Katarzyna Młyniec

Essential elements in depression and anxiety. Part II

In this paper we continue to discuss the involvement of essential elements in depression and anxiety, and the possible mechanisms that link elements to the neurobiology underlying depression/anxiety. The present paper is focused on copper, selenium, manganese, iodine and vanadium. Different aspects of relationship between elements and depression or anxiety are reviewed, e.g. the association of the amount of an element in a diet or the serum level of an element and depressive or anxiety-like symptoms. Moreover, the relation of selected elements to the pathophysiology of depression or anxiety is discussed in the context of enzymes which require these elements as co-factors and are involved in the underlying pathophysiology of these disorders.

The role of the GPR39 receptor in zinc deficient-animal model of depression

During the last decade it has been shown that zinc may activate neural transmissions via the GPR39 Zn(2+)-sensing receptor, which can be involved in the regulation of neuronal plasticity. According to the neurotrophic hypothesis of depression, decreased brain derived neurotrophic factor (BDNF) levels in depressed patients play a key role in the pathogenesis of this disorder. BDNF, similarly as zinc, is known to be involved in the process of neuron survival and the regulation of neuronal plasticity. The aim of the present study was to determine whether the administration of a 6-week diet deficient in zinc would cause depressive-like behaviour and if such behavioural alterations would correlate with changes in the expression of the BDNF protein and GPR39 receptor. In the first part of the present study the animal behaviour after a 6-week zinc-deficient diet, in the forced swim test (FST) was investigated. In the second part expression of the GPR39 and BDNF protein level in the frontal cortex was measured using the Western Blot method. Administration of a zinc-deficient diet for 6 weeks increased immobility time in the FST by 24%, so exerted depression-like behaviour. A biochemical study showed a significant reduction in GPR39 (by 53%) and BDNF (by 49%) protein expression in the frontal cortex in mice receiving the zinc deficient diet for 6 weeks. Our study provides evidence that the GPR39 Zn(2+)-sensing receptor may be responsible for lowering the BDNF protein level and in consequence may be involved in the pathogenesis of depression.

Zinc as a marker of affective disorders

Depression is considered as a chronic and recurring illness with functional impairment, significant disability, morbidity and mortality. Despite the extensive research carried out on depression, its pathophysiology is still poorly understood. An important problem concerning research into depressive disorder is the lack of biological markers which could improve diagnosis or indicate a risk of developing depression or risk of relapse. Several reports indicated decreased zinc concentrations and even its deficit in clinical depression, so the measurement of the concentration of this element in the blood of patients was suggested as a useful and specific clinical marker of depression. The reported results indicated that the serum zinc level might be a marker of depression as a state (state marker) in treatment responsive patients. However, in drug-resistant depression a decreased concentration of zinc may be a marker of traits (trait marker). It seems, however, that the measurement of the concentrations of zinc might be in the future a component of the battery of tests; of markers of immune activation and oxidative stress rather than itself alone.

GPR39 (zinc receptor) knockout mice exhibit depression-like behavior and CREB/BDNF down-regulation in the hippocampus.

Background: Zinc may act as a neurotransmitter in the central nervous system by activation of the GPR39 metabotropic receptors. Methods: In the present study, we investigated whether GPR39 knockout would cause depressive-like and/or anxiety-like behavior, as measured by the forced swim test, tail suspension test, and light/dark test. We also investigated whether lack of GPR39 would change levels of cAMP response element-binding protein (CREB),brain-derived neurotrophic factor (BDNF) and tropomyosin related kinase B (TrkB) protein in the hippocampus and frontal cortex of GPR39 knockout mice subjected to the forced swim test, as measured by Western-blot analysis. Results: In this study, GPR39 knockout mice showed an increased immobility time in both the forced swim test and tail suspension test, indicating depressive-like behavior and displayed anxiety-like phenotype. GPR39 knockout mice had lower CREB and BDNF levels in the hippocampus, but not in the frontal cortex, which indicates region specificity for the impaired CREB/BDNF pathway (which is important in antidepressant response) in the absence of GPR39. There were no changes in TrkB protein in either structure. In the present study, we also investigated activity in the hypothalamus-pituitary-adrenal axis under both zinc- and GPR39-deficient conditions. Zinc-deficient mice had higher serum corticosterone levels and lower glucocorticoid receptor levels in the hippocampus and frontal cortex. Conclusions: There were no changes in the GPR39 knockout mice in comparison with the wild-type control mice, which does not support a role of GPR39 in hypothalamus-pituitary-adrenal axis regulation. The results of this study indicate the involvement of the GPR39 Zn2+-sensing receptor in the pathophysiology of depression with component of anxiety.

The involvement of the GPR39-Zn(2+)-sensing receptor in the pathophysiology of depression. Studies in rodent models and suicide victims.

Zinc is one of the most important trace elements in our body. Patients suffering from depression show lower serum zinc levels compared to healthy controls. Zincs antagonism to the glutamatergic system seems to be responsible for mood recovery. Recent years have shown that zinc may regulate neurotransmission via the metabotropic GPR39 receptor. Activation of the GPR39-Zn(2+)-sensing receptor (GPR39) triggers diverse neuronal pathways leading to a cAMP-responsive element binding the protein (CREB) expression, which then induces synthesis of the brain-derived neurotrophic factor and, in turn, activation of the Tropomyosin receptor kinase B (TrkB) receptor. In the present study, we investigated the alteration of the GPR39 in different models of depression, such as zinc deficiency and olfactory bulbectomy and in suicide victims. Additionaly, we focused on CREB-BDNF/TrkB under zinc deficient conditions in mice. To demonstrate depressive-like behaviour, a standard and modified forced swim test (FST) was performed. To evaluate expression of GPR39, CREB, BDNF and TrkB, Western Blot analysis was used. Zinc deficient mice and rats showed decreased GPR39 expression in the hippocampus and frontal cortex. A decreased level of hippocampal and cortical GPR39 was also observed in suicide victims. In contrast, increased GPR39 in the hippocampus of olfactory bulbectomized rats was observed. Additionally, we found a decreased expression of CREB, BDNF and TrkB only in the hippocampus of zinc-deficient mice. Our present study demonstrates the associacion of the GPR39 Zn(2+)-sensing receptor in the pathomechanism of depression. Down-regulation of CREB, BDNF, TrkB and GPR39 receptor found under zinc-deficient conditions in the hippocampus, may play an important role in the pathophysiology of mood disorders, since most of patients suffering from depression show lower serum zinc.

