Synergy between l-DOPA and a novel positive allosteric modulator of metabotropic glutamate receptor 4: Implications for Parkinson's disease treatment and dyskinesia

Q2 · MEDICINE

Article

Author: Hermogenes N. Jimenez ; Darío Doller ; Khaled-Ezaheir Bennouar ; Paolo Gubellini ; Lydia Kerkerian-Le Goff ; Christophe Melon ; Manuel Cajina ; Michelle A. Uberti ; Maria D. Bacolod

Group III metabotropic glutamate (mGlu) receptors are localized in presynaptic terminals within basal ganglia (BG) circuitry that become hyperactive due to dopamine depletion in Parkinson's disease (PD). For this reason, group III mGlu receptors, in particular mGlu4, have been considered as key strategic targets for non-dopaminergic pharmacological treatments aimed at modulating these synapses, without producing the well known side-effects of l-DOPA, in particular the highly disabling l-DOPA-induced dyskinesia (LID). Herein we add physiological and functional support to this hypothesis using Lu AF21934, a novel selective and brain-penetrant mGlu4 receptor positive allosteric modulator (PAM) tool compound. By in vitro electrophysiological recordings we demonstrate that Lu AF21934 inhibits corticostriatal synaptic transmission and enhances the effect of the orthosteric mGlu4 receptor-preferred agonist LSP1-2111. In naïve rats, Lu AF21934 dose-dependently (10 and 30 mg/kg) alleviated haloperidol-induced catalepsy. In hemiparkinsonian rats (unilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta), Lu AF21934 alone did not affect akinesia at the doses tested (10 and 30 mg/kg). However, when Lu AF21934 was combined with sub-threshold doses of l-DOPA (1 and 5 mg/kg), it acted synergistically in alleviating akinesia in a dose-dependent manner and, notably, also reduced the incidence of LID but not its severity. Interestingly, these effects occurred at Lu AF21934 brain free concentrations that showed functional activity in in vitro screens (calcium flux and electrophysiology assays). These results support the potential for antiparkinsonian clinical use of a combined treatment consisting in l-DOPA and a mGlu4 receptor PAM to reduce efficacious l-DOPA doses (generally known as l-DOPA sparing), while maintaining the same benefit on PD motor troubles, and at the same time minimizing the development of LID. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

01 Mar 2013·NeuropharmacologyQ2 · MEDICINE

Anxiolytic- but not antidepressant-like activity of Lu AF21934, a novel, selective positive allosteric modulator of the mGlu4 receptor

Q2 · MEDICINE

Article

Author: Maria A. Bacolod ; Andrzej Pilc ; Joanna M. Wierońska ; Dario Doller ; Michelle A. Uberti ; Anna Sławińska ; Katarzyna Stachowicz ; Agnieszka Pałucha-Poniewiera

Previous studies demonstrated that the Group III mGlu receptor-selective orthosteric agonist, LSP1-2111 produced anxiolytic- but not antidepressant-like effects upon peripheral administration. Herein, we report the pharmacological actions of Lu AF21934, a novel, selective, and brain-penetrant positive allosteric modulator (PAM) of the mGlu(4) receptor in the stress-induced hyperthermia (SIH), four-plate, marble-burying and Vogel's conflict tests. In all models, except Vogel's conflict test, a dose-dependent anxiolytic-like effect was seen. The anti-hyperthermic effect of Lu AF21934 (5 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (10 mg/kg) and was not serotonin-dependent, as it persisted in serotonin-deficient mice and upon blockade of either 5-HT(1A) receptors by WAY100635, or 5-HT(2A/2C) receptors by ritanserin. These results suggest that the GABAergic system, but not the serotonergic system, is involved in the mechanism of the anxiolytic-like phenotype of Lu AF21934 in rodents. Lu AF21934 did not produce antidepressant-like effects in the tail suspension test (TST) in mice; however, it decreased the basal locomotor activity of mice that were not habituated to activity cages. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

01 Mar 2013·NeuropharmacologyQ2 · MEDICINE

Role of mGluR4 in acquisition of fear learning and memory

Q2 · MEDICINE

Article

Author: Jacob Raber ; Robert M. Duvoisin ; Francine C. Acher ; Ovidiu D. Iancu ; Blair M. Stewart ; Matthew J. Davis ; Massarra A. Eiwaz

Group III metabotropic glutamate receptors (mGluRs), which are generally located presynaptically, modulate synaptic transmission by regulating neurotransmitter release. Previously we showed enhanced amygdala-dependent cued fear conditioning in mGluR4(-/-) mice 24 h following training involving two tone-shock pairings. In this study, we assessed the effects of modulating mGluR4 signaling on acquisition and extinction of conditioned fear. mGluR4(-/-) and wild-type female and male mice received 10 tone-shock pairings during training. Compared to wild-type mice, mGluR4(-/-) mice showed enhanced acquisition and extinction of cued fear. Next, we assessed whether acute pharmacological stimulation of mGluR4 with the specific orthosteric mGluR4 agonist LSP1-2111 also affects acquisition and extinction of cued fear. Consistent with the enhanced acquisition of cued fear in mGluR4(-/-), LSP1-2111, at 2.5 and 5 mg/kg, inhibited acquisition of cued fear conditioning in wild-type male mice. The drug's effect on extinction was less clear and only a subtle effect was seen at 5 mg/kg. Finally, analysis of microarray data of amygdala tissues from mGluR4(-/-) versus wild-type and from wild-type mice treated with a mGluR4 agonist versus saline revealed a significant overlap in pattern of gene expression. Together, these data support a role for mGluR4 signaling in acquisition of fear learning and memory. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

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Indication	Highest Phase	Country/Location	Organization	Date
Central Nervous System Diseases	Preclinical	DK	H. Lundbeck A/S	23 Dec 2013

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