The multimodal serotonin compound Vilazodone alone, but not combined with the glutamate antagonist Amantadine, reduces l-DOPA-induced dyskinesia in hemiparkinsonian rats

Cohen, Sophie; Terry, Michelle; Coyle, Michael; Wheelis, Emily; Centner, Ashley; Smith, Samantha K.; Glinski, John; Lipari, Natalie; Budrow, Carla; Manfredsson, Fredric P.; Bishop, Christopher

doi:10.1016/j.pbb.2022.173393

“…Post hoc analyses revealed that ALO AIMs were elevated within a week of starting treatment compared to Day 1 and were maintained when tested a week later (both p < 0.05). When analyzing the effects of daily L-DOPA on ALO AIMs in Experiment 2, the same pattern of effects was observed (χ 2 (2) = 17.543, p < 0.05), supporting prior work that within 1 week of daily treatment, AIMs stabilize at this dose of L-DOPA [ 35 , 36 , 42 ].…”

Section: Resultssupporting

confidence: 82%

“…In recent years, in attempts to overcome prior limitations, several novel strategies have been pursued, including biased and selective 5-HT 1A R agonists [ 45 , 46 ], combination strategies [ 42 , 47 ], and multimodal 5-HT approaches [ 35 , 36 , 48 ]. With several studies now supporting a combined SERT blockade and 5-HT 1 R agonism as a promising profile, we sought to characterize the durability and pharmacology of the FDA-approved multimodal 5-HT antidepressant VTX in the hemiparkinsonian rodent.…”

Section: Discussionmentioning

confidence: 99%

Broad Serotonergic Actions of Vortioxetine as a Promising Avenue for the Treatment of L-DOPA-Induced Dyskinesia

Budrow

¹

,

Elder

²

,

Coyle

³

et al. 2023

Cells

Self Cite

View full text Add to dashboard Cite

Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by motor symptoms that result from loss of nigrostriatal dopamine (DA) cells. While L-DOPA provides symptom alleviation, its chronic use often results in the development of L-DOPA-induced dyskinesia (LID). Evidence suggests that neuroplasticity within the serotonin (5-HT) system contributes to LID onset, persistence, and severity. This has been supported by research showing 5-HT compounds targeting 5-HT1A/1B receptors and/or the 5-HT transporter (SERT) can reduce LID. Recently, vortioxetine, a multimodal 5-HT compound developed for depression, demonstrated acute anti-dyskinetic effects. However, the durability and underlying pharmacology of vortioxetine’s anti-dyskinetic actions have yet to be delineated. To address these gaps, we used hemiparkinsonian rats in Experiment 1, examining the effects of sub-chronic vortioxetine on established LID and motor performance. In Experiment 2, we applied the 5-HT1A antagonist WAY-100635 or 5-HT1B antagonist SB-224289 in conjunction with L-DOPA and vortioxetine to determine the contributions of each receptor to vortioxetine’s effects. The results revealed that vortioxetine consistently and dose-dependently attenuated LID while independently, 5-HT1A and 5-HT1B receptors each partially reversed vortioxetine’s effects. Such findings further support the promise of pharmacological strategies, such as vortioxetine, and indicate that broad 5-HT actions may provide durable responses without significant side effects.

show abstract

“…Conclusively, AMT is not recommended for the treatment of COVID-19 8 therapy. The main problems with the effective and safe administration of AMT and RMT in the treatment of the aforementioned disorders appear to be their low bioavailability and, despite intensive research, a lack of a clear explanation of the drug’s mechanism of action 9 – 14 .…”

Section: Introductionmentioning

confidence: 99%

Metabolic profiling to evaluate the impact of amantadine and rimantadine on the secondary metabolism of a model organism

Kostina-Bednarz,

Płonka,

Barchanska

2023

Sci Rep

1

0

View full text Add to dashboard Cite

Metabolic profiling offers huge potential to highlight markers and mechanisms in support of toxicology and pathology investigations during drug development. The main objective was to modify therapy with adamantane derivatives: amantadine and rimantadine, to increase their bioavailability and evaluate the influence of such therapy on drug metabolism using Saccharomyces cerevisiae as the model organism. In this study, the profile of endogenous metabolites of a model organism was measured and interpreted to provide an opportunity to investigate changes induced by treatment with amantadine and rimantadine. It was found that resveratrol supplementation synergistically enhanced the effects of amantadine treatment and increased rimantadine metabolism, potentially reducing side effects. The fingerprinting strategy was used as an efficient technique for qualitatively evaluating and monitoring changes in the profiles of endogenous components and their contents in a model organism. Chemometric tools were employed to find marker compounds that can be defined as characteristic indicators of a pharmacological response to a therapeutic intervention. An improved understanding of the mechanisms involved in drug effect and an increased ability to predict individual variations in the drug response of organisms will improve the treatment process and the development of new therapies.

show abstract

“…Conclusively, AMT is not recommended for the treatment of COVID-19 8 . The main problems with the effective and safe administration of AMT and RMT in the treatment of the aforementioned disorders appear to be their low bioavailability and, despite intensive research, a lack of a clear explanation of the drug's mechanism of action [9][10][11][12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

Metabolic profiling to evaluate the impact of amantadine and rimantadine on the secondary metabolism of a model organism

Kostina-Bednarz

¹

,

Płonka

²

,

Barchańska

³

2023

Preprint

0

View full text Add to dashboard Cite

Metabolic profiling offers huge potential to highlight markers and mechanisms in support of toxicology and pathology investigations during drug development. The main objective was to modify therapy with adamantane derivatives: amantadine and rimantadine, to increase their bioavailability and evaluate the influence of such therapy on drug metabolism using Saccharomyces cerevisiae as the model organism. In this study, the profile of endogenous metabolites of a model organism was measured and interpreted to provide an opportunity to investigate changes induced by treatment with amantadine and rimantadine. It was found that resveratrol supplementation synergistically enhanced the effects of amantadine treatment and increased rimantadine metabolism, potentially reducing side effects. The fingerprinting strategy was used as an efficient technique for qualitatively evaluating and monitoring changes in the profiles of endogenous components and their contents in a model organism. Chemometric tools were employed to find marker compounds that can be defined as characteristic indicators of a pharmacological response to a therapeutic intervention. An improved understanding of the mechanisms involved in drug effect and an increased ability to predict individual variations in the drug response of organisms will improve the treatment process and the development of new therapies.

show abstract

The multimodal serotonin compound Vilazodone alone, but not combined with the glutamate antagonist Amantadine, reduces l-DOPA-induced dyskinesia in hemiparkinsonian rats

Cited by 10 publications

References 77 publications

Broad Serotonergic Actions of Vortioxetine as a Promising Avenue for the Treatment of L-DOPA-Induced Dyskinesia

Broad Serotonergic Actions of Vortioxetine as a Promising Avenue for the Treatment of L-DOPA-Induced Dyskinesia

Metabolic profiling to evaluate the impact of amantadine and rimantadine on the secondary metabolism of a model organism

Metabolic profiling to evaluate the impact of amantadine and rimantadine on the secondary metabolism of a model organism

Contact Info

Product

Resources

About