Proteomics analysis in rats reveals convergent mechanisms between major depressive disorder and dietary zinc deficiency.

Background: Preclinical and clinical studies have shown that dietary zinc deficiency can lead to symptoms similar to those observed in major depressive disorder (MDD). However, the underlying molecular mechanisms remain unclear. To investigate these mechanisms, we examined proteomic changes in the prefrontal cortex (PFC) and hippocampus (HP) of rats, two critical brain regions implicated in the pathophysiology of depression.

Dietary Zinc Restriction and Chronic Restraint Stress Affect Mice Physiology, Immune Organ Morphology, and Liver Function.

Background: Preclinical and clinical studies suggest that zinc deficiency and chronic stress contribute to depressive symptoms. Our study explores the intricate relationship between these factors by examining their physiological and biochemical effects across various organs in C57Bl/6J mice.

Methods: The mice were divided into four groups: control, chronic restraint stress for 3 weeks, a zinc-restricted diet (<3 mg/kg) for 4 weeks, and a combination of stress and zinc restriction.

Stress resilience is an active and multifactorial process manifested by structural, functional, and molecular changes in synapses.

Stress resilience is the ability of neuronal networks to maintain their function despite the stress exposure. Using a mouse model we investigate stress resilience phenomenon. To assess the resilient and anhedonic behavioral phenotypes developed after the induction of chronic unpredictable stress, we quantitatively characterized the structural and functional plasticity of excitatory synapses in the hippocampus using a combination of proteomic, electrophysiological, and imaging methods.

The antidepressant-like and glioprotective effects of the Y2 receptor antagonist SF-11 in the astroglial degeneration model of depression in rats: Involvement of glutamatergic inhibition.

In this study, we explored the potential antidepressant-like properties of the brain-penetrant Y2 receptor (Y2R) antagonist SF-11 [N-(4-ethoxyphenyl)- 4-(hydroxydiphenylmethyl)- 1-piperidinecarbothioamide] in the astroglial degeneration model of depression with an emphasis on checking the possible mechanisms implicated in this antidepressant-like effect. The model of depression relies on the loss of astrocytes in the medial prefrontal cortex (mPFC) in Sprague-Dawley rats after administering the gliotoxin L-alpha-aminoadipic acid (L-AAA). SF-11 was administered intraperitoneally (i.

Ketamine - a long way from anesthetic to a prototype antidepressant: Review of potential mechanisms of action.

Published research studies on the antidepressant activity of ketamine in the last twenty years have significantly changed the way people think about potential new antidepressants and the biological basis of depression. The symptoms of depression may subside for several days after the administration of a dose of ketamine. In contrast, achieving a therapeutic effect with classic antidepressants requires chronic administration.

Combined hyperforin and lanicemine treatment instead of ketamine or imipramine restores behavioral deficits induced by chronic restraint stress and dietary zinc restriction in mice.

Clinical and preclinical studies show evidence that chronic stress or nutritional deficits in dietary zinc (Zn) intake may be risk factors for developing major depressive disorder (MDD). Furthermore, there may be possible links between low serum Zn levels and development of treatment-resistant depression. In the present work, we combined chronic restraint stress (CRS) and a low-zinc diet (ZnD) in mice and carried out a set of behavioral and biochemical studies.

New investigational agents for the treatment of major depressive disorder.

Introduction: Pharmacotherapy of depression is characterized by the delayed onset of action, chronic treatment requirements, and insufficient effectiveness. Ketamine, with its rapid action and long-lasting effects, represents a breakthrough in the modern pharmacotherapy of depression.

Areas Covered: The current review summarizes the latest findings on the mechanism of the antidepressant action of ketamine and its enantiomers and metabolites.

Zinc Deficiency Blunts the Effectiveness of Antidepressants in the Olfactory Bulbectomy Model of Depression in Rats.

Currently used antidepressants do not always provide the desired results, and many patients suffer from treatment-resistant depression. Clinical studies suggest that zinc deficiency (ZnD) may be an important risk factor for depression and might blunt the effect of antidepressants. This study aimed to examine whether ZnD might blunt the effectiveness of antidepressants in the olfactory bulbectomy model (OB) of depression in rats.

Ketamine and Ro 25-6981 Reverse Behavioral Abnormalities in Rats Subjected to Dietary Zinc Restriction.

Clinical and preclinical studies indicate that zinc (Zn) is an essential factor in the development and treatment of major depressive disorder (MDD). Conventional monoamine-based antidepressants mobilize zinc in the blood and brain of depressed patients as well as rodents. N-methyl-D-aspartate acid receptor (NMDAR) antagonists exhibit antidepressant-like activity.

