The anti-dyskinetic effect of the clinic-ready mGluRpositive allosteric modulator AZD8529 in the 6-OHDA-lesioned rat.

L-3,4-dihydroxyphenylalanine (L-DOPA) remains the main treatment for motor symptoms of Parkinson's disease (PD). However, chronic use is associated with the development of complications such as L-DOPA-induced dyskinesia. We previously demonstrated that LY-487,379, a highly selective metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulator (PAM), reduces the severity of L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD, without interfering with the anti-parkinsonian action of L-DOPA.

Positive allosteric mGluR modulation with BINA alleviates dyskinesia and psychosis-like behaviours in the MPTP-lesioned marmoset.

There is mounting evidence that positive allosteric modulation of metabotropic glutamate type 2 receptors (mGluR) is an efficacious approach to reduce the severity of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia, psychosis-like behaviours (PLBs), while conferring additional anti-parkinsonian benefit. However, the mGluR positive allosteric modulators (PAMs) tested so far, LY-487,379 and CBiPES, share a similar chemical scaffold. Here, we sought to assess whether similar benefits would be conferred by a structurally-distinct mGluR PAM, biphenylindanone A (BINA).

Autoradiographic labelling of metabotropic glutamate type 2/3 receptors in the hemi-parkinsonian rat brain.

L-3,4-dihydroxyphenylalanine (L-DOPA) is the treatment of choice for Parkinson's disease (PD) motor symptoms, but its chronic use is hindered by complications such as dyskinesia. Pre-clinical studies discovered that activation of metabotropic glutamate type 2 and 3 (mGlu) receptors alleviates L-DOPA-induced dyskinesia. To gain mechanistic insight into the anti-dyskinetic activity of mGlu activation, we performed autoradiographic binding with [H]-LY-341,495 in brain sections from L-DOPA-treated 6-hydroxydopamine (6-OHDA)-lesioned rats that developed mild or severe dyskinesia, as well as L-DOPA-untreated 6-OHDA-lesioned and sham-lesioned animals.

Activation of mGlu 2/3 receptors with the orthosteric agonist LY-404,039 alleviates dyskinesia in experimental parkinsonism.

LY-404,039 is an orthosteric agonist at metabotropic glutamate 2 and 3 (mGlu 2/3 ) receptors, with a possible additional agonist effect at dopamine D 2 receptors. LY-404,039 and its pro-drug, LY-2140023, have previously been tested in clinical trials for psychiatric indications and could therefore be repurposed if they were shown to be efficacious in other conditions. We have recently demonstrated that the mGlu 2/3 orthosteric agonist LY-354,740 alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat without hampering the anti-parkinsonian action of L-DOPA.

[H]-NFPS binding to the glycine transporter 1 in the hemi-parkinsonian rat brain.

L-3,4-dihydroxyphenylalanine (L-DOPA) is the main treatment for Parkinson's disease (PD) but with long term administration, motor complications such as dyskinesia are induced. Glycine transporter 1 (GlyT1) inhibition was shown to produce an anti-dyskinetic effect in parkinsonian rats and primates, coupled with an improvement in the anti-parkinsonian action of L-DOPA. The expression of GlyT1 in the brain in the dyskinetic state remains to be investigated.

Metronidazole-induced encephalopathy in a patient with cirrhosis.

Metronidazole is a commonly used antibiotic with anaerobic bacterial, protozoal, and microaerophilic bacterial coverage. Encephalopathy and peripheral neurotoxicity are rare but known adverse events with prolonged metronidazole use, which can be difficult to distinguish from other causes of delirium in acutely ill patients. Definitive diagnosis can be made by brain magnetic resonance imaging (MRI), which often reveals symmetric bilateral hypersignal demyelination lesions typically involving the dentate nuclei, splenium of the corpus collosum, midbrain, dorsal medulla, and pons.

