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-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.

Keywords: Befiradol; MPTP; Marmosets; NLX-112; Parkinson's disease; Serotonin 5-HT(1A) receptors; l-DOPA-Induced dyskinesia.

Fig. 1

Plasma Levels of NLX-112 in Marmosets. Symbols represent the mean of duplicate measures taken from the same plasma sample following administration of 0.4 mg/kg p.o. NLX-112 was quantified by LC-MS/MS. The same data are plotted on a linear scale y-axis (upper panel) and on a log₁₀ scale y-axis (lower panel). M: male, F: female.

Fig. 2

Time course of effects of NLX-112 in combination with l-DOPA (main panels) or alone (insets). Main panels: NLX-112 or vehicle and l-DOPA (7 mg/kg) were administered p.o. at t = 0 min (arrows). Benserazide was administered at t = −60 min. For dyskinesia and motor disability, data are presented as median values and were analyzed by two-way ANOVA on transformed data [y = sqrt(y)]. For locomotor activity, data are presented as mean values, and were analyzed by two-way ANOVA on raw data. *p < 0.05, **p < 0.01, versus l-DOPA alone at the considered time point, Dunnett's post-hoc tests. N = 7 per group. Insets: NLX-112 was administered alone p.o. at t = 0 min (arrows). For dyskinesia and motor disability, data are presented as median values and were analyzed by one-way ANOVA on transformed data [y = sqrt(y)]. For locomotor activity, data are presented as mean values, and were analyzed by one-way ANOVA on raw data. *p < 0.05, **p < 0.01 versus value at t = −60 min (dyskinesia and motor disability) or t = −90 min (locomotor activity), Dunnett's post-hoc tests.

Fig. 3

Time course of the effects of NLX-112 alone. NLX-112 or vehicle were administered at t = 0 min; benserazide was administered at t = −60 min. For dyskinesia and motor disability, data are presented as median values and were analyzed by two-way ANOVA on transformed data [y = sqrt(y)]. For locomotor activity, data are presented as mean values, and were analyzed by two-way ANOVA on raw data. *p < 0.05, **p < 0.01, versus vehicle at the considered time point, Dunnett's post-hoc tests. N = 7 per group.

Fig. 4

Time course of effects of (+)8-OH-DPAT alone or in combination with l-DOPA. Main panels: (+)8-OH-DPAT (8-OH) and its vehicle were administered i. p. and l-DOPA (7 mg/kg) was administered p. o. at t = 0 min (arrows). Benserazide was administered at t = −60 min. For dyskinesia and motor disability, data are presented as median values and were analyzed by two-way ANOVA on transformed data [y = sqrt(y)]. For locomotor activity, data are presented as mean values, and were analyzed by two-way ANOVA on raw data. *p < 0.05, **p < 0.01, versus l-DOPA alone at the considered time point, Dunnett's post-hoc tests. N = 7 per group. Insets: (+)8-OH-DPAT was administered alone i. p. at t = 0 min (arrows). For dyskinesia and motor disability, data are presented as median values and were analyzed by one-way ANOVA on transformed data [y = sqrt(y)]. For locomotor activity, data are presented as mean values, and were analyzed by one-way ANOVA on raw data.