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

Ria Fisher; Atsuko Hikima; Rebecca Morris; Michael J. Jackson; Sarah Rose; Mark A. Varney; Ronan Depoortere; Adrian Newman-Tancredi

doi:10.1016/j.neuropharm.2020.107997

The selective 5-HT_1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets

Ria Fisher, Atsuko Hikima, Rebecca Morris, Michael J. Jackson, Sarah Rose, Mark A. Varney, Ronan Depoortere, Adrian Newman-Tancredi^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

30 Citations (Scopus)

161 Downloads (Pure)

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-HT_1A receptor agonists. Here we describe the effects of NLX-112, a highly selective and efficacious 5-HT_1A 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-HT_1A 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.

Original language	English
Article number	107997
Journal	Neuropharmacology
Volume	167
Early online date	10 Feb 2020
DOIs	https://doi.org/10.1016/j.neuropharm.2020.107997
Publication status	Published - 1 May 2020

Keywords

Befiradol
L-DOPA-Induced dyskinesia
Marmosets
MPTP
NLX-112
Parkinson's disease
Serotonin 5-HT receptors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.neuropharm.2020.107997Licence: CC BY-NC-ND

The selective 5-HT_FISHER_Acc9Feb2020Epb10Feb2020_GOLD VoR(CC BY) NC NDFinal published version, 843 KBLicence: CC BY-NC-ND

Cite this

@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 {\textquoteleft}false neurotransmitter{\textquoteright} 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 {\textquoteleft}serotonin behavioral syndrome{\textquoteright} 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 = may,

day = "1",

doi = "10.1016/j.neuropharm.2020.107997",

language = "English",

volume = "167",

journal = "Neuropharmacology",

issn = "0028-3908",

publisher = "Elsevier Limited",

}

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

SN - 0028-3908

VL - 167

JO - Neuropharmacology

JF - Neuropharmacology

M1 - 107997

ER -