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

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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 J.; Rose, Sarah; Varney, Mark A.; Depoortere, Ronan; Newman-Tancredi, Adrian.

In: Neuropharmacology, Vol. 167, 107997, 01.05.2020.

Research output: Contribution to journalArticle

Harvard

Fisher, R, Hikima, A, Morris, R, Jackson, MJ, Rose, S, Varney, MA, Depoortere, R & Newman-Tancredi, A 2020, 'The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets', Neuropharmacology, vol. 167, 107997. https://doi.org/10.1016/j.neuropharm.2020.107997

APA

Fisher, R., Hikima, A., Morris, R., Jackson, M. J., Rose, S., Varney, M. A., ... Newman-Tancredi, A. (2020). The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets. Neuropharmacology, 167, [107997]. https://doi.org/10.1016/j.neuropharm.2020.107997

Vancouver

Fisher R, Hikima A, Morris R, Jackson MJ, Rose S, Varney MA et al. The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets. Neuropharmacology. 2020 May 1;167. 107997. https://doi.org/10.1016/j.neuropharm.2020.107997

Author

Fisher, Ria ; Hikima, Atsuko ; Morris, Rebecca ; Jackson, Michael J. ; Rose, Sarah ; Varney, Mark A. ; Depoortere, Ronan ; Newman-Tancredi, Adrian. / The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets. In: Neuropharmacology. 2020 ; Vol. 167.

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@article{1e11b8e0d1b84575878a9a65a73748ba,
title = "The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets",
abstract = "L-DOPA is the gold-standard pharmacotherapy for treatment of Parkinson's disease (PD) but can lead to the appearance of troubling dyskinesia which are attributable to ‘false neurotransmitter’ release of dopamine by serotonergic neurons. Reducing the activity of these neurons diminishes L-DOPA-induced dyskinesia (LID), but there are currently no clinically approved selective, high efficacy 5-HT1A receptor agonists. Here we describe the effects of NLX-112, a highly selective and efficacious 5-HT1A receptor agonist, on LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets, a non-human primate model of PD. NLX-112 exhibited modest plasma half-life (~2h) and marked plasma protein binding (96{\%}). When administered to parkinsonian marmosets with L-DOPA (7 mg/kg p.o.), NLX-112 (0.025, 0.1 and 0.4 mg/kg p.o.) reduced LID scores at early time-points after administration, whilst only minimally interfering with the L-DOPA-induced reversal of motor disability. In contrast, the prototypical 5-HT1A receptor agonist, (+)8-OH-DPAT (0.6 and 2 mg/kg p. o.), reduced LID but also abolished L-DOPA's anti-disability activity. Administered by itself, NLX-112 (0.1, 0.2 mg/kg p.o.) produced very little dyskinesia or locomotor activity, but reduced motor disability scores by about half the extent elicited by L-DOPA, suggesting that it may have motor facilitation effects of its own. Both NLX-112 and (+)8-OH-DPAT induced unusual and dose-limiting behaviors in marmoset that resembled ‘serotonin behavioral syndrome’ observed previously in rat. Overall, the present study showed that NLX-112 has anti-LID activity at the doses tested as well as reducing motor disability. The data suggest that additional investigation of NLX-112 is desirable to explore its potential as a treatment for PD and PD-LID.",
keywords = "Befiradol, L-DOPA-Induced dyskinesia, Marmosets, MPTP, NLX-112, Parkinson's disease, Serotonin 5-HT receptors",
author = "Ria Fisher and Atsuko Hikima and Rebecca Morris and Jackson, {Michael J.} and Sarah Rose and Varney, {Mark A.} and Ronan Depoortere and Adrian Newman-Tancredi",
year = "2020",
month = "5",
day = "1",
doi = "10.1016/j.neuropharm.2020.107997",
language = "English",
volume = "167",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Limited",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets

AU - Fisher, Ria

AU - Hikima, Atsuko

AU - Morris, Rebecca

AU - Jackson, Michael J.

AU - Rose, Sarah

AU - Varney, Mark A.

