Effect of the Metabotropic Glutamate Receptor Type 5 Negative Allosteric Modulator Dipraglurant on Motor and Non-Motor Symptoms of Parkinson's Disease

Abstract

Parkinson's disease (PD) patients suffer not only from the primary motor symptoms of the disease but also from a range of non-motor symptoms (NMS) that cause disability and low quality of life. Excessive glutamate activity in the basal ganglia resulting from degeneration of the nigrostriatal dopamine pathway has been implicated in the motor symptoms, NMS and dyskinesias in PD patients. In this study, we investigated the effects of a selective mGlu5 negative allosteric modulator (NAM), dipraglurant, in a rodent motor symptoms model of PD, but also in models of anxiety, depression and obsessive-compulsive disorder, all of which are among the most prevalent NMS symptoms. Dipraglurant is rapidly absorbed after oral administration, readily crosses the blood-brain barrier, and exhibits a high correlation between plasma concentration and efficacy in behavioral models. In vivo, dipraglurant dose-dependently reduced haloperidol-induced catalepsy, increased punished licks in the Vogel conflict-drinking model, decreased immobility time in the forced swim test, decreased the number of buried marbles in the marble-burying test, but had no effect on rotarod performance or locomotor activity. These findings suggest that dipraglurant may have benefits to address some of the highly problematic comorbid non-motor symptoms of PD, in addition to its antidyskinetic effect demonstrated in PD-LID patients.

Keywords: Parkinson’s disease; anxiety; depression; dipraglurant; mGlu5; obsessive-compulsive disorder.

Figure 1

Plasma and CSF concentrations of dipraglurant after oral administration of 10 mg/kg of the compound administered at 3 mL/kg in water. Sprague-Dawley rats (n = 5) were used to collect blood via jugular vein catheter for standard plasma preparation at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h. Simultaneously, 8 CSF samples were collected at the same time points. Each point represents the measured mean ± SD.

Figure 2

(A) Time spent by Sprague-Dawley rats (n = 10/group) on the vertical grid during the haloperidol-induced catalepsy test. Animals were pretreated with haloperidol (1 mg/kg, i.p.) before receiving either dipraglurant (1, 3, 10, 30 mg/kg p.o.), vehicle (distilled water, p.o.) or MTEP (30 mg/kg, i.p.) and then placed on the grid. Each point represents the observed mean ± SEM, ** p < 0.01, *** p < 0.001 compared to Vehicle (Veh). (B) Pharmacokinetic-pharmacodynamic relation between plasma concentration of dipraglurant and time on the grid. Each point represents individual animals.

Figure 3

Number of punished licks made by Sprague-Dawley rats (n = 8–10/group) during the Vogel test. Animals were treated with either dipraglurant (3, 10, 30 mg/kg p.o.), vehicle (distilled water, p.o.) or chlordiazepoxide (CDZ; 30 mg/kg, i.p.) Each point represents the observed mean ± SEM, * p < 0.05, ** p < 0.01, *** p < 0.001 compared to vehicle (Veh).

Figure 4

Number of buried marbles by C57Bl6/J mice (n = 10/group) during the marble burying test. Animals were treated with either dipraglurant (10, 30, 50 mg/kg p.o.), vehicle (distilled water, p.o.) or chlordiazepoxide (CDZ; 30 mg/kg, i.p.). Each point represents the observed mean ± SEM, ** p < 0.01, *** p < 0.001 compared to vehicle (Veh).

Figure 5

(A,B) Locomotor activity of male C57Bl6/J mice (n = 8/group) and (C,D) Sprague-Dawley rats (n = 8/group) during 60 min, expressed as time-course profiles (A,C) or total traveled distances (B,D). Mice were treated with either dipraglurant (10, 30, 50 mg/kg p.o.), vehicle (distilled water, p.o.) or chlordiazepoxide (CDZ; 10 mg/kg, i.p.). Rats were treated with either dipraglurant (3, 10, 30 mg/kg p.o.), vehicle (distilled water, p.o.), or CDZ (50 mg/kg, i.p.) Each point represents the observed mean ± SEM, *** p < 0.001 compared to vehicle (Veh).