An update on NMDA antagonists in depression.

: Current antidepressant therapies exhibit low therapeutic efficiency and delayed onset of antidepressant action. Thus, the search for better acting agents is a continuous process. One of the primary targets for the development of new antidepressant drugs is the glutamate N-methyl-D-aspartate (NMDA) receptor.

Characterization of the Brain Penetrant Neuropeptide Y Y2 Receptor Antagonist SF-11.

This paper discusses the biological and three-dimensional molecular structure of the novel, nonpeptide Y2R antagonist, SF-11 [-(4-ethoxyphenyl)-4-(hydroxydiphenylmethyl)-1-piperidinecarbothioamide]. Pharmacokinetic studies in a rat model indicated that, following intraperitoneal dosing, SF-11 crossed the blood-brain barrier and was able to penetrate the brain, making it a suitable tool for behavioral studies. We showed for the first time that SF-11 decreased the immobility time in the forced swim test (FST) after acute peripheral administration (10 and 20 mg/kg), indicating that it has antidepressant potential.

Antidepressant-like activity of hyperforin and changes in BDNF and zinc levels in mice exposed to chronic unpredictable mild stress.

Chronic unpredictable mild stress (CUMS) - a rodent model of depression mimics a variety of neurochemical and behavioral alterations similar to those seen in human depression. This study evaluated the antidepressant activity of hyperforin in the CUMS model using fluoxetine (FLX) as a reference drug. The antidepressant-like effects of hyperforin and FLX were evaluated in the tail suspension test (TST), forced swim test (FST), and splash test (SPT).

Hyperforin Potentiates Antidepressant-Like Activity of Lanicemine in Mice.

N-methyl-D-aspartate receptor (NMDAR) modulators induce rapid and sustained antidepressant like-activity in rodents through a molecular mechanism of action that involves the activation of Ca dependent signaling pathways. Moreover, ketamine, a global NMDAR antagonist is a potent, novel, and atypical drug that has been successfully used to treat major depressive disorder (MDD). However, because ketamine evokes unwanted side effects, alternative strategies have been developed for the treatment of depression.

Involvement of extracellular signal-regulated kinase (ERK) in the short and long-lasting antidepressant-like activity of NMDA receptor antagonists (zinc and Ro 25-6981) in the forced swim test in rats.

Short and long acting NMDA receptor (NMDAR) antagonists exert their antidepressant-like effects by activating signaling pathways involved in the synthesis of synaptic proteins and formation of new synaptic connections in the prefrontal cortex (PFC) of rats. The blockade of the ERK pathway abolishes ketamine and Ro 25-6981 antidepressant potency. However, the role of ERK in the antidepressant-like activity of short acting NMDAR antagonists is still unclear.

Antidepressant-like activity of the neuropeptide Y Y5 receptor antagonist Lu AA33810: behavioral, molecular, and immunohistochemical evidence.

Rationale: It has recently been found that chronic treatment with the highly selective, brain-penetrating Y5 receptor antagonist, Lu AA33810 [N-[[trans-4-[(4,5-dihydro [1] benzothiepino[5,4-d] thiazol-2-yl) amino] cyclohexyl]methyl]-methanesulfonamide], produces antidepressant-like effects in the rat chronic mild stress model.

Objective: In the present study, we investigated the possible antidepressant-like activity of Lu AA33810 in rats subjected to glial ablation in the prefrontal cortex (PFC) by the gliotoxin L-AAA, which is an astroglial degeneration model of depression.

Results: We observed that Lu AA33810 administered intraperitoneally at a single dose of 10 mg/kg both reversed depressive-like behavioral changes in the forced swim test (FST) and prevented degeneration of astrocytes in the mPFC.

The level of the zinc homeostasis regulating proteins in the brain of rats subjected to olfactory bulbectomy model of depression.

Background: Zinc transporters (ZnTs) and metallothioneins (MT) are important in maintaining Zn homeostasis in the brain. The present study was designed to find out whether alterations in ZnTs and MTs are associated with the pathophysiology of depression and the mechanism of antidepressant action.

Methods: Messenger RNA and proteins of ZnT1, ZnT3, ZnT4, ZnT5, ZnT6 and MT1/2 were measured in the prefrontal cortex (PFC) and hippocampus (Hp) of rats subjected to olfactory bulbectomy (OB) (a model of depression) and chronic amitriptyline (AMI) treatment by Real Time PCR and Western Blot/Immunohistochemistry (IHP).

Brain glutamic acid decarboxylase-67kDa alterations induced by magnesium treatment in olfactory bulbectomy and chronic mild stress models in rats.

