Synergistic effect of serotonin 1A and serotonin 1B/D receptor agonists in the treatment of L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats
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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. / Thomsen, Mikael; Stoica, Anca; Christensen, Kenneth Vielsted; Fryland, Tue; Mikkelsen, Jens D.; Hansen, John Bondo.
In: Experimental Neurology, Vol. 358, 114209, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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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
AU - Thomsen, Mikael
AU - Stoica, Anca
AU - Christensen, Kenneth Vielsted
AU - Fryland, Tue
AU - Mikkelsen, Jens D.
AU - Hansen, John Bondo
PY - 2022
Y1 - 2022
N2 - 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 (GocovriTM) 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. 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. .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 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 together a meaningful treatment for LID in PD.
AB - 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 (GocovriTM) 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. 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. .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 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 together a meaningful treatment for LID in PD.
KW - Dyskinesia
KW - Parkinson ?s
KW - Buspirone
KW - Zolmitriptan
KW - 5-HTR agonist
KW - LEVODOPA-INDUCED DYSKINESIA
KW - DORSAL RAPHE NUCLEUS
KW - AMANTADINE EXTENDED-RELEASE
KW - 10-YEAR FOLLOW-UP
KW - PARKINSONS-DISEASE
KW - MOTOR COMPLICATIONS
KW - 5-HT1B RECEPTORS
KW - EXTRACELLULAR DOPAMINE
KW - ANIMAL-MODELS
KW - 5-HYDROXYTRYPTAMINE RELEASE
U2 - 10.1016/j.expneurol.2022.114209
DO - 10.1016/j.expneurol.2022.114209
M3 - Journal article
C2 - 35988699
VL - 358
JO - Experimental Neurology
JF - Experimental Neurology
SN - 0014-4886
M1 - 114209
ER -
ID: 320638053