Repeated Sulforaphane Treatment Reverses Depressive-like Behavior and Exerts Antioxidant Effects in the Olfactory Bulbectomy Model in Mice.

Growing evidence suggests that activators of nuclear factor erythroid-derived 2-like 2 (Nrf2), such as sulforaphane, may represent promising novel pharmacological targets for conditions related to oxidative stress, including depressive disorder. Therefore, we conducted a study to explore the behavioral and biochemical effects of repeated (14 days) sulforaphane (SFN) treatment in the olfactory bulbectomy (OB) animal model of depression. An open field test (OFT), splash test (ST), and spontaneous locomotor activity test (LA) were used to assess changes in depressive-like behavior and the potential antidepressant-like activity of SFN.

Synthesis and biological evaluation of novel 3-(5-substituted-1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with a dual affinity for serotonin 5-HT receptor and SERT.

The serotonin 1A (5-HT) receptors and serotonin transporter (SERT) are important biological targets in the treatment of diseases of the central nervous system, especially for depression. In this study, new 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives linked with the 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole moiety were synthesised and evaluated for their affinity for 5-HT receptor and serotonin reuptake inhibition. Selected compounds were then tested for their affinity for D, 5-HT, 5-HT and 5-HT receptors, and also in in vitro metabolic stability assays in human microsomes.

TC-G 1008 facilitates epileptogenesis by acting selectively at the GPR39 receptor but non-selectively activates CREB in the hippocampus of pentylenetetrazole-kindled mice.

The pharmacological activation of the GPR39 receptor has been proposed as a novel strategy for treating seizures; however, this hypothesis has not been verified experimentally. TC-G 1008 is a small molecule agonist increasingly used to study GPR39 receptor function but has not been validated using gene knockout. Our aim was to assess whether TC-G 1008 produces anti-seizure/anti-epileptogenic effects in vivo and whether the effects are mediated by GPR39.

The role of GPR39 zinc receptor in the modulation of glutamatergic and GABAergic transmission.

Background: Despite our poor understanding of the pathophysiology of depression, a growing body of evidence indicates the role of both glutamate and gamma-aminobutyric acid (GABA) signaling behind the effects of rapid-acting antidepressants (RAADs). GPR39 is a zinc-sensing receptor whose activation leads to a prolonged antidepressant-like response in mice. Both GPR39 and zinc can modulate glutamatergic and GABAergic neurotransmission, however, exact molecular mechanisms are still elusive.

Analysis of hyperforin (St. John's wort) action at TRPC6 channel leads to the development of a new class of antidepressant drugs.

St. John's wort is an herb, long used in folk medicine for the treatment of mild depression. Its antidepressant constituent, hyperforin, has properties such as chemical instability and induction of drug-drug interactions that preclude its use for individual pharmacotherapies.

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.

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.

Alterations of Serum Magnesium Concentration in Animal Models of Seizures and Epilepsy-The Effects of Treatment with a GPR39 Agonist and Knockout of the Gene.

Several ligands have been proposed for the GPR39 receptor, including the element zinc. The relationship between GPR39 and magnesium homeostasis has not yet been examined, nor has such a relationship in the context of seizures/epilepsy. We used samples from mice that were treated with an agonist of the GPR39 receptor (TC-G 1008) and underwent acute seizures (maximal electroshock (MES)- or 6-hertz-induced seizures) or a chronic, pentylenetetrazole (PTZ)-induced kindling model of epilepsy.

Antidepressant-like Effects of Combined Fluoxetine and Zinc Treatment in Mice Exposed to Chronic Restraint Stress Are Related to Modulation of Histone Deacetylase.

Chronic stress is the key factor contributing to the development of depressive symptoms. Chronic restraint stress (CRS) is well validated and is one of the most commonly used models to induce depressive-like behavior in rodents. The present study aimed to evaluate whether fluoxetine (FLU 5 mg/kg) and zinc (Zn 10mg/kg) given simultaneously induce a more pronounced antidepressant-like effect in the CRS model than both those compounds given alone.

Pharmaco-Electroencephalography-Based Assessment of Antidepressant Drug Efficacy-The Use of Magnesium Ions in the Treatment of Depression.

Pharmaco-electroencephalography (pharmaco-EEG) is a technique used to assess the effects of psychotropic medications on the bioelectrical activity of the brain. The purpose of this study was to assess the treatment response with the use of the Hamilton Depression Rating Scale (HDRS) and via EEG. Over an 8-week period, we analyzed electroencephalographic tracings of 91 patients hospitalized for major depression at the Medical University of Warsaw.

GPCR oligomerization as a target for antidepressants: Focus on GPR39.

At present most of the evidence for the relevance of oligomerization for the pharmacology of depression comes from in vitro studies which identified oligomers, and from neuropsychopharmacological studies of receptors which participate in oligomerization. For example, behavioural and biochemical studies in knockout animals suggest that GPR39 may mediate the antidepressant action of monoaminergic antidepressants. We have recently found long-lasting antidepressant-like effects of GPR39 agonist, thus suggesting GPR39 as a target for the development of novel antidepressant drugs.

