High dose methylphenidate in the treatment of freezing of gait in advanced Parkinson’s disease

Reyes, Nikolai Gil D.; Bagnas, Marjorie Anne C.; Antonio, Athena Kate D.; Jamora, Roland Dominic G.

doi:10.1016/j.baga.2017.12.001

Cited by 2 publications

(2 citation statements)

References 27 publications

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“…[6] Moreover, we showed that Syn III is another key component of aSyn insoluble fibrils extracted from the post-mortem brains of sporadic PD patients [7] and that Syn III is a crucial mediator of aSyn aggregation and toxicity. [8] Strikingly, our most recent findings suggest that threo-methylphenidate (MPH), a monoamine re-uptake inhibitor clinically approved for the treatment of attention deficits and hyperactivity disorder (ADHD) [9] and for ameliorating gait freezing in advanced PD, [10][11][12][13][14] is able to stimulate an aSyn/Syn III-mediated locomotor response, specifically in aSyn transgenic mice at a pathological stage that exhibit severe dopaminergic functional deficits. [15] This MPH action is lost upon in vivo Syn III gene silencing, [15] thus suggesting that this protein may act as a target for MPH.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Fluorescent Methylphenidate Analogues for a FRET‐Based Assay of Synapsin III Binding

et al. 2020

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We previously described synapsin III (Syn III) as a synaptic phosphoprotein that controls dopamine release in cooperation with α‐synuclein (aSyn). Moreover, we found that in Parkinson's disease (PD), Syn III also participates in aSyn aggregation and toxicity. Our recent observations point to threo‐methylphenidate (MPH), a monoamine re‐uptake inhibitor that efficiently counteracts the freezing‐gait characteristic of advanced PD, as a ligand for Syn III. We have designed and synthesised two different fluorescently labelled MPH derivatives, one with Rhodamine Red (RHOD) and one with 5‐carboxytetramethylrhodamine (TAMRA), to be used for assessing MPH binding to Syn III by FRET. TAMRA‐MPH exhibited the ideal characteristics to be used as a FRET acceptor, as it was able to enter into the SK‐N‐SH cells and could interact specifically with human green fluorescent protein (GFP)‐tagged Syn III but not with GFP alone. Moreover, the uptake of TAMRA‐MPH and co‐localization with Syn III was also observed in primary mesencephalic neurons. These findings support that MPH is a Syn III ligand and that TAMRA‐conjugated drug molecules might be valuable tools to study drug‐ligand interactions by FRET or to detect Syn III in cytological and histological samples.

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Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Fluorescent Methylphenidate Analogues for a FRET‐Based Assay of Synapsin III Binding

et al. 2020

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“…Collectively, these findings support that the αSyn/Syn III complex can constitute a druggable therapeutic target for PD, and that MPH therapeutic efficacy in patients in advanced stages of disease with freezing of gait [18,19], which should not respond to MPH treatment in light of their marked reduction in striatal DAT [20], may be ascribed to the ability of this drug to stimulate the functional αSyn/Syn III interaction.…”

Section: Introductionmentioning

confidence: 53%

Methylphenidate Analogues as a New Class of Potential Disease-Modifying Agents for Parkinson’s Disease: Evidence from Cell Models and Alpha-Synuclein Transgenic Mice

et al. 2022

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Parkinson’s disease (PD) is characterized by dopaminergic nigrostriatal neurons degeneration and Lewy body pathology, mainly composed of α-synuclein (αSyn) fibrillary aggregates. We recently described that the neuronal phosphoprotein Synapsin III (Syn III) participates in αSyn pathology in PD brains and is a permissive factor for αSyn aggregation. Moreover, we reported that the gene silencing of Syn III in a human αSyn transgenic (tg) mouse model of PD at a pathological stage, manifesting marked insoluble αSyn deposits and dopaminergic striatal synaptic dysfunction, could reduce αSyn aggregates, restore synaptic functions and motor activities and exert neuroprotective effects. Interestingly, we also described that the monoamine reuptake inhibitor methylphenidate (MPH) can recover the motor activity of human αSyn tg mice through a dopamine (DA) transporter-independent mechanism, which relies on the re-establishment of the functional interaction between Syn III and α-helical αSyn. These findings support that the pathological αSyn/Syn III interaction may constitute a therapeutic target for PD. Here, we studied MPH and some of its analogues as modulators of the pathological αSyn/Syn III interaction. We identified 4-methyl derivative I-threo as a lead candidate modulating αSyn/Syn III interaction and having the ability to reduce αSyn aggregation in vitro and to restore the motility of αSyn tg mice in vivo more efficiently than MPH. Our results support that MPH derivatives may represent a novel class of αSyn clearing agents for PD therapy.

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High dose methylphenidate in the treatment of freezing of gait in advanced Parkinson’s disease

Cited by 2 publications

References 27 publications

Design and Synthesis of Fluorescent Methylphenidate Analogues for a FRET‐Based Assay of Synapsin III Binding

Design and Synthesis of Fluorescent Methylphenidate Analogues for a FRET‐Based Assay of Synapsin III Binding

Methylphenidate Analogues as a New Class of Potential Disease-Modifying Agents for Parkinson’s Disease: Evidence from Cell Models and Alpha-Synuclein Transgenic Mice

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