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. Canonical transient receptor potential channels 6 (TRPC6) are non-selective cation channels located in the cell membrane that play an important role in dendritic growth, synaptic plasticity and cognition in the brain. They can be activated by hyperforin, an ingredient of the herbal remedy St. John's wort for treatment of depression disorders. Because of their role in the context of major depression, we investigated the crosstalk between the ASM/ceramide system and TRPC6 ion channels in a pheochromocytoma cell line 12 neuronal cell model (PC12 rat pheochromocytoma cell line). Ca2+ imaging experiments indicated that hyperforin-induced Ca2+ influx through TRPC6 channels is modulated by ASM activity. While antidepressants, known as functional inhibitors of ASM activity, reduced TRPC6-mediated Ca2+ influx, extracellular application of bacterial sphingomyelinase rebalanced TRPC6 activity in a concentration-related way. This effect was confirmed in whole-cell patch clamp electrophysiology recordings. Lipidomic analyses revealed a decrease in very long chain ceramide/sphingomyelin molar ratio after ASM inhibition, which was connected with changes in the abundance of TRPC6 channels in flotillin-1-positive lipid rafts as visualized by western blotting. Our data provide evidence that the ASM/ceramide system regulates TRPC6 channels likely by controlling their recruitment to specific lipid subdomains and thereby fine-tuning their physical properties.

The Possibilities of Using Chromium Salts as an Agent Supporting Treatment of Polycystic Ovary Syndrome.

The polycystic ovary syndrome (PCOS) is the most frequent endocrinopathy in women in reproductive age with the so far undetermined causes of development. In the etiopathogenesis of PCOS, the role of insulin resistance is emphasised, which was an indication for the attempts at using chromium III salts (Cr) in augmenting pharmacotherapy applied in patients. The analysis of the usefulness and efficacy of this approach was the direct goal of this thesis. Animal tests confirmed the efficacy of chromium in maintaining the appropriate level of glycaemia and insulinaemia, normalisation of plasma concentrations of microelements and also a correlation between the Cr level, insulin and dehydroepiandrosterone (DHEA) was found. A decrease in the expression of 3ß-hydroxysteroid dehydrogenase and 17ß-hydroxysteroid dehydrogenase was identified in adipose tissue. Clinical studies, although sparse, show that the supplementation with chromium can improve BMI and the parameters evaluating the control of glycaemia and increase the chances for ovulation and regular menstruation. However, the small number and a variability in study protocols makes comparing them very difficult. A completely new subject that has not been yet studied is the possibility of using chromium in levelling mood disorders in patients with PCOS. Currently, there are still no sufficient proofs for introducing chromium as a standard in treating and preventing insulin resistance in patients with PCOS. However, this direction remains open, and treating insulin resistance is an important challenge in clinical practice.

Development of the 1,2,4-triazole-based anticonvulsant drug candidates acting on the voltage-gated sodium channels. Insights from in-vivo, in-vitro, and in-silico studies.

The treatment of epilepsy remains difficult mostly since almost 30% of patients suffer from pharmacoresistant forms of the disease. Therefore, there is an urgent need to search for new antiepileptic drug candidates. Previously, it has been shown that 4-alkyl-5-substituted-1,2,4-triazole-3-thione derivativatives possessed strong anticonvulsant activity in a maximal electroshock-induced seizure model of epilepsy. In this work, we examined the effect of the chemical structure of the 1,2,4-triazole-3-thione-based molecules on the anticonvulsant activity and the binding to voltage-gated sodium channels (VGSCs) and GABAA receptors. Docking simulations allowed us to determine the mode of interactions between the investigated compounds and binding cavity of the human VGSC. Selected compounds were also investigated in a panel of ADME-Tox assays, including parallel artificial membrane permeability assay (PAMPA), single cell gel electrophoresis (SCGE) and cytotoxicity evaluation in HepG2 cells. The obtained results indicated that unbranched alkyl chains, from butyl to hexyl, attached to 1,2,4-triazole core are essential both for good anticonvulsant activity and strong interactions with VGSCs. The combined in-vivo, in-vitro and in-silico studies emphasize 4-alkyl-5-substituted-1,2,4-triazole-3-thiones as promising agents in the development of new anticonvulsants.

Effects of Magnesium Supplementation on Unipolar Depression: A Placebo-Controlled Study and Review of the Importance of Dosing and Magnesium Status in the Therapeutic Response.

