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Essential elements in depression and anxiety. Part II
Abstract
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.
... Deficiency of this metal ion, has been reported in familial amyotrophic lateral sclerosis, Huntington's disease, Menkes disease, and occipital horn syndrome (Maes et al. 1997;Schlegel-Zawadzka and Nowak 2000;Stys et al. 2012;Bandmann et al. 2015). On the hand, excess amounts of it, have been implicated in neuronal cellular damage and in the development of neuropsychiatric disorders (Bandmann et al. 2015;Schlegel-Zawadzka et al. 1999;Manser, et al. 1989;Młyniec et al. 2015). Notably, high concentrations of copper were also reported in women with history of post-partum depression (Crayton and Walsh 2007). ...
... High concentration of copper has also been found in patients with Alzheimer's, Parkinson's, and Wilson's diseases and was also linked to decline in intelligence among young adolescents (Stys et al. 2012;Bandmann et al. 2015;Młyniec et al. 2015). Moreover, disturbances of copper metabolism have been found in patients with major depression and its abnormal serum level is being suggested for adoption as a potential biomarker of major depressive disorders (Liao et al. 2021;Russo 2011;Narang et al. 1991;Kułak-Bejda et al. 2020). ...
... It has also been reported that copper activates oxidative and nitrosative pathways (Styczeń et al. 2016). It worthy to note that many studies have established oxidative stress-mediated neuroinflammation and neuronal dysfunctions in major depression (Maes et al. 1997;Schlegel-Zawadzka and Nowak 2000;Manser et al. 1989;Młyniec et al. 2015;Maes et al. 2011). However, there are paucity of preclinical studies on the role of oxidative stress and pro-inflammatory cytokines in the pathophysiology of copper-induced depression (Styczeń et al. 2016). ...
Epidemiological studies have implicated copper as one of the key environmental risk factors for the pathogenesis of depression. However, the precise mechanism by which copper contribute to the genesis of depression particularly the involvement of oxidative stress-driven neuroinflammation is yet to be fully investigated. Thus, this study was designed to evaluate the effects of copper sulfate (CuSO4) on depression-like behaviors and the role of oxidative stress and pro-inflammatory cytokines in mice. Forty male Swiss mice were distributed into control and three test groups (n = 10), and were treated orally with distilled water (10 mL/kg) or CuSO4 (25, 50 and 100 mg/kg) daily for 28 days. Afterwards, the tail suspension, forced swim, and sucrose splash tests were used for the detection of depression-like effects. The animals were then euthanized and the brains were processed for the estimation of biomarkers of oxidative stress and pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6). The histomorphological features and neuronal viability of the prefrontal cortex, hippocampus and striatum were also determined. Mice exposed to CuSO4 displayed depression-like features when compared with controls. The brain concentrations of malondialdehyde, nitrite and pro-inflammatory cytokines were elevated in CuSO4-treated mice. Mice exposed to CuSO4 also had reduced brain antioxidant status (glutathione, glutathione-s-transferase, total thiols, superoxide-dismutase and catalase), as well as altered histomorphological features, and decreased population of viable neuronal cells. These findings suggest that CuSO4 increases oxidative stress and pro-inflammatory cytokines to elicit depression-like effects in mice.
... Numerous literature reports have shown that essential elements present in bhasmas are involved in the neurobiological mechanisms of various diseases including anxiety and depression. Deficiencies of these essential elements are associated with the pathogenesis of anxiety and depression [8][9][10]. Thus, taking cue from the literature, the present study was designed to evaluate the antianxiety and antidepressant activity of total ash of H. sabdariffa calyces. ...
... Results of the ICP-MS analysis evinced K, Mg and Ca to be the major elements in the total ash of H. sabdariffa calyces. Numerous studies have indicated that Mg, K and Ca play significant role in the pathogenesis of anxiety and depression and deficiencies of these are known to trigger the symptoms of anxiety or depression [9,10]. Thus, to ascertain their role in anxiety and depression, the antianxiety and antidepressant activity of commonly available salts of Mg, K and Ca, i.e., MgSO4, K2SO4 and CaCO3 were evaluated. ...
... The three salts exhibited significant antianxiety and antidepressant activity at their respective doses. Thus, the antianxiety and antidepressant activity of H. sabdariffa total ash may be attributed to high concentrations of Mg, K and Ca; which are known to have a significant role in affective disorders [9,10]. ...
Objective: Ash and its preparations have been used in Ayurveda for the treatment of various ailments since 7th century AD. Numerous studies suggest that the elements present in ash have significant role in affective disorders. Thus, the present study aimed at evaluating the antianxiety and antidepressant activity of total ash of H. sabdariffa calyces, and also of the tablets of total ash. Methods: Powdered calyces were taken in tared silica crucible, and were incinerated at a temperature not exceeding 450 °C. The resultant ash was cooled and weighed. This was evaluated for antianxiety and antidepressant activity using an elevated plus maze and Porsolt’s swim test, respectively. Further, the ash samples were analysed through ICP-MS to know their composition. The ash was formulated into tablets using the wet granulation technique, using only organic excipients. Results: Results indicated that the total ash of H. sabdariffa calyces exhibited significant (p<0.001) antianxiety and antidepressant activity at 50 and 100 mg/kg, po, respectively. The activities were comparable to the standard drugs. ICP-MS analysis showed the presence of magnesium, phosphorous, potassium and calcium as major elements. Tablets of H. sabdariffa total ash were as effective (p<0.001) as the total ash. Conclusion: Magnesium, phosphorous, potassium and calcium have been reported to play a significant role in affective disorders, explaining, thereby, as to why ash of H. sabdariffa calyces exhibited anti-anxiety and antidepressant activity.
... Elements play a variety of roles in the biological system ranging from participating in various metabolic reactions to regulating levels of oxidative stress in the body. Several studies have suggested that alterations of these elements levels in serum are linked with the etiology and pathophysiology of many mental disorders, including depression (Al-Fartusie et al. 2019;Młyniec et al. 2015). For example, zinc (Zn), magnesium (Mg), and copper (Cu) are important modulators of glutamate transmission and are closely related to the pathogenesis of depression (Szkup et al. 2017); Transition metals such as iron (Fe) and Cu induce the formation of hydroxyl radicals via the Fenton reaction, cause damage to important biological macromolecules in the body, thus promoting oxidative stress in patients with depression (Kim et al. 2011); Selenium (Se), manganese (Mn), etc., as important components of the biological enzyme system, may play a role in the anti-depression process (Młyniec et al. 2015). ...
... Several studies have suggested that alterations of these elements levels in serum are linked with the etiology and pathophysiology of many mental disorders, including depression (Al-Fartusie et al. 2019;Młyniec et al. 2015). For example, zinc (Zn), magnesium (Mg), and copper (Cu) are important modulators of glutamate transmission and are closely related to the pathogenesis of depression (Szkup et al. 2017); Transition metals such as iron (Fe) and Cu induce the formation of hydroxyl radicals via the Fenton reaction, cause damage to important biological macromolecules in the body, thus promoting oxidative stress in patients with depression (Kim et al. 2011); Selenium (Se), manganese (Mn), etc., as important components of the biological enzyme system, may play a role in the anti-depression process (Młyniec et al. 2015). ...
... Elements play important roles in many metabolic and physiological processes of the human body. These processes may be affected by the imbalance of the optimal level of elements, which is usually related to some diseases, such as depression (Młyniec et al. 2015;Szkup et al. 2017). This study found 7 differential elements and some element ratios by detecting the serum element levels of depressed rats, and their AUC values all exceeded 0.9, indicating good predictive abilities. ...
