RT Journal Article
SR Electronic
T1 Synergistic Effect of Serotonin 1A and Serotonin 1B/D Receptor Agonists in the Treatment of L-DOPA-Induced Dyskinesia in 6-Hydroxydopamine-Lesioned Rats
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.08.31.458314
DO 10.1101/2021.08.31.458314
A1 Mikael Thomsen
A1 Anca Stoica
A1 Kenneth Vielsted Christensen
A1 Jens Mikkelsen
A1 John Bondo Hansen
YR 2021
UL http://biorxiv.org/content/early/2021/09/01/2021.08.31.458314.abstract
AB Background The gold standard for symptomatic relief of Parkinson’s disease 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 people with Parkinson’s disease 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 Parkinson’s disease patients worldwide.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 Parkinson’s disease.Methods The hemi-parkinsonian 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 naive animals using forelimb adjusting, rotarod and open field tests.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.Conclusions The strong anti-dyskinetic effect found with combined 5-HT1A and 5-HT1B/D agonism renders buspirone and zolmitriptan a potential clinical candidate for LID in Parkinson’s disease.Competing Interest StatementJohn Bondo Hansen and Mikael Thomsen are co-inventors of the patent PCT-DK2011/050383 covering combinations of serotonin receptor agonists for treatment of movement disorders. Mikael Thomsen is consultant for Bukwang Pharm. Co., Ltd. 7, Sangdo-ro, Dongjak-gu, Seoul 06955 South Korea South Korean business reg. no.118-81-00450.