Animal studies using tests and models have demonstrated that magnesium exerts an antidepressant effect. The literature contains few studies in humans involving attempts to augment antidepressant therapy with magnesium ions. The purpose of our study was to assess the efficacy and safety of antidepressant treatment, in combination with magnesium ions. A total of 37 participants with recurrent depressive disorder who developed a depressive episode were included in this study. As part of this double-blind study, treatment with the antidepressant fluoxetine was accompanied with either magnesium ions (120 mg/day as magnesium aspartate) or placebo. During an 8-week treatment period, each patient was monitored for any clinical abnormalities. Moreover, serum fluoxetine and magnesium levels were measured, and pharmaco-electroencephalography was performed. The fluoxetine + magnesium and fluoxetine + placebo groups showed no significant differences in either Hamilton Depression Rating Scale (HDRS) scores or serum magnesium levels at any stage of treatment. Multivariate statistical analysis of the whole investigated group showed that the following parameters increased the odds of effective treatment: lower baseline HDRS scores, female gender, smoking, and treatment augmentation with magnesium. The parameters that increased the odds of remission were lower baseline HDRS scores, shorter history of disease, the presence of antidepressant-induced changes in the pharmaco-EEG profile at 6 h after treatment, and the fact of receiving treatment augmented with magnesium ions. The limitation of this study is a small sample size.

Allosteric Inhibition of Serotonin 5-HT7 Receptors by Zinc Ions.

The allosteric regulation of G protein-coupled receptors (GPCRs) is a well-known phenomenon, but there are only a few examples of allosteric modulation within the metabotropic serotonergic receptor family. Recently, we described zinc non-competitive interactions toward agonist binding at serotonin 5-HT1A receptors, in which biphasic effects, involving potentiation at sub-micromolar concentrations (10 µM) and inhibition at sub-millimolar concentrations (500 µM) of Zn2+ in radioligand binding assays, were consistent with both the agonist and antagonist-like effects of zinc ions observed in in vivo studies. Here, we showed new data demonstrating zinc allosteric inhibition of both agonist and antagonist binding at human recombinant 5-HT7 receptors stably expressed in HEK293 cells as observed by radioligand binding studies as well as zinc neutral antagonism displayed by the concentration of 10 µM in the functional LANCE assay. The allosteric nature of the effect of Zn on 5-HT7 receptors was confirmed (1) in saturation studies in which zinc inhibited the binding of potent orthosteric 5-HT7 receptor radioligands, the agonist [3H]5-CT, and the two antagonists [3H]SB-269970 and [3H]mesulergine, showing ceiling effect and differences in the magnitude of negative cooperativity (α = 0.15, 0.06, and 0.25, respectively); (2) in competition experiments in which 500 µM of zinc inhibited all radioligand displacements by non-labeled orthosteric ligands (5-CT, SB-269970, and clozapine), and the most significant reduction in affinity was observed for the 5-CT agonist (4.9-16.7-fold) compared with both antagonists (1.4-3.9-fold); and (3) in kinetic experiments in which 500 µM zinc increased the dissociation rate constants for [3H]5-CT and [3H]mesulergine but not for [3H]SB-269970. Additionally, in the functional LANCE test using the constitutively active HEK293 cell line expressing the 5-HT7 receptor, 10 µM zinc had features of neutral antagonism and increased the EC50 value of the 5-CT agonist by a factor of 3.2. Overall, these results showed that zinc can act as a negative allosteric inhibitor of 5-HT7 receptors. Given that the inhibiting effects of low concentrations of zinc in the functional assay represent the most likely direction of zinc activity under physiological conditions, among numerous zinc-regulated proteins, the 5-HT7 receptor can be considered a serotonergic target for zinc modulation in the CNS.

Are there differences in lipid peroxidation and immune biomarkers between major depression and bipolar disorder: Effects of melancholia, atypical depression, severity of illness, episode number, suicidal ideation and prior suicide attempts.

