Antiparkinsonian Effects of a Metabotropic Glutamate Receptor 4 Agonist in MPTP-Treated Marmosets

Abstract

Background: Increased firing across glutamatergic synapses may contribute to both the motor dysfunction and L-DOPA-induced dyskinesia seen in Parkinson's disease. Given their ability to reduce glutamate release, activation of group III metabotropic glutamate receptors such as metabotropic glutamate receptor 4 may prove effective against both motor dysfunction and dyskinesia in Parkinson's disease. Objectives: We hypothesised that activation of metabotropic glutamate receptor 4 by an orthosteric agonist ((2S)-2-amino-4-(hydroxy(hydroxy(4-hydroxy-3-methoxynitrophenyl)methyl)phosphoryl)butanoic acid, LSP1-2111) would produce antiparkinsonian activity and reduce expression of dyskinesia in a 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)treated marmoset model of Parkinson's disease. Methods: Common marmosets were previously treated with MPTP and pre-primed with L-DOPA for up to 28 days to express dyskinesia. LSP1-2111 (1, 3 or 6 mg/kg s.c.) or vehicle (0.9% saline s.c.) were administered immediately prior to L-DOPA (8 mg/kg + benserazide (10 mg/kg) p.o.) or vehicle (10% sucrose p.o.). Locomotor activity was measured in automated test cages and animals were scored for dyskinesia and disability. Results: As expected, L-DOPA reversed motor disability and induced moderate dyskinesia. By contrast, LSP1-2111 alone significantly reduced the motor disability without any accompanying expression of dyskinesia. When administered in combination with L-DOPA, LSP1-2111 did not significantly reduce the severity of L-DOPA-induced dyskinesia.Conclusions: Systemic administration of LSP1-2111 reduces motor disability without causing dyskinesia in MPTP-treated marmosets, supporting a role for metabotropic glutamate receptor 4 orthosteric agonists as promising monotherapy for PD. Conversely, this study found no evidence to support their use as antidyskinetic agents within the dose range tested.

A Randomized, Double‐Blind, Controlled Phase II Study of Foliglurax in Parkinson's Disease

“…This includes N ‐methyl‐D‐aspartate (NMDA) antagonists (MK‐801 or memantine), α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) antagonists (perampanel), and Metabotropic Glutamate Receptor 5 (mGlu5) allosteric modulators (mavoglurant). None of these development programs has succeeded so far 14,24‐26 . This might be explained by limitations in study designs, inadequate dosages, or inappropriate therapeutic windows to achieve efficacy without unacceptable adverse reactions 27 .…”

“…None of these development programs has succeeded so far. 14,[24][25][26] This might be explained by limitations in study designs, inadequate dosages, or inappropriate therapeutic windows to achieve efficacy without unacceptable adverse reactions. 27 However, the negative findings of the present trial, targeting another glutamate mechanism, namely, the mGLu4 receptors, further challenges the glutamate hypothesis for the treatment of PD, reinforcing the concept that the unique effects of amantadine in this disease might be attributed to mechanisms beyond its NMDA blocking effect.…”

A case study of foliglurax, the first clinical mGluR4 PAM for symptomatic treatment of Parkinson’s disease: translational gaps or a failing industry innovation model?

“…Further, the anti-dyskinetic effects of foliglurax reported by Charvin et al are of great interest not only because of the effect size but also because of the previous reports where activation of mGluR4 (by agonists or PAMs) did not inhibit severity of the already established L-DOPA-induced dyskinesia in rodents (Table 3) [65][66][67]. Interestingly, a recently published study in marmosets also failed to detect any anti-dyskinetic effects of the mGluR4 agonist LSP1-2111 [68].…”

Metabotropic Glutamate Receptor 4 (mGlu4) Positive Allosteric Modulators Lack Efficacy in Rat and Marmoset Models of L-DOPA-Induced Dyskinesia

“…In primate studies, a similarly mixed picture has emerged. While the mGlu 4 PAM, foliglurax (formerly PXT002331), reduced expression of established LID in MPTP-treated macaques [ 18 ], LSP1-2111 failed to reduce established AIMs in the MPTP-treated common marmoset [ 19 ]. Nevertheless, a recently published report found that ADX88188, while failing to reduce global LID, did reduce the severity of peak dose dyskinesia in marmosets [ 20 ].…”