The Role of D-Serine and D-Aspartate in the Pathogenesis and Therapy of Treatment-Resistant Schizophrenia

Насырова, Р. Ф.; Khasanova, Aiperi K.; Altynbekov, Kuanysh S.; Asadullin, Azat R.; Markina, Ekaterina A.; Gayduk, Arseny J.; Shipulin, German A.; Петрова, М. М.; Shnayder, Natalia A.

doi:10.3390/nu14235142

Cited by 13 publications

(6 citation statements)

References 113 publications

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“…D-serine is an NMDAR activator at the glycine site but actually inhibits non-canonical NMDAR [ 34 ]. D-serine has been demonstrated to be effective in treating schizophrenia [ 35 ], mood disorders [ 36 ], and cognitive enhancement in healthy subjects [ 37 ] which is mediated by activation of canonical NMDAR. In addition, D-serine reduced compulsion-like alcohol intake and this effect has been attributed to its inhibition of non-canonical NMDARs [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

NMDA Receptor Glycine Binding Site Modulators for Prevention and Treatment of Ketamine Use Disorder

et al. 2023

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Ketamine offers a fast-acting approach to relieving treatment-resistant depression, but its abuse potential is an issue of concern. As ketamine is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) ion channel blocker, modulation of NMDAR might be an effective strategy to counteract the abuse liability of ketamine and even to treat ketamine use disorder. This study evaluated whether NMDAR modulators that act on glycine binding sites can decrease motivation to obtain ketamine and reduce reinstatement to ketamine-seeking behavior. Two NMDAR modulators, D-serine and sarcosine were examined. Male Sprague–Dawley rats underwent training to acquire the ability to self-administer ketamine. The motivation to self-administer ketamine or sucrose pellets was examined under a progressive ratio (PR) schedule. The reinstatement of ketamine-seeking and sucrose pellet-seeking behaviors were assessed after extinction. The results showed that both D-serine and sarcosine significantly decreased the breakpoints for ketamine and prevented reinstatement of ketamine seeking. However, these modulators did not alter motivated behavior for sucrose pellets, the ability of the cue and sucrose pellets to reinstate sucrose-seeking behavior or spontaneous locomotor activity. These findings indicate that two NMDAR modulators can specifically reduce the measures of motivation and relapse for ketamine in rats, suggesting that targeting the glycine binding site of the NMDAR is a promising approach for preventing and treating ketamine use disorder.

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Section: Discussionmentioning

confidence: 99%

NMDA Receptor Glycine Binding Site Modulators for Prevention and Treatment of Ketamine Use Disorder

et al. 2023

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“…Evidence from studies that modulate glutamate via other pathways also supports targeting of glutamatergic signalling to improve cognition; for example, inhibitors of D-serine and D-aspartate (D-amino acids that play key roles in the pathogenesis of schizophrenia) have been used to successfully address CIAS [ 38 ]. Specifically, sodium benzoate, a D-amino acid oxidase inhibitor, when administered at a dose of 2 g per day as an add-on to clozapine treatment, improved positive and negative symptoms as well as quality of life measures in patients with schizophrenia compared with those treated with placebo [ 39 ].…”

Section: The Role Of Glutamatergic Signalling In Ciasmentioning

confidence: 99%

Development of the novel GlyT1 inhibitor, iclepertin (BI 425809), for the treatment of cognitive impairment associated with schizophrenia

Rosenbrock

Desch

Wunderlich

2023

Eur Arch Psychiatry Clin Neurosci

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Schizophrenia is a psychiatric disorder characterised by symptoms in three domains: positive (e.g. delusions, hallucinations), negative (e.g. social withdrawal, lack of motivation) and cognitive (e.g. working memory and executive function impairment). Cognitive impairment associated with schizophrenia (CIAS) is a major burden for patients and negatively impacts many aspects of a patient’s life. Antipsychotics are the standard-of-care treatment for schizophrenia but only address positive symptoms. So far there are no approved pharmacotherapies for the treatment of CIAS. Iclepertin (BI 425809) is a novel, potent and selective glycine transporter 1 (GlyT1) inhibitor, under development by Boehringer Ingelheim for the treatment of CIAS. Phase I studies have shown it to be safe and well tolerated in healthy volunteers, and central target engagement (inhibition of GlyT1) was achieved in a dose-dependent manner from 5 to 50 mg in healthy volunteers. A Phase II study has demonstrated that iclepertin is safe and well tolerated in patients with schizophrenia and improves cognition at doses of 10 mg and 25 mg. Phase III studies are ongoing to confirm these initial positive safety and efficacy findings with the 10 mg dose, and if successful, iclepertin could become the first approved pharmacotherapy used to treat CIAS.

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“…In simpler terms, this tool allows us to track and trace epialleles derived from a single precursor with 2 common methylation traits in complex DNA sequence populations derived from cells in the brain and other organs during postnatal differentiation [13,4]. D-amino acids play crucial roles in various physiological processes, especially in the brain, and their dysregulation has been implicated in psychiatric disorders such as schizophrenia [14]. Notably, D-Serine and D-Aspartate serve as co-agonists at N-methyl-D-Aspartate receptors (NMDARs), governing diverse brain activities [15,16].…”

Section: Introductionmentioning

confidence: 99%

Brain Area-Specific Methylation Signatures Mark Patients With Schizophrenia

Morgera,

Feola,

Improda

et al. 2024

Preprint

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D-Aspartate and D-Serine serve as primary agonists at glutamate receptors, playing a crucial role in modulating synaptic plasticity and cell migration within the central nervous system. The pre-cise regulation of their levels is essential and intricately linked to the expression of their synthetic and catabolic enzymes, which are, in turn, primarily influenced by epigenetic modifications. In a comprehensive analysis, we examined the methylation profiles of the promoters and transcription start sites of critical genes associated with D-Aspartate and D-Serine metabolism in human post-mortem brain tissues sourced from normal individuals and those diagnosed with schizo-phrenia. Our approach involved a qualitative method capable of identifying specific families of methylated alleles known as epialleles, sharing a common pattern of methylated non-contiguous CpGs, referred to as cores. These methylated traits exhibit stability and consistency within com-plex populations of diverse DNA-methylated molecules. Our findings reveal brain area-specific methylation signatures to the DDO, DAO and DAOA genes serving as distinctive markers that differentiate normal brain areas from those affected by schizophrenia. These methylation patterns align with the reported high D-Aspartate and low D-Serine levels observed in schizophrenic brain areas. The study suggests a potential link between epigenetic modifications and the dysreg-ulation of these neurotransmitters in schizophrenia.

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The Role of D-Serine and D-Aspartate in the Pathogenesis and Therapy of Treatment-Resistant Schizophrenia

Cited by 13 publications

References 113 publications

NMDA Receptor Glycine Binding Site Modulators for Prevention and Treatment of Ketamine Use Disorder

NMDA Receptor Glycine Binding Site Modulators for Prevention and Treatment of Ketamine Use Disorder

Development of the novel GlyT1 inhibitor, iclepertin (BI 425809), for the treatment of cognitive impairment associated with schizophrenia

Brain Area-Specific Methylation Signatures Mark Patients With Schizophrenia

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