BACKGROUND: There is evidence that major depression (MDD) and bipolar disorder (BD) are accompanied by activated immune & oxidative (I&O) pathways. METHODS: To compare I&O biomarkers between MDD and BD we assessed serum levels of thiobarbituric acid reactive substances (TBARS; a lipid peroxidation marker), soluble interleukin-2 receptor (sIL-2R), sIL-6R, IL-α, sIL-1R antagonist (sIL-1RA), tumor necrosis factor receptor 60kDa/80kDa (sTNFR60/R80) in 114 MDD and 133 BD patients, and 50 healthy controls. We computed z-unit weighted indices reflecting the 5 cytokine receptor levels (zCytR), cell-mediated immunity (zCMI) and I&O pathways (zCMI+TBARS). RESULTS: There are no significant differences in biomarkers between MDD and BD. BD/MDD with atypical features is characterized by increased sIL-6R and TBARS, whereas melancholia is associated with higher TBARS and lower sTNFR60 levels. Severity of illness, as measured with the Hamilton Depression Rating Scale, is correlated with increased sIL-6R, sTNFR80, TBARS, zCytR and zCMI+TBARS. The number of episodes the year prior to blood sampling is positively associated with sTNFR80, TBARS, zCMI, zCMI+TBARS, while number of hospitalizations is positively associated with sIL-1RA. Prior suicidal attempts are associated with increased sIL-1RA, IL-1α, zCMI, TBARS and zCMI+TBARS, while TBARS is associated with current suicidal ideation. CONCLUSIONS: There are no I&O biomarker differences between MDD and BD. Atypical depression is associated with increased IL-6 trans-signaling and lipid peroxidation. Severity of depression, number of episodes and suicidal attempts are associated with activated I&O pathways. Increased TBARS is the single best predictor of BD/MDD, atypical depression, melancholia and current suicidal ideation.

Lipid Peroxidation and Immune Biomarkers Are Associated with Major Depression and Its Phenotypes, Including Treatment-Resistant Depression and Melancholia.

To examine immune-inflammatory and oxidative (I&O) biomarkers in major depression (MDD) and its related phenotypes, we recruited 114 well-phenotyped depressed patients and 50 healthy controls and measured serum levels of interleukin (IL)-1α, soluble IL-1 receptor antagonist (sIL-1RA), soluble IL-2 receptor (sIL-2R), soluble IL-6 receptor (sIL-6R), soluble tumor necrosis factor receptor 60 and 80 kDa (sTNF-R1/R2), and thiobarbituric acid reactive substances (TBARS). Obtained results indicate that MDD is characterized by increased sIL-1RA, sTNF-R1, and TBARS concentrations. Melancholic depression is associated with increased sIL-6R but lowered IL-1α levels. A current episode of depression is accompanied by significantly increased sIL-6R compared to the remitted state. Treatment-resistant depression (TRD) is accompanied by increased sIL-6R and TBARS but lowered sTNF-R2 levels compared to non-TRD patients. These immune markers are not significantly correlated with Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Depression Scale (MADRS), number episodes, or age at onset. Our findings show that increased sIL-1RA, sTNF-R1, and TBARS levels may be trait markers of depression, while increased sIL-6R levels may be a state marker of melancholia and an acute phase of depression. MDD is accompanied by increased lipid peroxidation and simultaneous activation of immune pathways, and the compensatory anti-inflammatory reflex system (CIRS). TRD is characterized by highly increased oxidative stress and probably increased TNFα and IL-6 trans-signalling. Novel treatments for major depression should target oxidative stress pathways, while new treatments for TRD should primary target lipid peroxidation and also activated immune-inflammatory pathways.

Molecular mechanism of action and safety of 5-(3-chlorophenyl)-4-hexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione - a novel anticonvulsant drug candidate.

Previously, it was found that 5-(3-chlorophenyl)-4-hexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (TP-315) effectively protects mice from maximal electroshock-induced seizures. The aim of this study was to determine possible interactions between TP-315 and different molecular targets, i.e. GABAA receptors, voltage-gated sodium channels, and human neuronal α7 and α4ß2 nicotinic acetylcholine receptors. The influence of TP-315 on the viability of human hepatic HepG2 cells was also established using PrestoBlue and ToxiLight assays. It was found that the anticonvulsant activity of TP-315 results (at least partially) from its influence on voltage-gated sodium channels (VGSCs). Moreover, the title compound slightly affected the viability of human hepatic cells.

Associations of Serum Cytokine Receptor Levels with Melancholia, Staging of Illness, Depressive and Manic Phases, and Severity of Depression in Bipolar Disorder.

