Effect of the glycine transporter 1 inhibitor ALX-5407 on dyskinesia, psychosis-like behaviours and parkinsonism in the MPTP-lesioned marmoset

[3H]-NFPS binding to the glycine transporter 1 in the hemi-parkinsonian rat brain

“…We acknowledge this limitation of our study and urge the readers to keep it in mind while reading the paragraphs below. Encouragingly, in a study conducted with ALX-5407 in the MPTP-lesioned marmoset, we did not observe any difference between female and male animals (Frouni et al 2021 ), suggesting that sex-related differences may be minimal.…”

“…Admittedly, this compensatory mechanism would be only partly efficacious, as the animals in our experiments were severely parkinsonian. Accordingly, it is possible that the anti-parkinsonian benefit we obtained in 6-OHDA-lesioned rats with bitopertin (Frouni et al 2022 ) and in MPTP-lesioned marmosets with ALX-5407 (Frouni et al 2021 ) was mediated through an activation of the thalamo-cortical pathway.…”

“…In contrast to the hypothesis put forth in the previous paragraph regarding a possible compensatory mechanism of reduced GlyT1 in the thalamus, it is possible that this reduction in thalamic GlyT1 might contribute to the dyskinetic phenotype, as it would ultimately result in higher cortical activation. Then, how can these findings be reconciled with an anti-dyskinetic effect of GlyT1 inhibition in both the 6-OHDA-lesioned rat (Frouni et al 2022 ) and the MPTP-lesioned primate (Frouni et al 2021 )? When present in higher concentrations within the synapse, glycine may lead to NMDA receptor internalisation (Nong et al 2003 ), which would result in decreased glutamatergic transmission; along the thalamo-cortical pathway, it would lead to decreased cortical activation, and less abnormal movements.…”

“…More recently, we have shown that GlyT1 inhibition might also be a potential therapeutic option for treatment-related complications and we have discovered that bitopertin, a selective non-sarcosine-derived GlyT1 inhibitor, improves the severity of parkinsonism, attenuates the induction of dyskinesia and alleviates established dyskinesia in the 6-OHDA-lesioned rat (Frouni et al 2022 ). We also showed that ALX-5407 (also known as (R)-(N-[3-(4’-fluorophenyl)-3-(4’-phenylphenoxy)propyl])sarcosine [(R)-NFPS]), a selective sarcosine-based GlyT1 inhibitor, reduced L-DOPA-induced dyskinesia and improved parkinsonian disability in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset (Frouni et al 2021 ). Collectively, these studies indicate that GlyT1 inhibition might be a promising therapeutic strategy for PD and L-DOPA-induced dyskinesia.…”

Emerging role of psychosis in Parkinson's disease: From clinical relevance to molecular mechanisms

“…Dysfunction of N-methyl-D-aspartate receptors (NMDAR)-mediated neurotransmission is believed to contribute to neuropsychiatric symptoms of PD. Enhancing glutamatergic transmission through blocking of glycine re-uptake was found to ameliorate the psychosis-like behaviors in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD marmoset model[ 108 ]. NMDAR stimulation, accomplished through allosteric modulation via the glycine modulatory site, may be a potential therapeutic target for PD psychosis.…”