Depression is a common and serious psychiatric disorder, but current conventional antidepressants have limited efficacy and significant side effects. Thus, better antidepressants are urgently needed. This study aimed to investigate the antidepressant-like effects and potential mechanism of quercetin by evaluating the changes of serum elements in chronic unpredictable mild stress (CUMS) rats. Based on the results of the sucrose preference test (SPT), 96 rats were randomly assigned to six groups: control, different dosages of quercetin (10 and 50 mg/kg·bw, respectively), depressed, and different dosages quercetin plus depressed groups. After 8 weeks of CUMS modeling, rat serum was collected. Fifteen elements in serum were analyzed by inductively coupled plasma mass spectrometry (ICP-MS), and related enzyme indicators, antioxidant indicators, and inflammatory cytokines were detected to further explore the potential mechanism. Besides, the accuracy and precision of the method were evaluated. The results showed that the levels of iron (Fe), copper (Cu), and calcium (Ca) in serum significantly increased (p ≤ 0.001), while the levels of magnesium (Mg), zinc (Zn), selenium (Se), and cobalt (Co) significantly decreased (p ≤ 0.001) in depressed group compared with the control group. The levels of the remaining eight elements did not change significantly. When high-dose quercetin was administered to depressed rats, the levels of the above seven elements significantly restored (p ≤ 0.001). This study suggests that quercetin (50 mg/kg·bw) has a regulatory effect on serum elements in CUMS rats, which may be mediated by reducing oxidative stress, inhibiting inflammation, and regulating a variety of neurotransmitter systems.
... The most prevalence of anxiety disorders is observed in people aged 25-44 years, and lowest prevalence is related to subjects aged >65 years (Martin 2022;Vos et al. 2016). Different neurotransmitters play roles in the pathophysiology of anxiety, including monoamines especially serotonin and dopamine, glutamate, and GABA (Młyniec et al. 2015). Therefore, any factors involved in neurotransmitters synthesis, signaling pathways and metabolism (such as several enzymes) (Młyniec et al. 2015), and also in oxidative stress (Hovatta et al. 2010) are associated with both pathophysiology and treatment of anxiety disorders. ...
... Different neurotransmitters play roles in the pathophysiology of anxiety, including monoamines especially serotonin and dopamine, glutamate, and GABA (Młyniec et al. 2015). Therefore, any factors involved in neurotransmitters synthesis, signaling pathways and metabolism (such as several enzymes) (Młyniec et al. 2015), and also in oxidative stress (Hovatta et al. 2010) are associated with both pathophysiology and treatment of anxiety disorders. There are many evidences demonstrating the contribution of trace elements such as zinc, copper, magnesium, manganese, and selenium in anxiety, and their involvement in the regulation of neurotransmitters signaling (Dickerson et al. 2020;Shayganfard 2022). ...
This book reviews the role of trace elements in brain development, function, metabolism, and neurodegenerative disorders. It explores the molecular mechanisms of the effects of trace elements on metabolic pathways, mitochondrial nutrients, neurodegeneration, Central Nervous System (CNS) disorders, cell signaling, and neuronal functions. The book also discusses transport mechanisms of trace elements within CNS and their impact on neurotransmitter biology. Further, it examines the deleterious effects due to dyshomeostasis of trace elements in the central nervous system (CNS), resulting in damage to neurons and glial cells through the generation of reactive oxygen species and oxidative stress turn leading to neurodegeneration and neurological dysfunction. The book also explores the putative role of trace element deficiency in psychiatric disorders, including depression, and the imbalance of trace elements on neuronal genomic stability.
... Both PPAR-γ and selenium are parameters that may lead to changes associated with obesity and mood disorders. PPAR-γ is found in high amounts in hippocampal neurons and in areas that play an important role in depression [19,[72][73][74]. ...
... Alasfar et al. reported that selenium levels were significantly lower in about 15% of women with severe obesity compared to slim women from the control group [76]. According to Błażewicz et al., selenium may play a role in obesity (in their study, obese children had lower selenium levels) [19]. Another investigation conducted in the general Japanese population showed that the plasma selenium levels were directly related to waist circumference, but not to the BMI [77]. ...
The aim of this study was to evaluate the effect of serum selenium on PPAR-γ and the selected proinflammatory cytokines (IL-1β, IL-6, TNF-α) in relation to depressive symptoms and obesity in middle-aged women. The research procedure was as follows: a survey was performed using the authors' questionnaire and the BDI, anthropometric measurements, and the analysis of blood for the levels of selenium, cytokines, and genetic analysis of the PPAR-γ polymorphism (n = 443). It was found that the BMI increased along with the concentration of IL-6. No moderating effect of selenium was observed, although the cutoff values for "p" were established for IL-β*Se (p = 0.068) and IL-6*Se (p = 0.068), so there was a potential association with these two markers. At high selenium levels, the effect of higher IL-β levels on a decrease in BMI was stronger, as was the effect of an increase in IL-6 levels on an increase in BMI. No effect of selenium on PPAR-γ was found in relation to depressive symptoms and obesity. Higher selenium levels may have a beneficial effect on BMI even at high IL-β concentrations, however, at high IL-6 concentrations, this effect was not observed. Selenium levels had no impact on depressive symptoms.
... Fe, Cu, and Mn take part in the glutamatergic system, while Cu is also involved in the monoaminergic system. Additionally, Cu and Mn are involved in the GABAergic (GABA: gamma-aminobutyric acid) system [207][208][209]. ...
... Mlyniec stated that an inverse correlation between Fe and depression is likely; Cu might be positively associated with depression, while Mn could either be negatively or positively connected by means of the neurotransmitter systems involved in the pathophysiology of depression [207,208]. More observational studies and randomised clinical trials are required to further explore the connection between Mn deficiency/overexposure and depressive disorders [209]. ...
Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals play key roles in ensuring proper brain development and function. They also play vital roles in the central nervous system as significant cofactors for several enzymes, including the antioxidant enzyme superoxide dismutase (SOD) and other enzymes that take part in the creation and breakdown of neurotransmitters in the brain. An imbalance in the levels of these metals weakens the structural, regulatory, and catalytic roles of different enzymes, proteins, receptors, and transporters and is known to provoke the development of various neurological conditions through different mechanisms, such as via induction of oxidative stress, increased α-synuclein aggregation and fibril formation, and stimulation of microglial cells, thus resulting in inflammation and reduced production of metalloproteins. In the present review, the authors focus on neurological disorders with psychiatric signs associated with copper, iron, and manganese excess and the diagnosis and potential treatment of such disorders. In our review, we described diseases related to these metals, such as aceruloplasminaemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN) and other very rare classical NBIA forms, manganism, attention-deficit/hyperactivity disorder (ADHD), ephedrone encephalopathy, HMNDYT1-SLC30A10 deficiency (HMNDYT1), HMNDYT2-SLC39A14 deficiency, CDG2N-SLC39A8 deficiency, hepatic encephalopathy, prion disease and “prion-like disease”, amyotrophic lateral sclerosis, Huntington’s disease, Friedreich’s ataxia, and depression.
... Other consequences of iodine deficiency during pregnancy to the offspring are intellectual impairment like low intellectual coefficient, autism (Bła_ zewicz et al. 2016), schizophrenia (Harper and Brown 2012), and mental retardation (Walker et al. 2007;Pharoah, Buttfield, and Hetzel 1971). Recently, iodine deficiency has been associated also to anxiety (Młyniec et al. 2015), depression (Młyniec et al. 2015), obesity (Verheesen and Schweitzer 2008) and fibromyalgia (Verheesen and Schweitzer 2008). In the following section of this review we will discuss relevant clinical data of several diseases and health impairment associated with iodine deficiency. ...
... Other consequences of iodine deficiency during pregnancy to the offspring are intellectual impairment like low intellectual coefficient, autism (Bła_ zewicz et al. 2016), schizophrenia (Harper and Brown 2012), and mental retardation (Walker et al. 2007;Pharoah, Buttfield, and Hetzel 1971). Recently, iodine deficiency has been associated also to anxiety (Młyniec et al. 2015), depression (Młyniec et al. 2015), obesity (Verheesen and Schweitzer 2008) and fibromyalgia (Verheesen and Schweitzer 2008). In the following section of this review we will discuss relevant clinical data of several diseases and health impairment associated with iodine deficiency. ...
Adequate iodine nutrition is crucial for all mammals by playing his starring role as a component of thyroid hormones, which are key regulators of cellular processes for life such as differentiation, growth, function, and metabolism. Deficiency or excess of iodine in the diet are worldwide highly frequent conditions that are responsible of health problems like hypothyroidism, hypothyroxinemia, goiter, thyroiditis, hyperthyroidism, and autoimmune thyroid diseases among others. The incorporation of iodine in salt or other nutrients resolved the consequences of severe iodine deficiency like goiter, cretinism. However, this strategy in several countries led to other ailments like Hashimoto autoimmune thyroiditis, hyperthyroidism, and hypothyroidism. The goal of this review is to analyze and discuss the different aspects of iodine nutrition for human health comprising its biological role through thyroid hormones, pathogen control, and the regulation of the intestinal microbiota.