To examine cytokine receptor biomarkers in bipolar disorder (BD), we recruited 133 well-phenotyped BD patients and 50 normal controls and measured serum levels of soluble interleukin 1 receptor antagonist (sIL-1RA), soluble interleukin-2 receptor (sIL-2R), sIL-6R, and tumor necrosis factor receptor 60 and 80 kDa (sTNFR60/80). sIL-1RA and sTNFR80 are significantly higher in BD than in controls and sTNFR80 and higher in melancholic than in non-melancholic patients and controls. Kapczinski's stages 3 + 4 are characterized by lowered sIL-2R and increased sTNFR80 levels. Acute phase depression is characterized by increased sTNFR80 levels as compared with controls, manic, and euthymic patients. Both sTNFR60 and sTNFR80 levels are significantly and positively related with severity of depression but not mania. Logistic regression analysis showed that the significant predictors for BD are increased sIL-1RA levels, nicotine dependence and a family history of depression and alcoholism. The risk factors for stages 3 + 4 are lowered sIL-2R levels and nicotine dependence. Melancholia is predicted by higher sTNFR80 levels and female sex. Severity of depression is predicted by female sex, nicotine dependence, and increased sTNFR60 and sTNFR80 levels. Cell-mediated immunity is activated during a current episode of depression but not (hypo)mania or the euthymic state. There are no associations between the biomarkers and age at onset, duration of illness, severity of mania, bipolar (BP)2 or BP1 subtypes, rapid cycling, atypical depression, psychotic or suicidal symptoms, and a family history of psychiatric disease. The results show that increased sIL-1RA may be a trait marker of BD, increased sTNFR80 a state marker of the depressive phase, especially melancholia, while lower sIL-2R but higher sTNFR80 may be staging biomarkers.

Up-regulation of the GPR39 Zn2+-sensing receptor and CREB/BDNF/TrkB pathway after chronic but not acute antidepressant treatment in the frontal cortex of zinc-deficient mice.

BACKGROUND: The GPR39-Zn(2+)-sensing receptor seems to be involved in the pathophysiology of depression. GPR39 knockout animals show depressive- and anxiety-like behavior. Chronic treatment with selective antidepressants (ADs) up-regulates GPR39. OBJECTIVE AND METHODS: In the present study we investigated whether acute or chronic treatment with imipramine, escitalopram, reboxetine and bupropion would cause changes in CREB, BDNF, TrkB and GPR39-Zn(2+) receptor proteins (measured by Western Blot) in the frontal cortex of mice fed with a low-zinc diet. RESULTS: The administration of acute antidepressants induced diverse effects in the proteins that were examined (namely, GPR39 down-regulation and a reduction in CREB protein after administration of all ADs; a decrease in BDNF after administration of imipramine and escitalopram; an increase in BDNF after administration of reboxetine; no change in BDNF following administration of bupropion; and a decrease in TrkB following the administration of all ADs except bupropion). On the other hand, chronic treatment (which is required for depression relief) with all antidepressants increased the levels of all these proteins. CONCLUSIONS: The present study for the first time demonstrates the up-regulation of GPR39 (and CREB, BDNF, and TrkB) protein when induced by chronic treatment with antidepressants (with different pharmacological profiles) in a zinc-deficiency model in mice. These data further indicate that the GPR39 receptor may be an important target in the antidepressant response.

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. We observed that a single injection of Zn (5 mg/kg) induced an increase in the phosphorylation of mTOR and p70S6K 30 min and 3 h after Zn treatment at time points when Zn produced also an antidepressant-like effect in the forced swim test (FST). Furthermore, Zn administered 3 h before the decapitation increased the level of brain derived neurotrophic factor (BDNF), GluA1 and synapsin I. An elevated level of GluA1 and synapsin I was still observed 24 h after the Zn treatment, although Zn did not produce any effects in the FST at that time point. We also observed that pretreatment with rapamycin (mTORC1 inhibitor), LY294002 (PI3K inhibitor), H-89 (PKA inhibitor) and GF109203X (PKC inhibitor) blocked the antidepressant-like effect of Zn in FST in rats and blocks Zn-induced activation of mTOR signaling proteins (analyzed 30 min after Zn administration). These studies indicated that the antidepressant-like activity of Zn depends on the activation of mTOR signaling and other signaling pathways related to neuroplasticity, which can indirectly modulate mTOR function.

Tissue distribution of gold nanoparticles after single intravenous administration in mice.

