Abstract
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 Statement
John 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.
Footnotes
Financial Disclosure/Conflict of Interest concerning the research related to the manuscript:
John 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.