... Trace elements play crucial roles in mental illnesses (Młyniec et al., 2015;Alghadir et al., 2016). Numerous studies have shown an imbalance in the serum or plasma levels of trace and macro elements such as Zn, Cu, Fe and Mg, in individuals with depression compared to those without (Chang et al., 2014;Stanisławska et al., 2014). ...
Introduction: This study investigates the effects of social isolation on mental health and cognitive functions in Sprague Dawley (SD) and Wistar Albino (WIS) rat strains, prompted by the heightened awareness of such impacts amid the COVID-19 pandemic. This study aims to explore the impact of social isolation on memory, learning, and behavioral changes in middle-aged SD and WIS rat
strains and to investigate cortical trace element levels, seeking potential correlations between these levels and the observed behavioral responses to social isolation.
Methods: Four groups of 14-month-old male rats were established: control and isolated SDs and WIS rats (CONT-SD, ISO-SD, CONT-WIS, ISO-WIS). Morris Water Maze and Porsolt Forced Swimming tests were conducted for behavioral assessment. Following behavioral tests, rats were sacrificed under
general anesthesia and cortices were isolated for analysis of macro and trace element levels (ICP/MS).
Results: In behavioral tests, CONT-SD rats exhibited superior performance in the Morris Water Maze test compared to CONT-WIS rats, but displayed increased depressive behaviors following social isolation, as evident in the Porsolt Forced Swimming test (p < 0.05). ISO-SD rats showed elevated levels of Co and Cu, along
with reduced levels of Cs and As, compared to ISO-WIS rats. Moreover, isolation resulted in decreased Cu and Mo levels but increased Rb levels in WIS rats. Comparison of trace element levels in naïve groups from different strains revealed lower Zn levels in the WIS group compared to SD rats.
Discussion: The findings suggest that the SD strain learns faster, but is more susceptible to depression after isolation compared to the WIS strain. Increased Co and Cu levels in ISO-SD align with previous findings, indicating potential trace
element involvement in stress responses. Understanding these mechanisms could pave the way for preventive treatment strategies or therapeutic targets against the consequences of stressors, contributing to research and measures promoting a
balanced diet to mitigate neurobehavioral abnormalities associated with social isolation in the future
... Elements is crucial for many processes of metabolic and physiological in the human body. These processes might be influenced by the imbalance of elements levels, which is commonly associated to nervous disorder, such as depression [41]. Prefrontal cortex are key brain regions involved in the pathogenesis of depression [42]. ...
This study investigated the effects of quercetin on the alterations of serum elements in perimenopausal depression rat model induced by ovariectomy combined with chronic unpredictable mild stress (OVX-CUMS) and possible mechanisms. According to the results of the sucrose preference test, the rats were randomly assigned to four groups: sham, OVX-CUMS, OVX-CUMS + 17β-estradiol (17β-estradiol: 0.27 mg/kg.bw), and OVX-CUMS + Quercetin (Quercetin: 50 mg/kg.bw). At the end of experiment, serum and prefrontal cortex of rats were collected. The inductively coupled plasma mass spectrometry (ICP-MS) analysis showed that levels of calcium (Ca), magnesium (Mg), selenium (Se), cobalt (Co) and zinc (Zn) decreased, and levels of iron (Fe) and copper (Cu) increased in serum and prefrontal cortex of OVX-CUMS rats compared with sham group (p < 0.01). Meanwhile, the levels of the above elements in prefrontal cortex had correlation with behavioral characteristics in OVX-CUMS rats (p < 0.05 or p < 0.01). The abnormal elements in serum may cross blood–brain-barrier into the brain and induce oxidative stress, leading to ferroptosis. Furtherly, the expressions of ferroptosis-related protein including GPX4 and SLC7A11 were decreased in prefrontal cortex of OVX-CUMS rats (p < 0.01), which confirmed the above results. Quercetin treatment restored the above abnormal indicators (p < 0.05 or p < 0.01) induced by OVX-CUMS in rats. Our study suggested that quercetin regulated variation of elements in serum and prefrontal cortex, further inhibiting ferroptosis in prefrontal cortex through alleviating oxidative stress in OVX-CUMS rats.
... In addition, selenium is essential for the proper synthesis of thyroid hormones. Changes in these hormones are associated with neuropsychiatric manifestations such as mood disorders, cognitive dysfunction, and other psychiatric symptoms (Młyniec et al., 2015). But the evidence is limited and contradictory (Wang et al., 2018). ...
Background: Evidence suggests that dietary micronutrients may be associated with depression. The role of selenium as a risk or protective factor for depression was contradictory. Therefore, this study aimed to investigate the association between serum selenium concentrations and depression. Methods: This case-control study was conducted from 2018 to 2020 in Shahrekord, Iran. The case and control groups included patients with or without depression, respectively. Seventy-two participants were selected using the conventional method. In addition to recording demographic variables, the blood selenium concentration of the participants was measured. Results: There was no difference between case and control groups in terms of mean levels of blood selenium (P>0.05). Results showed that there was no statistically significant interaction between the effects of gender and group (P=0.51), age and group (P=0.13), Body mass index (BMI) and group (P=0.52) on blood selenium concentrations. However, females had significantly more selenium concentrations than males in both groups (P=0.005). Conclusion: Despite some confirming evidence for the association of depression and blood selenium concentration, this study did not show such a relationship. However, blood selenium concentration was higher in women than men in both groups.
... Mieko Nakamura et al. also observed a significant negative correlation between the dietary intake of copper and symptoms of anxiety and depression in Japan (22). Copper might decrease anxiety through various mechanisms, including its beneficial roles in modulating the glutamatergic, monoaminergic, and GABAergic systems and via reducing the oxidative stress due to its role in the activity of superoxide dismutase (23). ...
Background: The prevalence of stress, anxiety, and depression seems to be high in patients with chronic kidney disease (CKD), which may influence their quality of life. Due to limiting some food groups, these patients suffer from a deficiency of some nutrients, which may be related to mood disorders.
Objectives: This study aimed to investigate the correlation between nutrient intake, stress, anxiety, and depression in patients with CKD.
Methods: The present cross-sectional study was conducted on 90 patients with CKD. To assess the diet of the patients, the researchers completed three days of the 24-hour food recall. The short self-report Iranian version of the Depression, Anxiety, and Stress Scale 21 (DASS-21) was also used to investigate the participants' mental health.
Results: Of the 90 patients examined, 64 were men and 26 were women. There was a significant inverse correlation between depression and the dietary intake of polyunsaturated fatty acids (PUFAs) (β = -0.214, P = 0.039) and α-tocopherol (β = -0.225, P = 0.025). A significant inverse correlation was also found between anxiety and the dietary intake of iron (β = -0.319, P = 0.003), copper (β = -0.25, P = 0.031), vitamin B1 (β = -0.314, P = 0.004), vitamin B5 (β = -0.262, P = 0.016), vitamin B6 (β = -0.292, P = 0.007), vitamin B9 (β = -0.241, P = 0.026), fiber (β = -0.224, P = 0.04), and vitamin K (β = -0.26, P = 0.015).
Conclusions: The dietary intake of nutrients such as PUFAs, α-tocopherol, B vitamins, vitamin K, iron, copper, and fiber might be associated with depression and anxiety. However, further studies with longitudinal designs are needed to reveal cause-effect relationships in this regard.
... Patients with depressive disorders showed a significantly elevated concentration of ceruloplasmin and Cu in their blood [168]. Cu acts as a cofactor of enzymes involved in the turnover of catecholamines and in the catalytic activity of some antioxidant enzymes, and it participates in oxidative and nitrosative stress processes [169][170][171][172]. Moreover, elevated levels of Cu inhibit the function of NMDA and AMPA receptors, thus disturbing glutamatergic transmission [173,174]. ...