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. Then, the behavior of the rats was examined in the forced swim test, sucrose intake test and social interaction test. Western blot assays were used to study the alterations in NMDAR subunits GluN2A and GluN2B and proteins associated with NMDAR signaling in the hippocampus (Hp) and prefrontal cortex (PFC). RESULTS Following 4 or 6 weeks of zinc restriction, behavioral despair, anhedonia and a reduction of social behavior occurred in rats with concomitant increased expression of GluN2A and GluN2B and decreased expression of the PSD-95, p-CREB and BDNF protein levels in the Hp. The up-regulation of GluN2A protein was also found in the PFC, but only after prolonged (6 weeks) zinc deprivation. CONCLUSIONS The procedure of zinc restriction in rats causes behavioral changes that share some similarities to the pathophysiology of depression. Obtained data indicated that depressive-like behavior induced by zinc deficiency is associated with the changes in NMDAR signaling pathway.

Zinc deficiency alters responsiveness to antidepressant drugs in mice

BACKGROUND There is some evidence coming from preclinical and clinical studies suggesting a relationship between dietary zinc intake and depressive symptoms. The aim of the study was to determine whether zinc deficiency alters the response to antidepressants with a different mechanism of action. We examine also whether these changes are related to activity of the hypothalamic-pituitary-adrenal HPA axis. METHODS Male CD-1 mice were assigned to groups according to diet and antidepressant administration. To evaluate animal behavior, the immobility time in the forced swim test (FST) and locomotor activity were measured. To determine serum zinc levels the flame atomic absorption spectroscopy (FAAS) was used. The serum corticosterone was determined by radioimmunoassay (RIA). RESULTS Antidepressants administered to zinc-deprived mice induced an altered response in the FST when compared to animals fed with an adequate diet. There were no changes in locomotor activity. Animals subjected to a zinc-deficient diet showed a significant reduction in serum zinc levels, which was normalized by antidepressant treatment. An increase in serum corticosterone concentrations in mice fed with a zinc-deficient diet and treated with antidepressants was observed, so it can be concluded that reduced levels of zinc contribute hyperactivation of the HPA axis. CONCLUSION The results of this study suggest that a diet with a reduced zinc level alters antidepressant action, which is associated with a reduction in the serum zinc level and rise in the corticosterone level. The results of this study may indicate the involvement of zinc deficiency in the pathogenesis of depression.

GPR39 up-regulation after selective antidepressants.

Recent studies indicated that zinc activates neural transmission via the GPR39 Zn²⁺-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 Zn²⁺-sensing receptor in the antidepressant effect of selective monoamine reuptake inhibitors.

Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling

Zinc is a nutritionally fundamental trace element, essential to the structure and function of numerous macromolecules, including enzymes regulating cellular processes and cellular signaling pathways. The mineral modulates immune response and exhibits antioxidant and anti-inflammatory activity. Zinc retards oxidative processes on a long-term basis by inducing the expression of metallothioneins. These metal-binding cysteine-rich proteins are responsible for maintaining zinc-related cell homeostasis and act as potent electrophilic scavengers and cytoprotective agents. Furthermore, zinc increases the activation of antioxidant proteins and enzymes, such as glutathione and catalase. On the other hand, zinc exerts its antioxidant effect via two acute mechanisms, one of which is the stabilization of protein sulfhydryls against oxidation. The second mechanism consists in antagonizing transition metal-catalyzed reactions. Zinc can exchange redox active metals, such as copper and iron, in certain binding sites and attenuate cellular site-specific oxidative injury. Studies have demonstrated that physiological reconstitution of zinc restrains immune activation, whereas zinc deficiency, in the setting of severe infection, provokes a systemic increase in NF-κB activation. In vitro studies have shown that zinc decreases NF-κB activation and its target genes, such as TNF-α and IL-1β, and increases the gene expression of A20 and PPAR-α, the two zinc finger proteins with anti-inflammatory properties. Alternative NF-κB inhibitory mechanism is initiated by the inhibition of cyclic nucleotide phosphodiesterase, whereas another presumed mechanism consists in inhibition of IκB kinase in response to infection by zinc ions that have been imported into cells by ZIP8.

The role of glutamatergic, GABA-ergic, and cholinergic receptors in depression and antidepressant-like effect.

Depression is one of the most common mental disorders and social issue worldwide. Although there are many antidepressants available, the effectiveness of the therapy is still a serious issue. Moreover, there are many limitations of currently used antidepressants, including slow onset of action, numerous side effects, or the fact that many patients do not respond adequately to the treatment. Therefore, scientists are searching for new compounds with different mechanisms of action. Numerous data indicate the important role of glutamatergic, GABA-ergic, and cholinergic receptors in the pathomechanism of major depressive disorder. This review presents the role of glutamatergic, GABA-ergic, and cholinergic receptors in depression and antidepressant-like effect.