Ketamine and Ro 25-6981 reverse behaviorala 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. However, not much is known about the antidepressant efficacy of NMDAR antagonists in zinc-deficient (ZnD) animals. We evaluated the antidepressant-like activity of two NMDAR antagonists (ketamine; global NMDAR antagonist and Ro 25-6981 (Ro); selective antagonist of the GluN2B NMDAR subunit) in ZnD rats using the forced swim test (FST) and sucrose intake test (SIT). A single dose of either Ro 25-6981 or ketamine normalized depressive-like behaviors in ZnD rats; however, Ro was effective in both tests, while ketamine was only effective in the FST. Additionally, we investigated the mechanism of antidepressant action of Ro at the molecular (analysis of protein expression by Western blotting) and anatomical (density of dendritic spines by Golgi Cox-staining) levels. ZnD rats exhibited decreased phosphorylation of the p70S6K protein, and enhanced density of dendritic spines in the prefrontal cortex (PFC) compared to control rats. The antidepressant-like activity of Ro was associated with the increased phosphorylation of p70S6K and ERK in the PFC. In summary, single doses of the NMDAR antagonists ketamine and Ro exhibited antidepressant-like activity in the ZnD animal model of depression. Animals were only deprived of Zn for 4 weeks and the biochemical effects of Zn deprivation and Ro were investigated in the PFC and hippocampus. The shorter duration of dietary Zn restriction may be a limitation of the study. However, future studies with longer durations of dietary Zn restriction, as well as the investigation of multiple brain structures, are encouraged as a supplement to this study

Zinc Deficiency and Depression

Zinc deficiency has multiple effects, including neurological and somatic symptoms. Zinc deficiency can lead to depression, increased anxiety, irritability, emotional instability, and induced deficits in social behavior. Clinical studies have shown that low levels of zinc intake contributes to the symptoms of depression and patients suffering from depression have a lower serum zinc level. Also the animal studies have shown an important role of dietary zinc deficiency in the induction of depressive‐like symptoms. Moreover, both preclinical and clinical studies have indicated the potential benefits of zinc supplementation as an adjunct to conventional antidepressant drugs or as a stand‐alone intervention. This chapter focuses on the role of the zinc deficiency in the pathogenesis of depression, changes in animal behavior induced by dietary zinc restriction, the role of zinc supplementation in the treatment of depression, and the possible mechanisms involved in these relationships. Both clinical and preclinical studies related to these findings will be discussed

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. Methods. Magnesium was administered once daily for 14 days at three doses (10, 15, and 20 mg/kg, intraperitoneal) to sham and OB rats. Following treatment, open field and passive avoidance tests were performed in the sham and OB rats. After 24 h, the hippocampus, the prefrontal cortex (PFC), and the amygdala of rats treated with the most active dose (15 mg/kg) were harvested, and the protein and mRNA levels were determined. Results. Chronic administration of magnesium (15 and 20 mg/kg) reduced the number of trials required to learn passive avoidance and reduced the OB-induced hyperactivity. OB increased the P-S845 level in the hippocampus, which was reduced by magnesium treatment. Magnesium significantly increased the levels of BDNF, GluN2B, P-S831, and P-S845 protein (and mRNA) primarily in the PFC and the hippocampus in OB rats. Conclusion. For the first time, the present results demonstrate the antidepressant-like activity of magnesium in the OB animal model of depression and indicate the potential involvement of the AMPA/BDNF pathway in this activity

Selected plant materials used in migraine therapy

Migraine is a neurovascular disease characterized by idiopathic, throbbing, usually unilateral headache, accompanied by gastrointestinal disturbances and increased sensitivity to stimuli. Symptoms may persist for several days, and their severity prevents the patient from regular activity. According to estimates, about 3.5 million people of all ages suffer from it in Poland. The disease affects children and adults, with the vast majority (about 80%) of adult patients being women. It does not directly threaten life, but it has a destructive impact on the patient's quality of life, social and family functioning, and professional activity. It should be emphasized that the mechanisms causing migraine are not fully understood. Different types of serotonin (especially 5-HT1) receptors play an essential role in the pathophysiology of migraine. The evidence of the role of the CGRP neuropeptide in the pathomechanism of the development of a migraine attack led to the introduction of monoclonal antibodies (anti-CGRP) into the treatment, whose intravenous or oral administration to patients brings a significant improvement in their clinical condition. In addition, patients receive analgesics, antiemetics, and sedatives. A positive effect on the frequency and severity of migraine pain has a normalized lifestyle, properly selected physical activity, as well as diet. Herbal substances support the prevention of migraine attacks and soothe in the event of their occurrence. Recommended for phytotherapy are ergot, butterbur, feverfew and also ginger, administered as tablets, infusions, or tinctures. Another therapeutic option is the use of drugs and dietary supplements made from dried inflorescences of hemp and cannabis. Preparations containing in their composition tetrahydrocannabinol (THC) with a content greater than 0.2% are available only on prescription with a duplicate. Inhalations with essential oils of peppermint and lavender help alleviate the symptoms of the disease, mainly from the digestive system. It should be remembered that herbal preparations are not without side effects, and their use in migraine therapy should not be continuous. There are few randomized clinical trials confirming the effectiveness of migraine phytotherapy