BACKGROUND: Nanoparticles (a part of matter which size is less than 100 nm) have numerous potential applications in biomedicine, due to their unique surface, electronic and optical properties. The goal of the present study was to examine the distribution of gold nanoparticles (GNPs) in mice after single intravenous administration. METHODS: Spherical GNPs were synthesized by chemical reduction of tetrachloroauric acid with ascorbic acid as a reductant. GNPs were stabilized using polyvinyl alcohol (PVA, m.w. = 67000Da) a substance approved for use in the pharmaceutical industry. The size of colloidal gold particles (diameter equals 25 ± 8 nm) was determined using HR SEM and DLS techniques; ζ potential of GNPs was determined using Malvern Zetasizer Nano ZS and it equals -5.2 ± 5.4 mV. An aqueous dispersion of GNPs was administered to mice in a dose of about 10 cm(3)/kg and 24 h later the amount of gold in different organs was determined using the inductively coupled plasma mass spectrometer (ICP MS). Initial concentration of GNPs equals 29.55 mg/l. RESULTS: GNPs after single intravenous administration preferentially accumulated in the liver (12.7% of the applied dose), while the other organs accumulated around 0.1% or less. CONCLUSION: Colloidal GNPs of the used size (about 25 ± 8 nm) provide new potential route for direct delivery system to the liver, which may be important e.g., in liver cancer diagnosis.

GPR39 up-regulation after selective antidepressants.

Recent studies indicated that zinc activates neural transmission via the GPR39 Zn²âº-sensing receptor. Preclinical and clinical studies demonstrated the antidepressant properties of zinc. To investigate whether the GPR39 receptor is involved in the mechanism of antidepressant action, we measured the expression of the GPR39 receptor (Western Blot) in the frontal cortex of mice treated intraperitoneally with imipramine (30 mg/kg), escitalopram (4 mg/kg), reboxetine (10 mg/kg) or bupropion (15 mg/kg) for 14 days. The present study shows the up-regulation of the GPR39 receptor protein level after escitalopram (by 290%), reboxetine (by 816%) and bupropion (by 272%), but not imipramine treatment. This is the first report to indicate the involvement of the GPR39 Zn²âº-sensing receptor in the antidepressant effect of selective monoamine reuptake inhibitors.

New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates--Nrf2 activators and GSK-3 inhibitors.

This paper reviews new drug targets in the treatment of depression and new drug candidates to treat depression. Depression is characterized by aberrations in six intertwined pathways: (1) inflammatory pathways as indicated by increased levels of proinflammatory cytokines, e.g. interleukin-1 (IL-1), IL-6, and tumour necrosis factor α. (2) Activation of cell-mediated immune pathways as indicated by an increased production of interferon γ and neopterin. (3) Increased reactive oxygen and nitrogen species and damage by oxidative and nitrosative stress (O&NS), including lipid peroxidation, damage to DNA, proteins and mitochondria. (4) Lowered levels of key antioxidants, such as coenzyme Q10, zinc, vitamin E, glutathione, and glutathione peroxidase. (5) Damage to mitochondria and mitochondrial DNA and reduced activity of respiratory chain enzymes and adenosine triphosphate production. (6) Neuroprogression, which is the progressive process of neurodegeneration, apoptosis, and reduced neurogenesis and neuronal plasticity, phenomena that are probably caused by inflammation and O&NS. Antidepressants tend to normalize the above six pathways. Targeting these pathways has the potential to yield antidepressant effects, e.g. using cytokine antagonists, minocycline, Cox-2 inhibitors, statins, acetylsalicylic acid, ketamine, ω3 poly-unsaturated fatty acids, antioxidants, and neurotrophic factors. These six pathways offer new, pathophysiologically guided drug targets suggesting that novel therapies could be developed that target these six pathways simultaneously. Both nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators and glycogen synthase kinase-3 (GSK-3) inhibitors target the six above-mentioned pathways. GSK-3 inhibitors have antidepressant effects in animal models of depression. Nrf2 activators and GSK-3 inhibitors have the potential to be advanced to phase-2 clinical trials to examine whether they augment the efficacy of antidepressants or are useful as monotherapy.

Early lifetime zinc supplementation protects zinc-deficient diet-induced alterations.

Preclinical and clinical data indicate the involvement of zinc in the pathophysiology and therapy of depression. A relationship between zinc-deficiency and depression symptoms was recently proposed. The present study investigated alterations in spontaneous locomotor activity and zinc concentrations in the serum, hippocampus and frontal cortex; these alterations were induced by subjecting rats to a zinc-deficient diet, prior subjected after birth to zinc-supplemented diet. Body weight was significantly reduced in animals subjected to the four-week zinc-deficient diet compared to those subjected to the zinc-adequate diet. The two-week zinc-deficient diet induced a significant increase in locomotor activity in all measured time periods (5, 30 and 60 min by 44-62%). The four-week zinc-deficient diet did not affect locomotor activity, while the six-week zinc-deficient diet resulted in a 45% increase in the 5 min time period. Serum zinc concentrations were significantly reduced (by 29%) in animals subjected to the four-week zinc-deficient diet but not in those subjected to the two- or six-week zinc-deficient diets. The zinc-deficient diet did not influence the zinc concentration in the examined brain regions regardless of the length. These results indicate that post-birth supplementation with zinc may protect zinc-deficient diet-induced rapid alterations in zinc homeostasis.