Effect of the mGlu positive allosteric modulator ADX-88178 on parkinsonism, psychosis-like behaviours and dyskinesia in the MPTP-lesioned marmoset.

Rationale: Positive allosteric modulation of metabotropic glutamate type 4 (mGlu) receptors is a promising strategy to alleviate parkinsonian disability and L-3,4-dihydroxyphenylalanine (L-DOPA) induced dyskinesia. ADX-88178 is a highly selective mGlu positive allosteric modulator (PAM) that previously enhanced the anti-parkinsonian action of L-DOPA in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease (PD).

Objectives: We sought to explore the effects of ADX-88178 on psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset.

The 5-HT inverse agonist nelotanserin alleviates L-DOPA-induced dyskinesia in the MPTP-lesioned marmoset.

Nelotanserin is a serotonin 2A and 2C (5-HT) inverse agonist that was previously tested in the clinic for rapid-eye movement sleep behaviour disorder and psychosis in patients with Parkinson's disease (PD) dementia. Its effect on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia has however not been investigated. As 5-HT antagonism/inverse agonism is a validated approach to alleviate dyskinesia, we undertook the current study to evaluate the anti-dyskinetic potential of nelotanserin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset.

5-HT agonists for levodopa-induced dyskinesia in Parkinson's disease.

Levodopa is the most effective agent for treating the symptoms of Parkinson's disease (PD). However, levodopa-induced dyskinesia remains a significant complication that manifests after few years of treatment, for which therapeutic options remain limited. Several agonists of the serotonin type 1A (5-HT) receptor with varying levels of efficacy and interaction at other sites, have been tested in the clinic.

Distribution of [C]-JNJ-42491293 in the marmoset brain: a positron emission tomography study.

JNJ-42491293 is a metabotropic glutamate 2 (mGlu) positive allosteric modulator (PAM) that was radiolabelled with [C]- to serve as a positron emission tomography (PET) ligand. Indeed, in vitro, the molecule displays high selectivity at mGlu receptors. However, PET experiments performed in rats, macaques and humans, have suggested that [C]-JNJ-42491293 could interact with an unidentified, non-mGlu receptor binding site.

Metabotropic glutamate receptors in Parkinson's disease.

Parkinson's disease (PD) is a complex disorder that leads to alterations in multiple neurotransmitter systems, notably glutamate. As such, several drugs acting at glutamatergic receptors have been assessed to alleviate the manifestation of PD and treatment-related complications, culminating with the approval of the N-methyl-d-aspartate (NMDA) antagonist amantadine for l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia. Glutamate elicits its actions through several ionotropic and metabotropic (mGlu) receptors.

Anti-parkinsonian effect of the mGlu positive allosteric modulator LY-487,379 as monotherapy and adjunct to a low L-DOPA dose in the MPTP-lesioned marmoset.

In previous experiments, we have discovered that positive allosteric modulation of metabotropic glutamate 2 (mGlu) receptors enhances the anti-parkinsonian action of an optimal dose of L-3,4-dihydroxyphenylalanine (L-DOPA). Whether selective mGlu positive allosteric modulation would also alleviate parkinsonian disability as monotherapy or as adjunct to a sub-optimal dose of L-DOPA has not been determined. Here, we assessed the anti-parkinsonian effect of mGlu positive allosteric modulation as monotherapy and adjunct to a sub-optimal dose of L-DOPA in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets.

Effect of glycine transporter 1 inhibition with bitopertin on parkinsonism and L-DOPA induced dyskinesia in the 6-OHDA-lesioned rat.

Dyskinesia remains an unmet need in Parkinson's disease (PD). We have previously demonstrated that glycine transporter 1 (GlyT1) inhibition with ALX-5407 reduces dyskinesia and slightly improves parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we sought to determine the effect of bitopertin, a clinically-tested GlyT1 inhibitor, on parkinsonism and dyskinesia in the 6-hydroxydopamine (6-OHDA)-lesioned rat.