The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets

Fisher, Ria; Hikima, Atsuko; Morris, Rebecca; Jackson, Michael; Rose, Sarah; Varney, Mark A.; Depoortère, R.; Newman‐Tancredi, Adrian

doi:10.1016/j.neuropharm.2020.107997

Cited by 30 publications

(9 citation statements)

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“…In addition to the dopaminergic system, it has been compellingly demonstrated that the serotonergic system is involved in the pathophysiology of Parkinson's disease, whether in terms of motor symptoms [24]; [42] or non-motor symptoms such as cognitive impairment [43] and mood disorders [44], but also in the etiology of LID [45,46]. In this context, the 5-HT1AR appears to be a promising therapeutic target: in addition to having a potential therapeutic effect in treating motor [47][48][49][50] and cognitive [51] symptoms or mood disorders [52][53][54][55] associated with Parkinson's disease, 5-HT1A agonists are highly effective for treating LID in preclinical models [13,14,16,18,[56][57][58][59][60][61]. The main proposed mechanism for their antidyskinetic effects is the stimulation of autoreceptors in the raphe nuclei.…”

Section: -Ht1ar As a Promising Therapeutic Target For Parkinson's Disease?mentioning

confidence: 99%

“…Furthermore, changes of 5-HT1AR levels and functionality were also studied in rats that were chronically treated with L-DOPA to elicit LID. Importantly, unlabeled F13640 (also known as befiradol or NLX-112) has shown promising antidyskinetic properties in rat, marmoset and macaque models of Parkinson's disease [14,57,59]. Therefore, the binding of [ 18 F]F13640 points directly to the population of 5-HT1AR that are targeted by this antidyskinetic 5-HT1A receptor agonist and is likely to provide important information regarding the therapeutic mechanism of this class of drugs.…”

Section: The Contribution Of Pet Imaging In Deciphering the Involvement Of 5-ht1ar In Parkinson's Diseasementioning

confidence: 99%

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Different Alterations of Agonist and Antagonist Binding to 5-HT1A Receptor in a Rat Model of Parkinson’s Disease and Levodopa-Induced Dyskinesia: A MicroPET Study

Vidal

Levigoureux

Chaib

et al. 2021

JPD

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Background: The gold-standard treatment for Parkinson’s disease is L-DOPA, which in the long term often leads to levodopa-induced dyskinesia. Serotonergic neurons are partially responsible for this, by converting L-DOPA into dopamine before uncontrolled release as a “false neurotransmitter”. The stimulation of 5-HT1A receptors can reduce involuntary movements but this mechanism is poorly understood. Objective: This study aimed to investigate the functionality of 5-HT1A receptor using positron emission tomography in hemiparkinsonian rats with or without dyskinesia induced by 3-weeks daily treatment with L-DOPA. Imaging sessions were performed “off” L-DOPA. Methods: Each rat underwent a positron emission tomography scan with [18F]F13640, a 5-HT1AR agonist (which labels receptors in a high affinity state for agonists) or [18F]MPPF, a 5-HT1AR antagonist (which labels all the receptors). Results: There were decreases of [18F]MPPF binding in hemiparkinsonian rats in cortical areas. In dyskinetic animals, changes were slighter but also found in other regions. In hemiparkinsonian rats, [18F]F13640 uptake was decreased in the globus pallidus and thalamus. On the contralateral side, binding was increased in the insula, the hippocampus and the amygdala. In dyskinetic animals, [18F]F13640 binding was strongly increased in cortical and limbic areas, especially in the non-lesioned side. Conclusion: These data suggest that agonist and antagonist 5-HT1A receptor-binding sites are differently modified in Parkinson’s disease and levodopa-induced dyskinesia. In particular, these observations suggest an important involvement of the functional state of 5-HT1AR in levodopa-induced dyskinesia and emphasize the need to characterize this state using agonist radiotracers in physiological and pathological conditions.

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Section: -Ht1ar As a Promising Therapeutic Target For Parkinson's Disease?mentioning

confidence: 99%

Section: The Contribution Of Pet Imaging In Deciphering the Involvement Of 5-ht1ar In Parkinson's Diseasementioning

confidence: 99%

Different Alterations of Agonist and Antagonist Binding to 5-HT1A Receptor in a Rat Model of Parkinson’s Disease and Levodopa-Induced Dyskinesia: A MicroPET Study

Vidal

Levigoureux

Chaib

et al. 2021

JPD

Self Cite

View full text Add to dashboard Cite

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“…In the same study, we found that the effects of exogenous L-DOPA were blocked by removing serotonergic innervation (Lopez et al, 2001). Interestingly, removal of serotonin afferents or dampening of serotonin activity by 5-HT 1A and 5-HT 1B agonists blocked LID in rat and primate models (Carta et al, 2007;Muñoz et al, 2008;Fisher et al, 2020). Serotonergic neurons can convert L-DOPA into dopamine, which is stored and released as a ''false neurotransmitter.''…”

