7-Chlorokynurenic acid (7-CTKA) produces rapid antidepressant-like effects: through regulating hippocampal microRNA expressions involved in TrkB-ERK/Akt signaling pathways in mice exposed to chronic unpredictable mild stress

Liu, Binbin; Luo, Liu; Liu, Xiaolong; Geng, Di; Liu, Qing; Yi, Long

doi:10.1007/s00213-014-3690-3

Cited by 56 publications

(33 citation statements)

References 33 publications

(41 reference statements)

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“…However, the involvement of the glycine B site of the NMDA receptor in the antidepressant effects of GLYX-13 has not been directly demonstrated so far. Maj et al (1994) described antidepressant-like effects following repeated, but not single, administration of 7-Cl-KYNA (20 mg/kg) in the FST, and acute antidepressant-like effects were seen after a single injection of low doses of 7-Cl-KYNA in rats (Zhu et al, 2013;Liu et al, 2015). However, the latter findings were not replicated in our experiments.…”

Section: Fast-onset Antidepressant Effects Of 4-chlorokynureninecontrasting

confidence: 81%

The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/Glycine_B-Site Inhibition

Zanos

Piantadosi

et al. 2015

J Pharmacol Exp Ther

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Currently approved antidepressant drug treatment typically takes several weeks to be effective. The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown efficacy as a rapid-acting treatment of depression, but its use is associated with significant side effects. We assessed effects following blockade of the glycine B co-agonist site of the NMDA receptor, located on the GluN1 subunit, by the selective full antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), delivered by systemic administration of its brain-penetrant prodrug 4-chlorokynurenine (4-Cl-KYN) in mice. Following administration of 4-Cl-KYN, 7-Cl-KYNA was promptly recovered extracellularly in hippocampal microdialysate of freely moving animals. The behavioral responses of the animals were assessed using measures of ketamine-sensitive antidepressant efficacy (including the 24-hour forced swim test, learned helplessness test, and novelty-suppressed feeding test). In these tests, distinct from fluoxetine, and similar to ketamine, 4-Cl-KYN administration resulted in rapid, dose-dependent and persistent antidepressant-like effects following a single treatment. The antidepressant effects of 4-Cl-KYN were prevented by pretreatment with glycine or the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX). 4-Cl-KYN administration was not associated with the rewarding and psychotomimetic effects of ketamine, and did not induce locomotor sensitization or stereotypic behaviors. Our results provide further support for antagonism of the glycine B site for the rapid treatment of treatment-resistant depression without the negative side effects seen with ketamine or other channelblocking NMDA receptor antagonists.

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Section: Fast-onset Antidepressant Effects Of 4-chlorokynureninecontrasting

confidence: 81%

The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/Glycine_B-Site Inhibition

Zanos

Piantadosi

et al. 2015

J Pharmacol Exp Ther

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“…If major depression is due to lack of reward, the analysis of molecular profiles in the nucleus accumbens from CUMS‐induced depression and resilience should help to figure out the role of the nucleus accumbens in major depression and resilience based on molecules analyzed. The alternations of certain genes have not been observed in previous analyses (Bai et al, 2014; Elizalde et al, 2010; Li et al, 2013; Liu et al, 2015; Moreau, Bruse, David‐Rus, Buyske, & Brzustowicz, 2011; Rajkowska et al, 2015; Smalheiser et al, 2012, 2011, 2014), including Cckar , Tshr , Kcnj5 , Alox12 , Slc17a6 , Per2 , Rtn4r , and Nrn1 . These genes in the nucleus accumbens may be newly working for major depression or resilience.…”

Section: Discussionmentioning

confidence: 80%

microRNA and mRNA profiles in nucleus accumbens underlying depression versus resilience in response to chronic stress