Dysfunction of the complex cerebral networks underlying wakefulness and awareness is responsible for Disorders of Consciousness (DoC). Traumatic Brain Injury (TBI) is a common cause of DoC, and it is responsible for a multi-dimensional pathological cascade that affects the proper functioning of the brainstem and brain consciousness pathways. Iron (Fe), Zinc (Zn), and Copper (Cu) have a role in the neurophysiology of both the ascending reticular activating system, a multi-neurotransmitter network located in the brainstem that is crucial for consciousness, and several brain regions. We aimed to summarize the role of these essential metals in TBI and its possible link with consciousness alterations. We found that TBI alters many neuronal molecular mechanisms involving essential metals, causing neurodegeneration, neural apoptosis, synaptic dysfunction, oxidative stress, and inflammation. This final pattern resembles that described for Alzheimer’s disease (AD) and other neurological and psychiatric diseases. Furthermore, we found that amantadine, zolpidem, and transcranial direct current stimulation (tDCS)—the most used treatments for DoC recovery—seem to have an effect on essential metals-related pathways and that Zn might be a promising new therapeutic approach. This review summarizes the neurophysiology of essential metals in the brain structures of consciousness and focuses on the mechanisms underlying their imbalance following TBI, suggesting their possible role in DoC. The scenario supports further studies aimed at getting a deeper insight into metals’ role in DoC, in order to evaluate metal-based drugs, such as metal complexes and metal chelating agents, as potential therapeutic options.
... Moreover, zinc in the hypothalamic-pituitary-adrenal axis plays an active role in regulating the body's reaction to stress. The lower levels of zinc can thus stimulate this axis, elevating plasma cortisol and resulting in higher vulnerability to MH conditions [36,37]. The literature also highlights the effect of zinc on such disorders through its involvement in the inflammatory process. ...
Background
Considering different factors, such as high withdrawal rates in methadone maintenance treatment (MMT) programs alongside mental health (MH) problems appearing in patients with opioid use disorder and the lack of prior research on the effect of zinc supplementation in this respect, the present study aimed to investigate the effect of zinc supplementation on the probability of relapse (PoR) and MH problems in patients with opioid use disorder undergoing MMT.
Methods
For this purpose, a randomized controlled trial with a clinical basis was fulfilled on a total of 68 patients with opioid use disorder receiving MMT, allocated to two groups, viz. intervention, and control (each one consisting of 34 individuals). Then, the participants in the intervention group were given zinc supplements combined with methadone for three months, and the controls only took methadone, according to the treatment plan. The data were collected using the Relapse Prediction Scale (RPS) and the Depression, Anxiety, and Stress Scale 21 (DASS-21) before, one month after, and at the end of the intervention program.
Findings
Compared to the control group, the likelihood of drug use ( p = 0.01), drug craving ( p = 0.002), and the RPS total score ( p = 0.002) in the intervention group was significantly lower. Moreover, the results revealed a significant decreasing trend in depression ( p = 0.01), anxiety ( p < 0.001), stress ( p = 0.001), and the DASS-21 total score ( p = 0.001) in the intervention. Compared to the control group, the DASS-21 total score ( p < 0.001) in the intervention group was significantly lower.
Conclusion
Accordingly, it was concluded that zinc supplementation could reduce the PoR and improve MH problems in patients with opioid use disorder experiencing MMT. However, further research is recommended to fill the gaps.
Trial registration
The research protocol has also been listed on the Iranian Registry of Clinical Trials (IRCT) with code no. IRCT2020050904736N1.
... Meat is considered an important source of nutrients for the human diet and food beneficial for consumer health. Meat and meat products contain important levels of proteins, vitamins, minerals, and essential fatty acids, which are indispensable during growth and development, as well as for the maintenance of consumers' physiological and psychological health [1,2]. Nevertheless, associated with its chemical composition (high proportions of polyunsaturated fatty acids in membrane phospholipids and low presence of ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ATBS), methanol and ethanol (HPLC grade), potassium ferricyanide (K₃[Fe(CN)₆]), potassium persulfate (K2S2O8), potassium hydroxide (KOH), 2,4,6-tri(2-pyridyl)-s-triazine (TPTZ), 2,4-dinitrophenylhydrazine (DNPH), guanidine HCl, iron(III) chloride 6-hydrate (FeCl3 • 6H2O), iron(II) sulfate 7hydrate (FeSO4 • 7H2O), acetic acid (CH3COOH), hydrochloric acid (HCl), sulfuric acid (H2SO4), sodium hydroxide (NaOH), aluminum chloride (AlCl3), glucose, gallic acid, tetramethoxypropane (TMP), butylated hydroxytoluene (BHT), and rutin were purchased from Sigma Chemicals (St. Louis, MO, USA). ...
Lipid and protein oxidation are the major causes of meat quality deterioration. Edible mushrooms have been proposed as a strategy to prevent quality deterioration during cold storage. This study aimed to assess the effects of Pleurotus ostreatus powder (POP) on the oxidative stability of pork patties during cold storage and after in vitro gastrointestinal digestion (ivGD). Pork patties were subjected to four treatments: control (without antioxidant), T1 (2% POP, w/w) and T2 (5% POP, w/w), and T3 as positive control (0.02% BHT, fat basis). POP aqueous, ethanolic, and aqueous ethanol extract were subjected to phytochemical and antioxidant assays. Raw pork patties were subjected to a chemical proximate composition evaluation. At the same time, raw and cooked pork patties were stored at 2 °C for 9 days and subjected to meat quality measurements. Furthermore, the total antioxidant activity of cooked pork patties was determined after ivGD. Results showed that POP ethanol extract showed the highest polysaccharide, phenol, and flavonoid content, as well as antiradical and reducing power properties. POP incorporation into raw and cooked pork patties enhances meat quality traits, including pH, water-holding capacity, cooking-loss weight, texture, color, lipid, and protein oxidation (p < 0.05). Furthermore, incorporating POP into cooked samples increases the phytochemical content and antioxidant activity during ivGD. In conclusion, POP has great potential as a natural antioxidant for meat products.
... The comorbidity of pain and depression has long been recognized in the clinic, and the two conditions together are more difficult to treat than either condition alone. Antidepressants have been used to treat chronic pain since the 1960s, and analgesic treatments can alleviate the manifestation of depression in patients with pain symptoms [10,11]. ...
... Moreover, zinc in the hypothalamic-pituitary-adrenal axis plays an active role in regulating the body's reaction to stress. The lower levels of zinc can thus stimulate this axis, elevating plasma cortisol and resulting in higher vulnerability to MH conditions (40,41). The literature also highlights the effect of zinc on such disorders through its involvement in the in ammatory process. ...
Background Considering different factors such as high withdrawal rates in methadone maintenance treatment (MMT) programs alongside mental health (MH) problems appearing in patients with substance abuse disorder and the lack of prior research on the effect of zinc supplementation in this respect, the present study aimed to investigate the effect of zinc supplementation on probability of relapse (PoR) and MH problems in patients with substance abuse disorder undergoing MMT.
Methods For this purpose, a randomized controlled trial with a clinical basis was fulfilled on a total of 68 patients with substance abuse disorder receiving MMT, allocated to two groups, viz. intervention and control (each one consisting of 34 individuals). Then, the participants in the intervention group were given zinc supplements combined with methadone for three months and the controls only took methadone, according to the treatment plan. The data were collected using the Relapse Prediction Scale (RPS) and the Depression, Anxiety and Stress Scale 21 (DASS-21) before, one month after, and at the end of the intervention program.
Findings Compared to the control group, PoR (p=0.01), drug craving (p=0.002), and the RPS total score (p=0.002) in the intervention group were significantly lower. Moreover, the results revealed a significant decreasing trend in depression (p=0.01), anxiety (p<0.001), stress (p = 0.001), and the DASS-21 total score (p=0.001) in the intervention. Compared to the control group, the DASS-21 total score (p<0.001) in the intervention group were significantly lower.
Conclusion Accordingly, it was concluded that zinc supplementation could reduce the PoR and improve MH problems in patients with substance abuse disorder experiencing MMT. However, further research is recommended to fill the gaps.
