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Synergistic effect of serotonin 1A and serotonin 1B/D receptor agonists in the treatment of L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats.
- Source :
-
Experimental neurology [Exp Neurol] 2022 Dec; Vol. 358, pp. 114209. Date of Electronic Publication: 2022 Aug 18. - Publication Year :
- 2022
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Abstract
- Background: The gold standard for symptomatic relief of Parkinson's disease (PD) is L-DOPA. However, long-term treatment often leads to motor complications such as L-DOPA-induced dyskinesia (LID). While amantadine (Gocovri™) is the only approved therapy for dyskinesia in PD patients on the American market, it is associated with neurological side effects and limited efficacy. Thus, there remains a high unmet need for addressing LID in PD patients worldwide.<br />Objective: The objective of this study was to evaluate the efficacy, safety and performance compared to approved treatments of the serotonin receptor 1A (5-HT1A) and 5-HT1B/D agonists buspirone and zolmitriptan in the 6-hydroxydopamine unilaterally lesioned rat model for PD.<br />Methods: The hemiparkinsonian 6-OHDA-lesioned rats underwent chronic treatment with L-DOPA to induce dyskinesia and were subsequently used for efficacy testing of buspirone, zolmitriptan and comparison with amantadine, measured as abnormal involuntary movement (AIM) scores after L-DOPA challenge. Safety testing was performed in model and naïve animals using forelimb adjusting, rotarod and open field tests.<br />Results: 5-HT1A and 5-HT1B/D agonism effectively reduced AIM scores in a synergistic manner. The drug combination of buspirone and zolmitriptan was safe and did not lead to tolerance development following sub-chronic administration. Head-to-head comparison with amantadine showed superior performance of buspirone and zolmitriptan in the model.<br />Conclusions: The strong anti-dyskinetic effect found with combined 5-HT1A and 5-HT1B/D agonism renders buspirone and zolmitriptan together a meaningful treatment for LID in PD.<br /> (Copyright © 2022. Published by Elsevier Inc.)
- Subjects :
- Amantadine therapeutic use
Animals
Antiparkinson Agents adverse effects
Buspirone pharmacology
Buspirone therapeutic use
Levodopa pharmacology
Oxazolidinones
Oxidopamine toxicity
Rats
Rats, Sprague-Dawley
Receptors, Serotonin
Serotonin
Serotonin 5-HT1 Receptor Agonists pharmacology
Serotonin 5-HT1 Receptor Agonists therapeutic use
Tryptamines
Dyskinesia, Drug-Induced drug therapy
Dyskinesia, Drug-Induced etiology
Parkinson Disease complications
Parkinson Disease etiology
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2430
- Volume :
- 358
- Database :
- MEDLINE
- Journal :
- Experimental neurology
- Publication Type :
- Academic Journal
- Accession number :
- 35988699
- Full Text :
- https://doi.org/10.1016/j.expneurol.2022.114209