Song

Sun

et al. 2018

American J of Med Genetics Pt B

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Major depression in negative mood is presumably induced by chronic stress with lack of reward. However, most individuals who experience chronic stress demonstrate resilience. Molecular mechanisms underlying stress‐ induced depression versus resilience remain unknown, which are investigated in brain reward circuits. Mice were treated by chronic unpredictable mild stress (CUMS) for 4 weeks. The tests of sucrose preference, Y‐maze, and forced swimming were used to identify depression‐like emotion behavior or resilience. High‐throughput sequencing was used to analyze mRNA and miRNA quantity in the nucleus accumbens (NAc) harvested from the mice in the groups of control, CUMS‐induced depression (CUMS‐MDD), and CUMS‐resistance to identify molecular profiles of CUMS‐MDD versus CUMS‐resilience. In data analyses and comparison among three groups, 1.5‐fold ratio in reads per kilo‐base per million reads (RPKM) was set to judge involvements of mRNA and miRNA in CUMS, MDD, or resilience. The downregulations of serotonergic/dopaminergic synapses, MAPK/calcium signaling pathways, and morphine addiction as well as the upregulations of cAMP/PI3K‐Akt signaling pathways and amino acid metabolism are associated with CUMS‐MDD. The downregulations of chemokine signaling pathway, synaptic vesicle cycle, and nicotine addiction as well as the upregulations of calcium signaling pathway and tyrosine metabolism are associated with CUMS‐resilience. The impairments of serotonergic/dopaminergic synapses and PI3K‐Akt/MAPK signaling pathways in the NAc are associated with depression. The upregulation of these entities is associated with resilience. Consistent results from analyzing mRNA/miRNA and using different methods validate our finding and conclusion.

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“…Similar to these findings, 4-chlorokynurenine, a brain-penetrant pro-drug of 7-chlorokynurenic acid, induced fast-onset antidepressant behavioral actions in several animal tests including the 24-h forced-swim test, learned helplessness and novelty-suppressed feeding paradigms [46]. Neither 7-chlorokynurenic acid nor 4-chlorokynurenine administration were associated with ketamine-like psychostimulant effects, sensory dissociation, or abuse liability in rodents [46, 97, 98]. 4-chlorokynurenine is currently in a phase II clinical trial for the treatment of major depression (Clinical Trial ID: NCT02484456).…”

Section: Mechanisms Underlying Fast/rapid Onset Antidepressants Acmentioning

confidence: 86%

“…(2013) [97] demonstrated that peripheral administration of 7-chlorokynurenic acid, a glycine B antagonist, exerted rapid antidepressant actions in the novelty-suppressed feeding and the learned helplessness paradigms following a single injection. Chronic stress-induced anhedonia was also reversed by administration of 7-chlorokynurenic acid, as it reversed decreased sucrose preference [97, 98]. Similar to these findings, 4-chlorokynurenine, a brain-penetrant pro-drug of 7-chlorokynurenic acid, induced fast-onset antidepressant behavioral actions in several animal tests including the 24-h forced-swim test, learned helplessness and novelty-suppressed feeding paradigms [46].…”

Section: Mechanisms Underlying Fast/rapid Onset Antidepressants Acmentioning

confidence: 86%

Convergent Mechanisms Underlying Rapid Antidepressant Action

et al. 2018

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Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal and anti-anhedonic actions following a single administration to depressed patients. Proposed mechanisms of ketamine’s antidepressant action include N-methyl-D-aspartate receptor (NMDAR) modulation, GABAergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergoing pre-clinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine - pro-drug of the glycineB NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists (i.e. GLYX-13 (rapastinel)), metabotropic glutamate receptor 2/3 (mGluR2/3) antagonists, GABAA receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation.

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7-Chlorokynurenic acid (7-CTKA) produces rapid antidepressant-like effects: through regulating hippocampal microRNA expressions involved in TrkB-ERK/Akt signaling pathways in mice exposed to chronic unpredictable mild stress

Abstract: This demonstrated that the 15 miRNA targets shared by TrkB-ERK/Akt pathways might participate in rapid-acting molecular mechanism of antidepressant 7-CTKA.

Cited by 56 publications

References 33 publications

The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/Glycine_B-Site Inhibition

The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/Glycine_B-Site Inhibition

microRNA and mRNA profiles in nucleus accumbens underlying depression versus resilience in response to chronic stress

Convergent Mechanisms Underlying Rapid Antidepressant Action

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7-Chlorokynurenic acid (7-CTKA) produces rapid antidepressant-like effects: through regulating hippocampal microRNA expressions involved in TrkB-ERK/Akt signaling pathways in mice exposed to chronic unpredictable mild stress

Abstract: This demonstrated that the 15 miRNA targets shared by TrkB-ERK/Akt pathways might participate in rapid-acting molecular mechanism of antidepressant 7-CTKA.

Cited by 56 publications

References 33 publications

The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/GlycineB-Site Inhibition

The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/GlycineB-Site Inhibition

microRNA and mRNA profiles in nucleus accumbens underlying depression versus resilience in response to chronic stress

Convergent Mechanisms Underlying Rapid Antidepressant Action

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Product

Resources

About

The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/Glycine_B-Site Inhibition

The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/Glycine_B-Site Inhibition