, N" uniqKey="Vilceus N" first="N" last="Vilceus">N. Vilceus</name></author><author><name sortKey="Conti, M M" sort="Conti, M M" uniqKey="Conti M" first="M" last="Conti">M Conti</name></author><author><name sortKey="Bishop, C" sort="Bishop, C" uniqKey="Bishop C" first="C" last="Bishop">C. Bishop</name></author></analytic><series><title level="j">British Journal of Pharmacology</title><idno type="ISSN">0007-1188</idno><idno type="e-ISSN">1476-5381</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>BACKGROUND AND PURPOSE</title><p>Treatment of Parkinson's disease (PD) with L-DOPA eventually causes abnormal involuntary movements known as dyskinesias in most patients. Dyskinesia can be reduced using compounds that act as direct or indirect agonists of the 5-HT<sub>1</sub><sub>A</sub> receptor, but these drugs have been reported to worsen PD features and are known to produce ‘5-HT syndrome’, symptoms of which include tremor, myoclonus, rigidity and hyper-reflexia.</p></sec><sec><title>EXPERIMENTAL APPROACH</title><p>Sprague-Dawley rats were given unilateral nigrostriatal dopamine lesions with 6-hydroxydopamine. Each of the following three purportedly anti-dyskinetic 5-HT compounds were administered 15 min before L-DOPA: the full 5-HT<sub>1</sub><sub>A</sub> agonist ±-8-hydroxy-2-dipropylaminotetralin (±8-OH-DPAT), the partial 5-HT<sub>1</sub><sub>A</sub> agonist buspirone or the 5-HT transporter inhibitor citalopram. After these injections, animals were monitored for dyskinesia, 5-HT syndrome, motor activity and PD akinesia.</p></sec><sec><title>KEY RESULTS</title><p>Each 5-HT drug dose-dependently reduced dyskinesia by relatively equal amounts (±8-OH-DPAT ≥ citalopram ≥ buspirone), but 5-HT syndrome was higher with ±8-OH-DPAT, lower with buspirone and not present with citalopram. Importantly, with or without L-DOPA, all three compounds provided an additional improvement of PD akinesia. All drugs tempered the locomotor response to L-DOPA suggesting dyskinesia reduction, but vertical rearing was reduced with 5-HT drugs, potentially reflecting features of 5-HT syndrome.</p></sec><sec><title>CONCLUSIONS AND IMPLICATIONS</title><p>The results suggest that compounds that indirectly facilitate 5-HT<sub>1</sub><sub>A</sub> receptor activation, such as citalopram, may be more effective therapeutics than direct 5-HT<sub>1</sub><sub>A</sub> receptor agonists because they exhibit similar anti-dyskinesia efficacy, while possessing a reduced side effect profile.</p></sec></div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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