Trial Registration The research protocol has been also listed on the Iranian Registry of Clinical Trials (IRCT) with the code no. IRCT2020050904736N1
... Of course, further prospective and randomized clinical trials would be encouraged for imple-which regulate metabolism of the whole body. Clinicians and researchers agree on the evidence that some neuropsychiatric manifestations, such as mood disorders, cognitive dysfunction and depression, may be related to altered thyroid functionality 210,211 . Indeed, a US study 212 revealed that high dietary selenium intake or supplementation may improve mood in terms of reduced subscores of anxiety, confusion and total mood disturbance. ...
Objective:
The occurrence of side effects related to the use of combined oral contraceptives (COCs) - or even the fear of them - often affects patients' compliance and their quality of life. Such adverse effects include both physical and psychological alterations. Therapies based on COCs are related to lower levels of vitamins and minerals, including vitamins B, C and E, zinc, magnesium, and selenium. This review gathers scientific evidence about the effectiveness of the administration of specific micronutrients to address nutritional needs and recover adverse conditions.
Materials and methods:
We reviewed literature searching through different databases (MEDLINE, Scopus, Google Scholar). We used different keywords, including micronutrients, COCs, side effects, B vitamins, vitamin C, vitamin E, vitamin D, zinc, magnesium, selenium and Centella Asiatica. We narrowed the search down to English literature, including both preclinical and clinical studies. The outcome of database search was to highlight beneficial effects of specific micronutrients on the evaluated side reactions.
Results:
Based on the collected evidence, dietary supplementations of specific micronutrients, whose depletion occurs during COC treatments, have significant beneficial effects. By acting on different aspects and pathways, such supplementation prevents and counteracts discomforts and side effects related to COC treatments.
Conclusions:
Considering the wide use of OCs, taking appropriate dietary supplements could be an effective approach in clinical practice, tailoring therapies and improving both safety and tolerability.
... Selenium deficiency can disrupt the function of multiple antioxidant enzymes such as glutathione peroxidase and thioredoxin reductases, which protect cells against oxidative damage 57,58 . Furthermore, inflammation is regarded as a part of depression pathogenesis 59 . Therefore, anti-inflammatory properties of selenium may help to improve depressive symptoms 60,61 . ...
The results of human studies are inconsistent regarding selenium and depressive disorders. Therefore, we aimed to conduct a systematic review and meta-analysis of observational and interventional studies and provided an overview of the role of selenium in depression. Three databases including Medline, Scopus, and Web of Science were searched on June 30, 2020 and updated on April 12, 2021. Also, we searched in electronical databases of WHO Global Index Medicus and ClinicalTrials.gov. No time or language restrictions were used for the search. A random effects model was used to pool effect sizes. In total, 20 studies were included in the systematic review, and 15 studies were included in the meta-analysis. There were no significant differences in serum selenium levels between patients with depression and healthy subjects (WMD: 2.12 mg/L; 95% CI: − 0.11, 4.36; I ² = 98.0%, P < 0.001). Also, no significant correlation was found between serum levels of selenium and depression scores (r: − 0.12; 95% CI: − 0.33, 0.08; I ² = 73.5%, P = 0.010). Nevertheless, there was a significant negative association between high selenium intake and the risk of postpartum depression (OR: 0.97; 95% CI: 0.95, 0.99; I ² = 0.0%, P = 0.507). In addition, selenium supplementation significantly reduced depressive symptoms (WMD: − 0.37; 95% CI: − 0.56, − 0.18; I ² = 0.0%, P = 0.959). Taken these results together, selenium seems to have a protective role against postpartum depression and can be considered as a beneficial adjuvant therapy in patients with depression. Further studies are necessary to draw definitive conclusions.
... Beyond mood and general well-being, the role of selenium on mental health is complex and has yet to be fully understood (Conner et al. 2014), and research linking the two is growing at a rapid rate. In recent years, evidence has shown that a drop in blood selenium levels correlates with the development of mental health conditions, including depression and anxiety disorders (Miyniec et al. 2015). ...
Selenium is an essential component of more than two dozen enzymes and other selenoproteins that play critical roles in reproduction, DNA synthesis, thyroid hormone metabolism, and protection from oxidative damage and infection. Selenium has a protective action against some forms of cancer and cardiovascular diseases, modulates levels of inflammatory mediators, promotes to maintain bone homeostasis and protects against bone loss. Selenium significance as a cardioprotective agent may be associated not only with its antioxidant properties, but also with its ability to prevent inflammation, autophagy, as well as the intrinsic and extrinsic apoptosis pathways. Signaling pathways, such as p-AMPK, PARP, Nrf2, STAT, are involved in the protective effects of selenium. Selenium protects against cardiovascular damage by increasing the survival rate of cardiomyocytes, including a mitochondria-dependent pathway and autophagy through peroxisome proliferator-activated receptors. Research demonstrating neuroprotective and cardioprotective effects of selenium preparations – selenoline, selenocysteine and selenomethionine – is growing at a rapid rate. It has been established that these compounds are able to normalize the levels of heat shock proteins (HSP70), which limit the cytotoxic effects of free radicals, produce energotropic action, prevent a decrease in the membrane mitochondria charge, and the opening of the mitochondrial pore. Also regulate the expression of transmembrane factors NF-kB, c-fos, which is associated with their main biological function of chaperone proteins, providing protection of neurons from damage. In this review, we want to emphasize pharmacological role of Selenium and its derivatives on human health is very complex and has yet to be fully understood.
... 1989-2017 yılları arasında yapılmış 2.199 çalışmayı inceleyen bir metaanalizde, depresyon hastalarındaki bakır eksikliğinin sağlıklı bireylerden çok daha yüksek olduğu gözlemlenmiştir. [49][50][51] Depresyon hastalarında kandaki bakır seviyelerinin anormal değişimi ve depresyonun bakırla ilişkisi incelendiğinde, bakırın potansiyel bir depresyon belirteci olduğu ve depresyon tanı ve tedavisinde görev alabileceği söylenebilir. 29 Amerikan vatandaşları üzerinde yapılmış bir çalışmada, bakır ve selenyum alımının depresyon ile ilişkili olduğu savunulmuştur. ...
Depression is a common mood disorder seen in over 300
million people worldwide. Causes of depression may be caused by ge�netic factors or environmental factors. Nutritional status is one of the
most important environmental factors. In addition to many factors such
as socioeconomic status, various psychological factors, chronic dis�eases, pregnancy, postpartum, menopause, stress factors, sleep patterns;
nutrition-related factors such as inadequate or unbalanced nutritional
habits, caffeine consumption levels and so on, play an important role in
the development of depression symptoms. On the other hand, the elim�ination of certain nutrient deficiencies, especially vitamins and miner�als, can prevent the development of or help treating depression. Among
the factors related to nutrition, one of the most investigated subjects is
micronutrient deficiencies. Both vitamin and mineral deficiencies are
among the most important factors affecting neurological pathways and
neurological functions. Therefore, it is thought that vitamins and min�erals might be involved in the prevention and treatment of depres�sion.Many researches and clinical studies have been done in this area,
especially on minerals; however, there is still a need for more data to
reach a definitive conclusion. The important effect of minerals on neu�rological functions and enzymes involved in this level has been demon�strated in many studies. In this review, various databases were scanned
and publications investigating the roles of iron, zinc, copper and mag�nesium elements in the prevention of depression and the treatment of
depression are examined.
... As an important cofactor of neurotransmitters and signaling pathways, Cu is involved in many physiological metabolic processes of brain. Cu deficiency and overload have shown to be associated with the dysfunction of the neuropsychiatric system [11,12]. Other studies indicated that many genes may be linked to the efficacy of depression. ...