Background: The preclinical results indicate that magnesium, an N-methyl-d-aspartate receptor (NMDAR) blocker has anxiolytic and antidepressant-like activity. One of the mechanisms involved in these activities is modulation of glutamate, γ-aminobutyric acid (GABA) system. Based on this, the aim of the present study was to investigate the effect of magnesium on the level of glutamic acid decarboxylase-67kDa (GAD-67) in the different brain areas in the chronic mild stress (CMS) and olfactory bulbectomy (OB) models of depression in rats.

Group II mGlu receptor antagonist LY341495 enhances the antidepressant-like effects of ketamine in the forced swim test in rats.

Rationale: Numerous preclinical and clinical studies have reported the rapid and sustained antidepressant effects of the NMDA receptor antagonist ketamine. Because ketamine induces several undesirable and dangerous effects, a variety of strategies have been suggested to avoid such effects.

Objectives: Here, we propose to enhance the sub-effective doses of ketamine by co-administration with the group II metabotropic glutamate (mGlu) receptor antagonist LY341495.

Concentration-Dependent Dual Mode of Zn Action at Serotonin 5-HT1A Receptors: In Vitro and In Vivo Studies.

Recent data has indicated that Zn can modulate serotonergic function through the 5-HT receptor (5-HTR); however, the exact mechanisms are unknown. In the present studies, radioligand binding assays and behavioural approaches were used to characterize the pharmacological profile of Zn at 5-HTRs in more detail. The influence of Zn on agonist binding to 5-HTRs stably expressed in HEK293 cells was investigated by in vitro radioligand binding methods using the agonist [H]-8-OH-DPAT.

Activation of mTOR dependent signaling pathway is a necessary mechanism of antidepressant-like activity of zinc.

The rapid antidepressant response to the N-methyl-D-aspartate (NMDA) receptor antagonists is mediated by activation of the mammalian target of the rapamycin (mTOR) signaling pathway, an increase in the synthesis of synaptic proteins and formation of new synapses in the prefrontal cortex (PFC) of rats. Zinc (Zn), which is a potent NMDA receptor antagonist, exerts antidepressant-like effects in screening tests and models of depression. We focused these studies in investigating whether activation of the mTOR signaling pathway is also a necessary mechanism of the antidepressant-like activity of Zn.

Relationship between Zinc (Zn (2+) ) and Glutamate Receptors in the Processes Underlying Neurodegeneration.

The results from numerous studies have shown that an imbalance between particular neurotransmitters may lead to brain circuit dysfunction and development of many pathological states. The significance of glutamate pathways for the functioning of the nervous system is equivocal. On the one hand, glutamate transmission is necessary for neuroplasticity, synaptogenesis, or cell survival, but on the other hand an excessive and long-lasting increased level of glutamate in the synapse may lead to cell death.

Zinc deficiency in rats is associated with up-regulation of hippocampal NMDA receptor.

Rationale: Data indicated that zinc deficiency may contribute to the development of depression; however changes induced by zinc deficiency are not fully described.

Objectives: In the present paper we tested whether the dietary zinc restriction in rats causes alterations in N-methyl-D-aspartate receptor (NMDAR) subunits in brain regions that are relevant to depression.

Methods: Male Sprague Dawley rats were fed a zinc adequate diet (ZnA, 50 mg Zn/kg) or a zinc deficient diet (ZnD, 3 mg Zn/kg) for 4 or 6weeks.

Antidepressant-like activity of magnesium in the olfactory bulbectomy model is associated with the AMPA/BDNF pathway.

Rationale: Numerous studies suggest agents that act on glutamatergic transmission as potential antidepressants. Preclinical and clinical evidence suggests that magnesium, an N-methyl-D-aspartate receptor blocker, may be useful in the treatment of depression.

Objective: The aim of this study was to investigate the effects of magnesium on behavior; protein levels of GluN2A, GluN2B [N-methyl-D-aspartate receptor (NMDAR) subunits], GluA1 [α-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA) subunit], phospho-Ser-831-GluA1 (P-S831), phospho-Ser-845-GluA1 (P-S845), and brain-derived neurotrophic factor (BDNF); and messenger RNA (mRNA) levels of GluN2A and GluN2B in different brain areas in the olfactory bulbectomy (OB) model of depression in rats.

NMDA antagonists under investigation for the treatment of major depressive disorder.

Introduction: Mood disorders, including depression, are becoming increasingly prevalent in the developed world. Furthermore, treatment of depression therapeutics, mainly influencing the serotonergic and adrenergic systems, is considered insufficient. The original NMDA-glutamate hypothesis mechanism of antidepressant action was first proposed ∼ 20 years ago.