Section: Involvement Of Serotonin In L-dopa-induced Dyskinesiasmentioning

confidence: 77%

Interactions Between the Serotonergic and Other Neurotransmitter Systems in the Basal Ganglia: Role in Parkinson’s Disease and Adverse Effects of L-DOPA

et al. 2020

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Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. However, other non-dopaminergic neuronal systems such as the serotonergic system are also involved. Serotonergic dysfunction is associated with non-motor symptoms and complications, including anxiety, depression, dementia, and sleep disturbances. This pathology reduces patient quality of life. Interaction between the serotonergic and other neurotransmitters systems such as dopamine, noradrenaline, glutamate, and GABA controls the activity of striatal neurons and are particularly interesting for understanding the pathophysiology of PD. Moreover, serotonergic dysfunction also causes motor symptoms. Interestingly, serotonergic neurons play an important role in the effects of L-DOPA in advanced PD stages. Serotonergic terminals can convert L-DOPA to dopamine, which mediates dopamine release as a "false" transmitter. The lack of any autoregulatory feedback control in serotonergic neurons to regulate L-DOPA-derived dopamine release contributes to the appearance of L-DOPA-induced dyskinesia (LID). This mechanism may also be involved in the development of graft-induced dyskinesias (GID), possibly due to the inclusion of serotonin neurons in the grafted tissue. Consistent with this, the administration of serotonergic agonists suppressed LID. In this review article, we summarize the interactions between the serotonergic and other systems. We also discuss the role of the serotonergic system in LID and if therapeutic approaches specifically targeting this system may constitute an effective strategy in PD.

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“…In fact, the modulation of serotoninergic signaling via administration of citalopram [ 103 ] or tandospirone [ 104 ] had a positive impact on Alzheimer’s disease (AD) and frontotemporal dementia-related symptoms. In addition, befiradol similarly showed antiparkinsonian properties [ 105 ]. Its administration was also capable of reverting dyskinesia associated with prolonged L-DOPA treatment [ 106 , 107 ].…”

Section: Discussionmentioning

confidence: 99%

Aripiprazole Offsets Mutant ATXN3-Induced Motor Dysfunction by Targeting Dopamine D2 and Serotonin 1A and 2A Receptors in C. elegans

et al. 2022

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The atypical antipsychotic aripiprazole is a Food and Drug Administration-approved drug for the treatment of psychotic, mood, and other psychiatric disorders. Previous drug discovery efforts pinpointed aripiprazole as an effective suppressor of Machado–Joseph disease (MJD) pathogenesis, as its administration resulted in a reduced abundance and aggregation of mutant Ataxin-3 (ATXN3) proteins. Dopamine partial agonism and functional selectivity have been proposed as the main pharmacological mechanism of action of aripiprazole in the treatment of psychosis; however, this mechanism remains to be determined in the context of MJD. Here, we focus on confirming the efficacy of aripiprazole to reduce motor dysfunction in vivo, using a Caenorhabditis elegans (C. elegans) model of MJD, and on unveiling the drug targets required for its positive action against mutant ATXN3 pathogenesis. We employed pharmacogenetics and pharmacological approaches to identify which dopamine and serotonin receptors are critical for aripiprazole-mediated improvements in motor function. We demonstrated that dopamine D2-like and serotonin 5-HT1A and 5-HT2A receptors play important roles in this process. Our findings strengthen the relevance of dopaminergic and serotoninergic signaling modulation against mutant ATXN3-mediated pathogenesis. The identification of aripiprazole’s cellular targets, relevant for MJD and perhaps other neurodegenerative diseases, may pave the way for prospective drug discovery and development campaigns aiming to improve the features of this prototypical compound and reduce side effects not negligible in the case of aripiprazole.

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The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets

Cited by 30 publications

References 50 publications

Different Alterations of Agonist and Antagonist Binding to 5-HT1A Receptor in a Rat Model of Parkinson’s Disease and Levodopa-Induced Dyskinesia: A MicroPET Study

Different Alterations of Agonist and Antagonist Binding to 5-HT1A Receptor in a Rat Model of Parkinson’s Disease and Levodopa-Induced Dyskinesia: A MicroPET Study

Interactions Between the Serotonergic and Other Neurotransmitter Systems in the Basal Ganglia: Role in Parkinson’s Disease and Adverse Effects of L-DOPA

Aripiprazole Offsets Mutant ATXN3-Induced Motor Dysfunction by Targeting Dopamine D2 and Serotonin 1A and 2A Receptors in C. elegans

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