Depression is one of the most common neuropsychiatric disorders. Although the pathogenesis of depression is still unknown, environmental risk factors and genetics are implicated. Copper (Cu), a cofactor of multiple enzymes, is involved in regulating depression-related processes. Depressed patients carrying the apolipoprotein ε4 allele display more severe depressive symptoms, indicating that ApoE4 is closely associated with an increased risk of depression. The study explored the effect of low-dose Cu exposure and ApoE4 on depression-like behavior of mice and further investigates the possible mechanisms. The ApoE4 mice and wild-type (WT) mice were treated with 0.13 ppm CuCl2 for 4 months. After the treatment, ApoE4 mice displayed obvious depression-like behavior compared with the WT mice, and Cu exposure further exacerbated the depression-like behavior of ApoE4 mice. There was no significant difference in anxiety behavior and memory behavior. Proteomic analysis revealed that the differentially expressed proteins between Cu-exposed and nonexposed ApoE4 mice were mainly involved in the Ras signaling pathway, protein export, axon guidance, serotonergic synapse, GABAergic synapse, and dopaminergic synapse. Among these differentially expressed proteins, immune response and synaptic function are highly correlated. Representative protein expression changes are quantified by western blot, showing consistent results as determined by proteomic analysis. Hippocampal astrocytes and microglia were increased in Cu-exposed ApoE4 mice, suggesting that neuroglial cells played an important role in the pathogenesis of depression. Taken together, our study demonstrated that Cu exposure exacerbates depression-like behavior of ApoE4 mice and the mechanisms may involve the dysregulation of synaptic function and immune response and overactivation of neuroinflammation.
... [24,25] On the other hand, preclinical evidence suggests that selenium-containing organic molecules hold striking biological activities. [26,27] Organoselenium compounds exhibit diverse pharmacological effects, for example cardioprotective, anti-inflammatory, antioxidant and antidepressant-like activities. [28,29] Considering the pharmacological effects of imidazopyridine and organoselenium, the combination of both could be a feasible strategy to develop more efficient drugs to manage obesity and its comorbidities, for example dyslipidemia and psychiatric disorders. ...
Objective
While chronic feeding with high-fat or high-sugar diets is known related to obesity and type 2 diabetes, later data have indicated that it is also related to depression and anxiety appearance. In this regard, multi-target drugs raise considerable interest as promising therapeutic solutions to complex diseases. Considering the pharmacological effects of the imidazopyridine-derivative moiety imidazo[1,2-a]pyridine and the organoselenium molecules, the combination of both could be a feasible strategy to develop efficient drugs to handle obesity and related comorbidities, for example dyslipidemia and mood disorders.
Methods
The antidepressant- and anxiolytic-like properties of a selanylimidazopyridine compound, 2-Phenyl-3-(phenylselanyl)imidazo[1,2-a]pyridine (3-SePh-IP), were evaluated on high-fat/high-fructose diet (HFFD)-fed female Swiss mice.
Key findings
Our results showed that a short-term HFFD (16 days) could promote a significant body weight gain, hypercholesterolemia, glucose intolerance, and anxiety- and depressive-like behaviour in mice. Concomitant treatment with 3-SePh-IP (10 mg/kg; i.p.) attenuated the HFFD-induced increase in cholesterol levels and blunted the anxiety- and depressive-like behaviour in mice.
Conclusions
3-SePh-IP holds multimodal pharmacological properties, which provide a rationale for further studies, for example to assess the underlying mechanisms linked to its anxiolytic- and antidepressive-like activities.
... [24,25] On the other hand, preclinical evidence suggests that selenium-containing organic molecules hold striking biological activities. [26,27] Organoselenium compounds exhibit diverse pharmacological effects, for example cardioprotective, anti-inflammatory, antioxidant and antidepressant-like activities. [28,29] Considering the pharmacological effects of imidazopyridine and organoselenium, the combination of both could be a feasible strategy to develop more efficient drugs to manage obesity and its comorbidities, for example dyslipidemia and psychiatric disorders. ...
Objective While chronic feeding with high-fat or high-sugar diets is known related to obesity and type 2 diabetes, later data have indicated that it is also related to depression and anxiety appearance. In this regard, multi-target drugs raise considerable interest as promising therapeutic solutions to complex diseases. Considering the pharmacological effects of the imidazopyridine-derivative moiety imidazo[1,2-a]pyridine and the organoselenium molecules, the combination of both could be a feasible strategy to develop efficient drugs to handle obesity and related comorbidities, for example dyslipidemia and mood disorders. Methods The antidepressant-and anxiolytic-like properties of a selanylimidazopyridine compound , 2-Phenyl-3-(phenylselanyl)imidazo[1,2-a]pyridine (3-SePh-IP), were evaluated on high-fat/ high-fructose diet (HFFD)-fed female Swiss mice. Key findings Our results showed that a short-term HFFD (16 days) could promote a significant body weight gain, hypercholesterolemia, glucose intolerance, and anxiety-and depressive-like behaviour in mice. Concomitant treatment with 3-SePh-IP (10 mg/kg; i.p.) attenuated the HFFD-induced increase in cholesterol levels and blunted the anxiety-and depressive-like behaviour in mice. Conclusions 3-SePh-IP holds multimodal pharmacological properties, which provide a rationale for further studies, for example to assess the underlying mechanisms linked to its anxiolytic-and antidepressive-like activities.
... Copper is involved in oxidative stress processes. This influences the catalytic and structural properties of antioxidant enzymes, which may be among the main causes of the development of depression [25,26]. Some studies suggest that the induction of oxidative stress pathways in depression is accompanied by the activation of the inflammatory reaction [27]. ...
Changes in serum copper concentration are observed in patients with depressive symptoms. Unmet needs in contemporary antidepressant treatment have increased interest in non-monoaminergic antidepressants, such as ketamine, an anaesthetic drug that has demonstrated a rapid antidepressant effect in patients with treatment-resistant depression (TRD). The purpose of this study was to examine whether serum copper concentrations change during ketamine treatment and whether there is an association between the copper concentrations and treatment response measured using psychometric scale scores. Moreover, the interlink between somatic comorbidities and copper concentration was studied. Patients with major depressive disorder or bipolar disorder were rated weekly by a clinician using the Montgomery–Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). Copper level assessments were carried out weekly before the start of ketamine treatment and then after every second infusion and one week after the last ketamine infusion. The serum concentration of copper before ketamine treatment was significantly higher than that after the fifth infusion (p = 0.016), and the serum concentration after the treatment was significantly higher than that after the fifth infusion (p = 0.048). No significant correlations between changes in the copper serum concentrations and MADRS or YMRS were found. The serum copper level was not associated with somatic comorbidities during the course of treatment. This study provides data on the role of copper in short-term intravenous ketamine treatment in TRD, although no clear evidence of a connection between the copper level and treatment response was found.
... Generally, at optimal doses, copper (Cu) can assure the proper functioning of the central nervous system (CNS) (Abdellatif et al. 2017). Cu participates in energy metabolism, myelin formation, antioxidative defense, and neurotransmitter synthesis (Młyniec et al. 2015). But conversely, excess of Cu can seriously influence brain functions (Bulcke and Dringen 2016). ...
Copper (Cu) is an essential trace element with the ability to induce, at high levels, neurobehavioral alterations, and oxidative stress (OS). On the other hand, melatonin (Mel) is a neurohormone that protects neurons from OS and has a modulatory effect on several behavioral processes. The present study was aimed to investigate the effect of Mel treatment on Cu-induced anxiety-like, depression-like behaviors, memory impairment, and OS in hippocampus. Herein, adult male and female Wistar rats received daily Mel (4 mg/kg) thirty minutes before CuCl2 (1 mg/kg), by intraperitoneal injections for 8 weeks. After the
administration period, all rats were submitted to the behavioral tests. Thereafter, OS parameters and histology of the hippocampus were evaluated. The results demonstrate that Mel treatment attenuated Cu-induced anxiety-like and depression-like behaviors, and it improved memory deficits in male and female Cu-treated rats. Furthermore, Mel attenuated Cu-provoked OS by reducing lipid peroxidation (LPO) and nitric oxide (NO) levels and enhancing superoxide dismutase (SOD) and catalase (CAT) activities in the hippocampus.
The histopathological studies in the hippocampus of rats also supported these results. In conclusion, these findings show that Mel treatment exerted neuroprotective effects against Cu-induced neurobehavioral changes which may be related to reduction of hippocampal OS. Besides, the effects of Cu and Mel were gender dependent, being more marked in females compared to male rats.