Synthesis of Novel Pyrido[1,2-]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT Receptor Ligands.

Two series of novel 4-aryl-2H-pyrido[1,2-c]pyrimidine (6a-i) and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine () derivatives were synthesized. The chemical structures of the new compounds were confirmed by H and C NMR spectroscopy and ESI-HRMS spectrometry. The affinities of all compounds for the 5-HT receptor and serotonin transporter protein (SERT) were determined by in vitro radioligand binding assays.

Interaction between zinc, the GPR39 zinc receptor and the serotonergic system in depression.

Zinc signalling has a crucial impact on the proper functioning of the brain. Disturbances within the zincergic system may lead to neuropsychological disorders, including major depression. Studying this disease and designing effective treatment is hampered by its heterogeneous etiology and the diversified nature of the symptoms.

Vorinostat (SAHA) May Exert Its Antidepressant-Like Effects Through the Modulation of Oxidative Stress Pathways.

Suberoylanilide hydroxamic acid (SAHA/Vorinostat), a potent inhibitor of histone deacetylases (HDACs), is known to possess antidepressant properties. However, the exact mechanisms underlying this activity are unknown. In this study, we evaluated the effect of SAHA on the expression of GluN2A, GluN2B (NMDA receptor subunits), (p-)AMPK, and ΔFos proteins which are an integral part of the signal transduction pathways in the brain and also involved in the pathophysiology of depression as well as the mechanism of antidepressant action.

Imipramine Influences Body Distribution of Supplemental Zinc Which May Enhance Antidepressant Action.

Zinc (Zn) was found to enhance the antidepressant efficacy of imipramine (IMI) in human depression and animal tests/models of depression. However, the underlying mechanism for this effect remains unknown. We measured the effect of intragastric () combined administration of IMI (60 mg/kg) and Zn (40 mg Zn/kg) in the forced swim test (FST) in mice.

Targeting zinc metalloenzymes in coronavirus disease 2019.

Several lines of evidence support a link between the essential element zinc and the coronavirus disease 2019 (COVID-19). An important fact is that zinc is present in proteins of humans and of viruses. Some zinc sites in viral enzymes may serve as drug targets and may liberate zinc ions, thus leading to changes in intracellular concentration of zinc ions, while increased intracellular zinc may induce biological effects in both the host and the virus.

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.

Synthesis of new 4-butyl-arylpiperazine-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives and evaluation for their 5-HT and D receptor affinity and serotonin transporter inhibition.

A series of novel 4-butyl-arylpiperazine-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesized and evaluated for their 5-HT/D receptor affinity and serotonin reuptake inhibition. The compounds exhibited high affinity for the 5-HT receptor, (especially 4dK = 0.4 nM) which depended on the substitution pattern at the phenylpiperazine moiety.

Analysis of Density Changes of Selected Brain Receptors After a 14-Day Supply of Chromium(III) and Evaluation of Chromium(III) Affinity to Selected Receptors and Transporters.

Chromium(III) is one of the most controversial biometals. Although, it is no longer on the list of minerals necessary for the proper functioning of the human body, and its pharmacological effect is still under discussion. One of the purposes of Cr(III) administration is to use it in patients with mood disorders and it is strictly related to its pharmacological, not dietary effect.

Preclinical evaluation of 1,2,4-triazole-based compounds targeting voltage-gated sodium channels (VGSCs) as promising anticonvulsant drug candidates.

Epilepsy is a chronic neurological disorder affecting nearly 65-70 million people worldwide. Despite the observed advances in the development of new antiepileptic drugs (AEDs), still about 30-40% of patients cannot achieve a satisfactory seizure control. In our current research, we aimed at using the combined results of radioligand binding experiments, PAMPA-BBB assay and animal experimentations in order to design a group of compounds that exhibit broad spectrum of anticonvulsant activity.

Synthesis and biological evaluation of new multi-target 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with potential antidepressant effect.

A series of novel 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesised and evaluated for their 5-HT/D/5-HT/5-HT/5-HT receptor affinity and serotonin reuptake inhibition. Most of the evaluated compounds displayed high affinities for 5-HT receptors (e.g.

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.

Synthesis of new 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives with rigidized tryptamine moiety as potential SSRI and 5-HT receptor ligands.

Extended studies in the 4-aryl-pyrido[1,2-c]pyrimidine group resulted in 27 new compounds (10.1-10.27), 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives.

Acid sphingomyelinase - a regulator of canonical transient receptor potential channel 6 (TRPC6) activity.

Recent investigations propose the acid sphingomyelinase (ASM)/ceramide system as a novel target for antidepressant action. ASM catalyzes the breakdown of the abundant membrane lipid sphingomyelin to the lipid messenger ceramide. This ASM-induced lipid modification induces a local shift in membrane properties, which influences receptor clustering and downstream signaling.