AU - Depoortere, Ronan

AU - Newman-Tancredi, Adrian

PY - 2020/5/1

Y1 - 2020/5/1

N2 - L-DOPA is the gold-standard pharmacotherapy for treatment of Parkinson's disease (PD) but can lead to the appearance of troubling dyskinesia which are attributable to ‘false neurotransmitter’ release of dopamine by serotonergic neurons. Reducing the activity of these neurons diminishes L-DOPA-induced dyskinesia (LID), but there are currently no clinically approved selective, high efficacy 5-HT1A receptor agonists. Here we describe the effects of NLX-112, a highly selective and efficacious 5-HT1A receptor agonist, on LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets, a non-human primate model of PD. NLX-112 exhibited modest plasma half-life (~2h) and marked plasma protein binding (96%). When administered to parkinsonian marmosets with L-DOPA (7 mg/kg p.o.), NLX-112 (0.025, 0.1 and 0.4 mg/kg p.o.) reduced LID scores at early time-points after administration, whilst only minimally interfering with the L-DOPA-induced reversal of motor disability. In contrast, the prototypical 5-HT1A receptor agonist, (+)8-OH-DPAT (0.6 and 2 mg/kg p. o.), reduced LID but also abolished L-DOPA's anti-disability activity. Administered by itself, NLX-112 (0.1, 0.2 mg/kg p.o.) produced very little dyskinesia or locomotor activity, but reduced motor disability scores by about half the extent elicited by L-DOPA, suggesting that it may have motor facilitation effects of its own. Both NLX-112 and (+)8-OH-DPAT induced unusual and dose-limiting behaviors in marmoset that resembled ‘serotonin behavioral syndrome’ observed previously in rat. Overall, the present study showed that NLX-112 has anti-LID activity at the doses tested as well as reducing motor disability. The data suggest that additional investigation of NLX-112 is desirable to explore its potential as a treatment for PD and PD-LID.

AB - L-DOPA is the gold-standard pharmacotherapy for treatment of Parkinson's disease (PD) but can lead to the appearance of troubling dyskinesia which are attributable to ‘false neurotransmitter’ release of dopamine by serotonergic neurons. Reducing the activity of these neurons diminishes L-DOPA-induced dyskinesia (LID), but there are currently no clinically approved selective, high efficacy 5-HT1A receptor agonists. Here we describe the effects of NLX-112, a highly selective and efficacious 5-HT1A receptor agonist, on LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets, a non-human primate model of PD. NLX-112 exhibited modest plasma half-life (~2h) and marked plasma protein binding (96%). When administered to parkinsonian marmosets with L-DOPA (7 mg/kg p.o.), NLX-112 (0.025, 0.1 and 0.4 mg/kg p.o.) reduced LID scores at early time-points after administration, whilst only minimally interfering with the L-DOPA-induced reversal of motor disability. In contrast, the prototypical 5-HT1A receptor agonist, (+)8-OH-DPAT (0.6 and 2 mg/kg p. o.), reduced LID but also abolished L-DOPA's anti-disability activity. Administered by itself, NLX-112 (0.1, 0.2 mg/kg p.o.) produced very little dyskinesia or locomotor activity, but reduced motor disability scores by about half the extent elicited by L-DOPA, suggesting that it may have motor facilitation effects of its own. Both NLX-112 and (+)8-OH-DPAT induced unusual and dose-limiting behaviors in marmoset that resembled ‘serotonin behavioral syndrome’ observed previously in rat. Overall, the present study showed that NLX-112 has anti-LID activity at the doses tested as well as reducing motor disability. The data suggest that additional investigation of NLX-112 is desirable to explore its potential as a treatment for PD and PD-LID.

KW - Befiradol

KW - L-DOPA-Induced dyskinesia

KW - Marmosets

KW - MPTP

KW - NLX-112

KW - Parkinson's disease

KW - Serotonin 5-HT receptors

UR - http://www.scopus.com/inward/record.url?scp=85079413015&partnerID=8YFLogxK

U2 - 10.1016/j.neuropharm.2020.107997

DO - 10.1016/j.neuropharm.2020.107997

M3 - Article

C2 - 32057799

AN - SCOPUS:85079413015

VL - 167

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

M1 - 107997

ER -

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