Keywords: Copper; Melatonin; Anxiety-like; Depression-like; Memory; Oxidative stress
... There is a potential link between essential minerals and neuropsychiatric disorders, because their levels and functional properties in the body are important factors in the etiology and pathophysiology of anxiety and depression [44]. Therefore, we analyzed the levels of essential minerals such as zinc, magnesium, iron, copper, lithium, manganese and phosphate for the brain. ...
Alterations of essential elements in the brain are associated with the pathophysiology of many neuropsychiatric disorders. It is known that chronic/overwhelming stress may cause some anxiety and/or depression. We aimed to investigate the effects of two different chronic immobilization stress protocols on anxiety-related behaviors and brain minerals. Adult male Wistar rats were divided into 3 groups as follows (n = 10/group): control, immobilization stress-1 (45 minutes daily for 7-day) and immobilization stress-2 (45 minutes twice a day for 7-day). Stress-related behaviors were evaluated by open field test and forced swimming test. In the immobilization stress-1 and immobilization stress-2 groups, percentage of time spent in the central area (6.38 ± 0.41% and 6.28 ± 1.03% respectively, p < 0.05) and rearing frequency (2.75 ± 0.41 and 3.85 ± 0.46, p < 0.01 and p < 0.05, respectively) were lower, latency to center area (49.11 ± 5.87 s and 44.92 ± 8.04 s, p < 0.01 and p < 0.01, respectively), were higher than the control group (8.65 ± 0.49%, 5.37 ± 0.44 and 15.3 ± 3.32 s, respectively). In the immobilization stress-1 group, zinc (12.65 ± 0.1 ppm, p < 0.001), magnesium (170.4 ± 1.7 ppm, p < 0.005) and phosphate (2.76 ± 0.1 ppm, p < 0.05) levels were lower than the control group (13.87 ± 0.16 ppm, 179.31 ± 1.87 ppm and 3.11 ± 0.06 ppm, respectively). In the immobilization stress-2 group, magnesium (171.56 ± 1.87 ppm, p < 0.05), phosphate (2.44 ± 0.07 ppm, p < 0.001) levels were lower, and manganese (373.68 ± 5.76 ppb, p < 0.001) and copper (2.79 ± 0.15 ppm, p < 0.05) levels were higher than the control group (179.31 ± 1.87 ppm, 3.11 ± 0.06 ppm, 327.25 ± 8.35 ppb and 2.45 ± 0.05 ppm, respectively). Our results indicated that 7-day chronic immobilization stress increased anxiety-related behaviors in both stress groups. Zinc, magnesium, phosphate, copper and manganese levels were affected in the brain.
Nutrition management is fundamental for children with chronic kidney disease (CKD). Fluid balance and low-protein and low-sodium diets are the more stressed fields from a nutritional point of view. At the same time, the role of micronutrients is often underestimated. Starting from the causes that could lead to potential micronutrient deficiencies in these patients, this review considers all micronutrients that could be administered in CKD to improve the prognosis of this disease.
Aim
To analyze the associations between infertility or dietary selenium intake and depressive symptoms as well as the role of selenium intake on the association between infertility and depressive symptoms in women.
Methods
This study retrieved the data of 4949 women from National Health and Nutrition Examination Survey (NHANES) database. Univariable and multivariable weighted logistic regression analyses were applied to assess the associations of selenium intake or infertility with the risk of depressive symptoms as well as the regulation of selenium intake on the risk of depressive symptoms related to infertility.
Results
The elevated risk of depressive symptoms was found in participants with infertility (odds ratio [OR] = 1.54, 95% confidence interval [CI]: 1.11–2.15). The risk of depressive symptoms was reduced in women with selenium intake ≥55 μg (OR = 0.64, 95%CI: 0.46–0.90). Compared with women without infertility who had selenium intake <55 μg, those with infertility and had selenium intake <55 μg were associated with elevated risk of depressive symptoms after adjusting for confounding factors (OR = 2.01, 95%CI: 1.03–3.90). The risk of depressive symptoms was not significantly increased in women with infertility who had selenium intake ≥55 μg in comparison with subjects without infertility who had selenium intake ≥55 μg ( p > 0.05).
Conclusion
Selenium intake regulated the association between infertility and depressive symptoms.
Introduction
The etiology and pathophysiology of major depressive disorders (MDDs) remain unclear. Increasing evidence has demonstrated that essential trace elements (ETEs), such as iodine (I), zinc (Zn), copper (Cu), selenium (Se), cobalt (Co), and molybdenum (Mo), play vital roles in MDDs.
Methods
In total, 72 patients with MDD and 75 healthy controls (HCs) in the Zhumadian Second People's Hospital, Henan Province, China were recruited in our study. The levels of different ETEs were examined in both serum and urine, using an inductively coupled plasma mass spectrometer (ICP-MS), for both the MDD patients and HCs.
Results
The serum levels of I, Se, Cu, and Mo were significantly lower in the MDD patients compared to the HCs (p < 0.05), and the urinary levels of I and Zn were significantly higher in the MDD patients compared to the HCs (p < 0.05). The serum concentration of I (Q3: OR = 0.210, Q4: OR = 0.272) was negatively associated with MDD after adjusting for potential confounders, including age, gender, and BMI, and the urinary concentration of I (Q4: OR = 2.952) was positively associated.
Conclusions
The higher levels of I, Se, Cu, and Mo in serum might be protective against the development of MDD, and the excess I and Zn in urine may be associated with MDD pathogenesis. Future research needs to gain a deeper understanding of the metabolic pathways of ETEs, especially I, Se, Zn, Cu, and Mo, in MDD, and their role in the pathogenesis of depression.
The multifactorial etiology of major depressive disorder (MDD) includes biological, environmental, genetic, and psychological aspects. Recently, there has been an increasing interest in metallomic studies in psychiatry, aiming to evaluate the role of chosen trace elements in the MDD etiology as well as the progression of symptoms. This narrative review aims to summarize the available literature on the relationship between the concentration of chosen elements in the serum of patients with MDD and the onset and progression of this psychiatric condition. The authors reviewed PubMed, Web of Science, and Scopus databases searching for elements that had been investigated so far and further evaluated them in this paper. Ultimately, 15 elements were evaluated, namely, zinc, magnesium, selenium, iron, copper, aluminium, cadmium, lead, mercury, arsenic, calcium, manganese, chromium, nickel, and phosphorus. The association between metallomic studies and psychiatry has been developing dynamically recently. According to the results of current research, metallomics might act as a potential screening tool for patients with MDD while at the same time providing an assessment of the severity of symptoms. Either deficiencies or excessive amounts of chosen elements might be associated with the progression of depressive symptoms or even the onset of the disease among people predisposed to MDD.
In recent years, there has been a significant increase in depression, which is related to, among other things, the COVID-19 pandemic. Depression can be fatal if not treated or if treated inappropriately. Depression is the leading cause of suicide attempts. The disease is multifactorial, and pharmacotherapy often fails to bring satisfactory results. Therefore, increasingly more importance is attached to the natural healing substances and nutrients in food, which can significantly affect the therapy process and prevention of depressive disorders. A proper diet is vital to preventing depression and can be a valuable addition to psychological and pharmacologic treatment. An inadequate diet may reduce the effectiveness of antidepressants or increase their side effects, leading to life-threatening symptoms. This study aimed to review the literature on the pathogenesis of the development and treatment of depression, with particular emphasis on dietary supplements and the role of nutrition in the prevention and treatment of depressive disorders.