Nitric oxide synthase inhibitor attenuates the effects of repeated restraint stress on synaptic transmission in the paraventricular nucleus of the rat hypothalamus

Corticotropin-releasing hormone (CRH)-synthesizing parvocellular neuroendocrine cells (PNCs) of the hypothalamic paraventricular nucleus (PVN) play a key role in the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Several studies have demonstrated that synaptic inputs to these cells may undergo stress-related enhancement but, on the other hand, it has been reported that exposition to the same stressor for prolonged time periods may induce a progressive reduction in the response of the HPA axis to homotypic stressors. In the present study rats were subjected to 10 min restraint sessions, repeated twice daily for 3 or 7 days. Miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs) were then recorded from PNCs in ex vivo hypothalamic slice preparations obtained 24 h after the last restraint. Restraint stress repeated over 3 days resulted in increased mean frequency and decreased rise time and decay time constant of mEPSCs, accompanied by a decrease in the excitability of PNCs, however, no such changes were evident in slices obtained from rats subjected to restraint over 7 days. There were no changes in mIPSCs after repeated restraint. Administration of the unspecific nitric oxide synthase (NOS) blocker Nω-Nitro-L-arginine (L-NNA) before each restraint, repeated over 3 days, prevented the occurrence of an increase in mEPSC frequency. However, animals receiving L-NNA and subjected to repeated restraint had similar changes in PNCs membrane excitability and mEPSC kinetics as stressed rats not receiving L-NNA. Comparison of the effects of a single 10 min restraint session followed by either an immediate or delayed (24 h) decapitation revealed an increase in the mean mEPSC frequency and a decrease in the mean mIPSC frequency in slices prepared immediately after restraint, with no apparent effects when slice preparation was delayed by 24 h. These results demonstrate that restraint, lasting 10 min and repeated twice daily for 3 days, induces a selective and long-lasting enhancement of excitatory synaptic input onto PNCs, partially by a NOS-dependent mechanism, and reduces PNC excitability, whereas prolongation of repeated stress for up to 7 days results in an adaptation

Determination of the content of bioelements in an aerosol produced from commercially available mineral waters using a Mini Graduation Tower-2018 device

There are various types of bottled water available, including: spring water and high-, medium- or low-mineralized mineral water. Water with the highest content of mineral salts (>1000 ppm), i.e. medicinal water, has been the most widely used in medicine. One of the most commonly used forms of application of the described water types are e.g. inhalations. It is worth mentioning, however, that the use of these types of water, due to the high content of minerals (barium, chloride, sulphate ions), has the influence on human health. Although a little is known about the limitations of using the external method, and particularly the recently popular aerosol therapy. The popularity of this method of treatment is due to the fact that it can be used at different age groups of patients and in contrary to oral drug dosage, aerosol therapy has faster onset of action and a much greater safety profile of the therapy. It is worth noting that not all producers of medicinal water provide information about the total mineral content of their products. Moreover, producers do not declare if mineral water can be applied in children. The aim of the study was the quantitative analysis of selected metals: sodium, potassium, magnesium, iron and zinc in 7 selected medicinal and mineral waters. The newly constructed Mini-Graduation Tower 2018 device was used to generate the aerosol. In most of the tested waters (except for the zinc content in the Słotwinka water), statistically significant changes in the content of the tested ions were demonstrated in relation to the control sample which were mineralizates obtained from catontrol (the filter subject to the 4-time distilled water aerosol). The highest content of divalent and trivalent ions was found in the mineralizate obtained from Zabłocka Mgiełka Solankowa, while the highest content of monovalent cations was found in Franciszek and Helena water. In all samples, the ion content obtained indicates the possibility of using the tested water in aerosol therapy. The obtained results show that the "Minitężnia-2018" device can be used to study aerosols