Evaluation of oxidative status and depression-like responses in Brown Norway rats with acute myeloid leukemia.

It has been proved that oxidative stress increases when leukemia is accompanied by depression. This fact may indicate the role of oxidative stress in the development of depression in cancer patients. The aim of this study was to determine whether the acute myeloid leukemia of Brown Norway rats, which is accompanied by oxidative stress, evoked behavioral and receptor changes resembling alterations characteristic of rat models of depression. The rats were divided into two groups: leukemic rats and healthy control. Leukemia was induced through intraperitoneal injection of 10(7) promyelocytic leukemia cells to the Brown Norway rats. Depression-like behavior was evaluated in the forced swim test at 30 or 34 days after leukemic cells injection. The rats were killed after the evaluation and the spleen, brain cortex and hippocampus were excised. The red-ox state was assessed in homogenates of tissues by measuring total glutathione (GSH) content, the ferric ion reducing ability of plasma (FRAP) level, expression of heme oxygenase-1 (HO-1), biliverdin reductase (BvR) and ferritin mRNA, superoxide dismutase (SOD) activity, as well as malondialdehyde (MDA) concentration. Radioligand binding assay was used to assess of the effect of leukemia on cortical receptors. Leukemic cells were identified using RM-124 antibody by FACS Calibur flow cytometry. Leukemia influenced locomotory activity as well as forced swim test behavior in a 34-day series of experiments. Signs of oxidative stress in leukemic rats were observed in each examined stage of leukemia development. The FRAP values and glutathione contents, were significantly lowered whereas HO-1 mRNA expression, and malonodialdehyde concentrations were significantly increased in the spleen and brain structures of leukemic rats in comparison with the healthy controls. A significant increase in the potency of glycine to displace [(3)H]L-689,560 from the strychnine-insensitive glycine site of the N-methyl-D-aspartic (NMDA) receptors receptor complex in cortical homogenates of the leukemic rats in 30- and 34-day experimental series was observed in comparison with the control. Upregulation of 5-HT(2A) receptors was observed in rat cortex after 30 days of leukemia development but not in 34-days series compared with the control. It is concluded that disturbances in antioxidant system in brain cortex were accompanied by an activation of glycine sites of the NMDA receptor complex, regardless of stage of leukemia development, which are characteristic of model of depression. Findings of our study demonstrate the link between glutamatergic activity, oxidative stress and leukemia.

Antidepressant-like activity of 8-Br-cAMP, a PKA activator, in the forced swim test.

The PKA activator, 8-Br-cAMP, dose-dependently reduced the immobility time in the forced swim test in rats. This effect was antagonized by co-treatment with selective PKA inhibitor Rp-cAMPS. This is the first demonstration of the antidepressant-like activity of the PKA activator.

Antidepressant-like effects of acute and chronic treatment with zinc in forced swim test and olfactory bulbectomy model in rats.

The activity of zinc administered intraperitoneally, acutely (in single dose), sub-chronically (in triple doses) or chronically (once daily for 14 days) were assessed in the forced swim test (FST) and olfactory bulbectomy (OB) model of depression in rats. Previously, we have demonstrated that acute administration of zinc sulfate is active in FST in rats and mice. In the present study, zinc hydroaspartate in a dose of 65 mg/kg (11.5 mgZn/kg), all: acute, sub-chronic and chronic administration, reduced the immobility time in the FST in rats. Removal of olfactory bulbs (OB surgery) in rats is associated with variety of behavioral abnormalities such as deficit in a step-down passive avoidance or hyperactivity in the "open field" test. Both acute and chronic administration of zinc hydroaspartate reduced the number of trials needed to the learning passive avoidance and reduced the OB-induced hyperactivity in rats. At the time schedule following zinc hydroaspartate administration, when behavioral experiments were performed, the serum zinc concentrations were significantly higher than control-physiological values. These results confirm activity of zinc in the FST, show its antidepressant-like activity in the OB rat model of depression, demonstrate the lack of tolerance to these effects and suggest relationship of these antidepressant-like effects with the rise in serum zinc. These animal data further suggest antidepressant activity of zinc in human depression.