Anti-dyskinetic efficacy of 5-HT3 receptor antagonist in the hemi-parkinsonian rat model

Abstract

Parkinson's disease is a progressive debilitative neurodegenerative disease characterised mostly with bradykinesia, tremor, catatonia, drooping posture, unsteady gate and unstable steps. Levodopa has been proven to be among the most effective and acceptable treatment that can reconstitute dopamine in Parkinson's disease. However, there is a relation between levodopa long term administration and dyskinesia. Regarding the effectiveness of ondansetron in Parkinson's disease, we planned to test its effect on levodopa-induced dyskinesia (LID). In this study, Parkinsonism was induced in 40 adult male rats using 6-OHDA injection into the striatum via stereotaxic surgery. After 2 weeks, all animals tested for Parkinson's disease using apomorphine rotation test. Then, animals with positive symptoms for Parkinsonism divided into 4 equal groups, the first group treated with levodopa 50 mg/kg i.p, the second group received only distilled water, the third and forth groups treated with levodopa 50 mg/kg i.p plus two different doses of ondansetron (0.04 and 0.08 mg/kg i.p) for 3 weeks. Animals tested for dyskinesia using AIMs and rotarod tests at specific days and a week after discontinuation of ondansetron. Evaluations of AIMs test showed significant changes in dyskinetic movements and reduction in scores in groups treating with ondansetron when compared with the first group. Upon discontinuations of ondansetron in the last two groups, AIMs scores significantly increased. While in rotarod test, ondansetron had no additional benefit when added to levodopa in motor coordination of animals. Findings of this study suggest that co administration of ondansetron with levodopa is effective in attenuating dyskinesia.

Current Knowledge on the Background, Pathophysiology, and Treatment of Levodopa-Induced Dyskinesia – Literature Review.

“…Interestingly, ondansetron administration was discontinued on day 23, resulting in significant differences between the L-DOPA + ondansetron and control groups on day 30. These results indicate the potential of 5-HT3 antagonists such as ondansetron, in controlling LID in the treatment of PD [121].…”

Current Knowledge on the Background, Pathophysiology and Treatment of Levodopa-Induced Dyskinesia—Literature Review

“…Interestingly, ondansetron administration was discontinued on day 23, resulting in significant differences between the L-DOPA and ondansetron and the control groups on day 30. These results suggest the potential of 5-HT3 antagonists, such as ondansetron, in controlling LID in the treatment of PD, although further research is necessary in order to understand this correlation [ 127 ].…”

Amantadine: reappraisal of the timeless diamond—target updates and novel therapeutic potentials

“…2 , Tables 3 , 4 ); nevertheless, this action should not be neglected and may have supportive potential as add-on to other actions. Serotonergic (5-HT) receptors type 5-HT3 Ondansetron (5-HT3 antagonist) has been shown to inhibit dyskinesia-like behavior in rats treated with L-DOPA (Aboulghasemi et al 2019 ). Moreover, 5-HT3 antagonism has been proposed as a therapeutic approach for a number of indications such as depression, emesis, irritable bowel syndrome (IBS), schizophrenia, anxiety, cognitive deficit, pruritis, inflammation, and pain (Thompson and Lummis 2007 ) Potassium channels At drug concentrations approximately three times higher than therapeutically relevant (Table 4 ), amantadine blocks inwardly rectifying potassium channels (Kir2) that control the intrinsic excitability of GABAergic spiny projection neurons (SPNs, IC 50 = 27 µm), without significantly diminishing synaptic NMDA currents (Shen et al 2020 ).…”

“…Serotonergic (5-HT) receptors type 5-HT3 Ondansetron (5-HT3 antagonist) has been shown to inhibit dyskinesia-like behavior in rats treated with L-DOPA (Aboulghasemi et al 2019 ). Moreover, 5-HT3 antagonism has been proposed as a therapeutic approach for a number of indications such as depression, emesis, irritable bowel syndrome (IBS), schizophrenia, anxiety, cognitive deficit, pruritis, inflammation, and pain (Thompson and Lummis 2007 )…”