Study of the serum copper levels in patients with major depressive disorder

Copper may be involved in the pathophysiology of depression. Clinical data on this issue are very limited and not conclusive. The purpose of the study was to determine the copper concentration in the serum of patients with major depressive disorder and to discuss its potential clinical usefulness as a biomarker of the disease. A case–control clinical study included 69 patients with current depressive episode, 45 patients in remission and 50 healthy volunteers. Cu concentration was measured by electrothermal atomic absorption spectrometry (ETAAS). The mean serum copper level in depressed patients was slightly lower (by 11 %; not statistically significant) than in the control group. Furthermore, there was no significant difference in Cu(2+) concentration between depressive episode and remission, nor between remission and control group. In the remission group were observed significant correlations between copper levels and the average number of relapses over the past years or time of remission. There was no correlation between serum copper and severity of depression, as measured by HDRS and MADRS. The obtained results showed no significant differences between the copper concentration in the blood serum of patients (both with current depressive episode and in remission) and healthy volunteers, as well as the lack of correlations between the copper level in the active stage of the disease and clinical features of the population. Our study is the first conducted on such a large population of patients, so the results may be particularly important and reliable source of knowledge about the potential role of copper in depression

Synthesis of Novel Pyrido[1,2-c]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT1A 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 (7a–i) derivatives were synthesized. The chemical structures of the new compounds were confirmed by 1H and 13C NMR spectroscopy and ESI-HRMS spectrometry. The affinities of all compounds for the 5-HT1A receptor and serotonin transporter protein (SERT) were determined by in vitro radioligand binding assays. The test compounds demonstrated very high binding affinities for the 5-HT1A receptor of all derivatives in the series (6a–i and 7a–i) and generally low binding affinities for the SERT protein, with the exception of compounds 6a and 7g. Extended affinity tests for the receptors D2, 5-HT2A, 5-HT6 and 5-HT7 were conducted with regard to selected compounds (6a, 7g, 6d and 7i). All four compounds demonstrated very high affinities for the D2 and 5-HT2A receptors. Compounds 6a and 7g also had high affinities for 5-HT7, while 6d and 7i held moderate affinities for this receptor. Compounds 6a and 7g were also tested in vivo to identify their functional activity profiles with regard to the 5-HT1A receptor, with 6a demonstrating the activity profile of a presynaptic agonist. Metabolic stability tests were also conducted for 6a and 6d

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 (p.o.) combined administration of IMI (60 mg/kg) and Zn (40 mg Zn/kg) in the forced swim test (FST) in mice. The effect of Zn + IMI on serum, brain, and intestinal Zn concentrations; Zn transporter (ZnT, ZIP) protein levels in the intestine and ZnT in the brain; including BDNF (brain-derived neurotrophic factor) and CREB (cAMP response element-binding protein) protein levels in the brain were evaluated. Finally, the effect of IMI on Zn permeability was measured in vitro in colon epithelial Caco-2 cells. The co-administration of IMI and Zn induced antidepressant-like activity in the FST in mice compared to controls and Zn or IMI given alone. This effect correlated with increased BDNF and the ratio of pCREB/CREB protein levels in the prefrontal cortex (PFC) compared to the control group. Zn + IMI co-treatment increased Zn concentrations in the serum and brain compared to the control group. However, in serum, co-administration of IMI and Zn decreased Zn concentration compared to Zn alone treatment. Also, there was a reduction in the Zn-induced enhancement of ZnT1 protein level in the small intestine. Zn + IMI also induced an increase in the ZnT4 protein level in the PFC compared to the control group and normalized the Zn-induced decrease in the ZnT1 protein level in the hippocampus (Hp). The in vitro studies revealed enhanced Zn permeability (observed as the increased transfer of Zn through the intestinal cell membrane) after IMI treatment. Our data indicate that IMI enhances Zn transfer through the intestinal tract and influences the redistribution of Zn between the blood and brain. These mechanisms might explain the enhanced antidepressant efficacy of combined IMI/Zn treatment observed in the FST in mice

The serum magnesium concentration as a potential state marker in patients with unipolar affective disorder

Aim. The growing body of evidence suggests that magnesium levels can serve as a marker of major depressive disorder (MDD), but findings from clinical trials remain inconclusive. The aim of the presented study was to determine the magnesium concentration in serum of patients with MDD (in the active stage of the disease or in remission) and to analyze the role of magnesium levels as a potential marker of the disease. Methods. Sixty-nine patients with current depressive episode, 45 patients in remission and 50 healthy volunteers were enrolled into the case-control study. The magnesium concentration was measured by flame atomic absorption spectrometry (FAAS). Results. The mean serum magnesium concentration of patients in the depressed phase was significantly higher, compared to the control group. Moreover, magnesium levels of patients in the remission were not significantly different from the concentrations recorded in the healthy volunteers. There was also a positive correlation between the magnesium levels and the severity of depression measured by the Hamilton Rating Scale for Depression (HDRS) and the Montgomery-Asberg Depression Rating Scale (MADRS). Conclusions. The obtained results may suggest a role of magnesium as a state marker reflecting the pathophysiological changes underlying MDD and accompanying severe depressive episodes