Inhibition of Glycine Transporter-I as a Novel Mechanism for the Treatment of Depression

Huang, Chih‐Chia; Wei, I-Hua; Huang, Chieh-Liang; Chen, Kuang-Ti; Tsai, Mang-Hung; Tsai, Priscilla; Tun, R. Y. M.; Huang, Kuo-Hao; Chang, Yue‐Cune; Lane, Hsien‐Yuan; Tsai, Guochuan E.

doi:10.1016/j.biopsych.2013.02.020

Cited by 121 publications

(97 citation statements)

References 46 publications

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“…This hypothesis is in accord with findings that functional inactivation of NR2A in knockout mice reduced anxiety-and depression-related behaviors [25]. Related to this, functional inhibitors of NMDA receptor activity including the non-competitive antagonist ketamine [13,14,[26][27][28] or the glycine transporter-I antagonist sarcosine (N-methylglycine) [29] have been identified as rapid-acting antidepressants in controlled trials, further supporting a putative proximal contribution of GRIN2A overexpression to the pathophysiology of MDD.…”

Section: Discussionsupporting

confidence: 82%

Aberrant NMDA receptor DNA methylation detected by epigenome-wide analysis of hippocampus and prefrontal cortex in major depression

Kaut

Schmitt

Hofmann

et al. 2015

Eur Arch Psychiatry Clin Neurosci

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Current perspectives on the molecular underpinnings of major depressive disorder (MDD) posit a mechanistic role of epigenetic DNA modifications in mediating the interaction between environmental risk factors and a genetic predisposition. However, conclusive evidence for differential methylation signatures in the brain's epigenome of MDD patients as compared to controls is still lacking. To address this issue, we conducted a pilot study including an epigenome-wide methylation analysis in six individuals diagnosed with recurrent MDD and six control subjects matched for age and gender, with a priori focus on the hippocampus and prefrontal cortex as pathophysiologically relevant candidate regions. Our analysis revealed differential methylation profiles of 11 genes in hippocampus and 20 genes in prefrontal cortex, five of which were selected for replication of the methylation status using pyrosequencing. Among these replicated targets, GRIN2A was found to be hypermethylated in both prefrontal cortex and hippocampus. This finding may be of particular functional relevance as GRIN2A encodes the glutamatergic N-methyl-D-aspartate receptor subunit epsilon-1 (NR2A) and is known to be involved in a plethora of synaptic plasticity-related regulatory processes probably disturbed in MDD.

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Section: Discussionsupporting

confidence: 82%

Aberrant NMDA receptor DNA methylation detected by epigenome-wide analysis of hippocampus and prefrontal cortex in major depression

Kaut

Schmitt

Hofmann

et al. 2015

Eur Arch Psychiatry Clin Neurosci

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“…Several GlyT1 inhibitors are currently in clinical development for the treatment of schizophrenia and obsessivecompulsive disorder (Umbricht et al, 2014;ClinicalTrials.gov Identifier: NCT01674361), and a recent clinical study has demonstrated that sarcosine, a GlyT1 inhibitor, improves psychic anxiety, as assessed by means of the 17-item Hamilton Depression Rating Scale, in patients with major depression (Huang et al, 2013). Our findings further demonstrate the anxiolytic effects of GlyT1 inhibitors and provide new insights into the mechanism of these anxiolytic effects.…”

Section: Discussionsupporting

confidence: 60%

Involvement of the strychnine-sensitive glycine receptor in the anxiolytic effects of GlyT1 inhibitors on maternal separation-induced ultrasonic vocalization in rat pups

Komatsu

Furuya

Sawada

et al. 2015

European Journal of Pharmacology

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“…Among them, GLYX-13 has been proved to have sustained effects. On the other hand, D-serine (Malkesman et al 2012) and glycine transporter-I inhibitor sarcosine (Chen et al 2015;Huang et al 2013), which are assumed to potentiate NMDAR function through glycine site, can also improve depression-like behaviors in rodent models and in human depression (Huang et al 2013). Modulation of NMDAR glycine site might be majorly contributed to the rapid and sustained antidepressant-like effect of betaine, although betaine elevated 5-HT levels and has been suggested to be like a traditional antidepressant (Kim et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Betaine enhances antidepressant-like, but blocks psychotomimetic effects of ketamine in mice

et al. 2016

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Ketamine is emerging as a new hope against depression, but ketamine-associated psychotomimetic effects limit its clinical use. An adjunct therapy along with ketamine to alleviate its adverse effects and even potentiate the antidepressant effects might be an alternative strategy. Betaine, a methyl derivative of glycine and a dietary supplement, has been shown to have antidepressant-like effects and to act like a partial agonist at the glycine site of N-methyl-D-aspartate receptors (NMDARs). Accordingly, betaine might have potential to be an adjunct to ketamine treatment for depression. The antidepressant-like effects of ketamine and betaine were evaluated by forced swimming test and novelty suppressed feeding test in mice. Both betaine and ketamine produced antidepressant-like effects. Furthermore, we determined the effects of betaine on ketamine-induced antidepressant-like and psychotomimetic behaviors, motor incoordination, hyperlocomotor activity, and anesthesia. The antidepressant-like responses to betaine combined with ketamine were stronger than their individual effects. In contrast, ketamine-induced impairments in prepulse inhibition, novel object recognition test, social interaction, and rotarod test were remarkably attenuated, whereas ketamine-induced hyperlocomotion and loss of righting reflex were not affected by betaine. These findings revealed that betaine could enhance the antidepressant-like effects, yet block the psychotomimetic effects of ketamine, suggesting that betaine can be considered as an add-on therapy to ketamine for treatment-resistant depression and suitable for the treatment of depressive symptoms in patients with schizophrenia.

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Inhibition of Glycine Transporter-I as a Novel Mechanism for the Treatment of Depression

Cited by 121 publications

References 46 publications

Aberrant NMDA receptor DNA methylation detected by epigenome-wide analysis of hippocampus and prefrontal cortex in major depression

Aberrant NMDA receptor DNA methylation detected by epigenome-wide analysis of hippocampus and prefrontal cortex in major depression

Involvement of the strychnine-sensitive glycine receptor in the anxiolytic effects of GlyT1 inhibitors on maternal separation-induced ultrasonic vocalization in rat pups

Betaine enhances antidepressant-like, but blocks psychotomimetic effects of ketamine in mice

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