Trace elements are essential nutrients exist in all organisms in small amounts. They are involved in many physiological processes in the nervous system, but they have two faces; they may be beneficial and/or detrimental. Trace elements are mainly provided by diet, however, some of them exist in environment. Chronic exposure to high levels of some trace elements can lead to toxic effects on all parts of the body, especially the nervous system. Trace elements play important roles in mental health due to the involvement in learning and memory, mood, affective and social behaviors, cognitive processes, etc. Disturbance in their homeostasis is associated with pathogenesis of mental diseases and neuropsychiatric disorders. In this chapter, the role of trace elements in neuropsychiatric disorders including depression, anxiety, and schizophrenia will be reviewed.KeywordsTrace elementsZincCopperManganeseMagnesiumSeleniumNeuropsychiatric disordersDepressionAnxietySchizophrenia
Trace elements or trace metals are essential components of enzymes, proteins, hormones and play a key role in biochemical processes, cell growth and differentiation, as well as in neurotransmission, affecting human physiology. In nature there are also heavy metals that exhibit toxic effects on the human body, including the brain. The importance of trace elements has been established in neurodegenerative disorders, schizophrenia, depression among others. In parallel, an important regulatory element in the above diseases is cyclooxygenase-2 (COX-2), a modulator of the arachidonic acid (AA) pathway, and a cause of neuroinflammation, and glutamate (Glu) dysregulation, affecting calcium (Ca) metabolism in cells. This review presents the effects of major trace elements and heavy metals on COX-2 expression. Calcium (Ca), zinc (Zn), cadmium (Cd), vanadium (V), nickel (Ni), copper (Cu), and iron (Fe) can potentially increase COX-2 expression, inducing neuroinflammation and Glu excitotoxicity; while magnesium (Mg), lithium (Li), and selenium (Se) can potentially decrease COX-2 expression. The associated mechanisms are described in the article.
Depression is a mental illness with several categories that have common symptoms such as chronic sorrow, lack of interest, lack of pleasure, mood swings between guilt and poor self-esteem, sleep disturbances, and a loss of appetite. Over 300 million individuals globally suffer from depression, and the socioeconomic cost of this debilitating disorder is expected to rise dramatically in the future decades. Behavioral health illnesses can be prevented and treated to some extent with dietary and nutritional means. Nutritional psychiatry has produced observational and effectiveness evidence regarding the role of healthy dietary patterns in the onset and treatment of depressive symptoms. Diet is associated with depressive symptoms or depression, meaning that an increase in depressive disorders coincide with a deterioration in healthy living choices, including poor quality diets. Healthy eating habits and adequate intake of essential nutrients via the diet can help prevent and treat depression by reducing symptoms of mental illness. In addition, because nutrition is a modifiable risk factor for depression, it is practical for the public to consider dietary changes to reduce the prevalence of depressive disorders. This paper reviews the potential value of diet-based actions to manage depression, and ways in which dietary changes could be made to improve mental and cognitive health. Furthermore, some practical solutions for preventing and controlling depression are proposed based on health-related effects of improving dietary habits and life style.
Cardiovascular diseases (CVD) are the leading causes of death in technologically developed and developing countries. Copper, an active redox element, is involved in energy production through various mechanisms. Copper and coronary artery disease can be associated directly, through its direct effect on the vascular endothelium, or indirectly through lipoprotein metabolism. Hence an evaluation of copper in the coronary artery disease individual is important.
The aim is to compare the relationship of serum copper levels between coronary artery disease patients and control individuals based on age, sex, hypertension and diabetes mellitus.
Materials and methods: The study design was a case-control study in which proven coronary artery disease patients attending cardiology OPD were selected as cases. Control individuals were mainly selected from the master health check-up. Serum copper levels, plasma glucose, cholesterol, serum triglycerides, and serum HDL & LDL cholesterol were done. Glycated haemoglobin (HbA1C) was also measured. The data were analyzed using IBM SPSS software version 24.
Result: The correlation of serum copper level with other quantitative parameters is determined by calculating Pearson’s correlation coefficient among cases and controls.
Conclusion: The serum copper level is significantly (p=0.001) higher in CAD patients than in age, sex, DM, and HT-matched controls. The serum copper level has a significant (p=0.001) effect on disease, and the adjusted odds ratio is 1.032 (CI 1.011–1.054). In addition, the serum copper level has a significant (0.01) negative correlation with LDL cholesterol and total cholesterol.
Observational studies have suggested a relationship between selenium status and mental disorders (MDs). However, it remains unclear whether selenium status was causally associated with MDs. Thus, we performed a two-sample Mendelian randomization analysis using genome-wide association studies (GWAS) summary statistics to investigate the causal effects of selenium levels on seven MDs, including schizophrenia, major depressive disorder (MDD), autism spectrum disorder (ASD), bipolar disorder (BD), anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), and panic disorder (PD). Strong genetic instruments of blood selenium (n = 9) and blood-toenail selenium (n = 12) were applied to the above seven MDs GWAS datasets from Psychiatric Genomics Consortium, which were further replicated in the FinnGen Biobank. The inverse-variance weighted method was employed to calculate the causal effects. The results showed that genetically predicted blood selenium levels were associated with a decreased risk of schizophrenia (odds ratio [OR] = 0.90, 95% CI: 0.87-0.95) and AN (OR = 0.87, 95% CI: 0.77-0.97). However, both blood and blood-toenail selenium levels were linked to an increased risk of MDD (blood: OR = 1.08, 95% CI: 1.05-1.12; blood-toenail: OR = 1.08, 95% CI: 1.04-1.13) and ASD (blood: OR = 1.11, 95% CI: 1.05-1.17; blood-toenail: OR = 1.13, 95% CI: 1.05-1.21), respectively. No obvious associations were found between selenium levels and BD as well as ADHD. Our findings highlighted a protective role of selenium in SZ and AN, while a risk effect in MDD and ASD. Further studies are required to verify the underlying mechanism mediating the unequal effects of Se on different MDs, which will pave a new path for the intervention of MDs.
Depression is one of the most common diseases in the older population. Difficulties in recognizing the etiology and its recurrence make depression a major challenge for healthcare professionals. The risk of developing depression is influenced by many factors, including lifestyle and diet. Research studies have shown a relationship between the consumption of specific macro and micro elements and depression. However, so far no nutritional recommendations on how to reduce the risk of the disease and its relapses in older adults have been developed. In this review, we will outline research results of conducted studies and focus on both basic and potentially promising elements of diet such as proteins, carbohydrates, fats, dietary fiber, vitamins D, E, C and B as well as microelements such as magnesium, zinc, selenium or iron.
The importance of daily consumed foods as affecting factors on cognition and emotion has been recognized more than ever. Due to the growing knowledge that dietary factors have a significant impact on neural functions, people become more enthusiastic about choosing good food in each phase of life. The purpose of this chapter is to give a broad overview of the effects of various kinds of nutrients including macronutrients (carbohydrates, proteins, and fats) and micronutrients (polyphenols, vitamins, and minerals) on children, adults, and the elderly. Moreover, this chapter aims to show how malnutrition impacts cognition and emotion.KeywordsCognitive functionsEmotionsNutritionMacronutrientsMicronutrients
The development and implementation of new technologies for enriching the finished product with trace elements is important and relevant. Deviations in the elemental state of the body are found in the vast majority of the adult population of Russia, significantly differing in nature and degree of severity in representatives of different regions and persons divided by profession and occupation. At the same time, it is recognized that in Russia, on average, about two-thirds of adults and three-quarters of children are classified as at risk for hypomicroelementosis, on the other hand, about one-third of the population is more or less susceptible to hypermicroelementosis. The most common deficiency of trace elements such as iron, zincum, copper, chromium, iodine, selenium, cobalt, silicium. The main problem of detecting microelementosis is that the deficiency of essential elements does not have a pronounced clinical picture. To correct the finished formulations of products, it is necessary to take into account the indicators of the level of absorption and the rate of release of these elements, as well as ways of their disposal in the body. One of the most effective ways to introduce essential and conditionally essential elements into formulations is the immobilization of colloidal solutions with a high content of these elements on a polymeric materialor protein carrier, followed by introduction into the composition of the prepared product. The efficiency of using elements such as silver, gold, zinc, cobalt and selenium as a colloidal phase is described. Antagonistic and synergistic interactions of essential elements, their effect on the body, taking into account the indicators of absorption and the rate of their excretion, are described.
In the past two decades, rapid urbanization and globalization have adversely changed our lifestyle and diet habits. Our traditional healthy food habits have been replaced by processed foods with low nutritive value. These measures also saw a high prevalence of depression and other psychiatric disorders not only in western, urbanized countries but also in other developing countries as well. Long-term undernutrition due to deficiency of micronutrients such as iodine and iron can lead to increased chances of physical and mental disabilities. Undernourished children have less energy, decreased curiosity, and less interest in physical activities as well as they lack communication skills. These factors impair their physical, mental, and cognition. The aim of this article was to find the association of micronutrients especially minerals in patients with major depressive disorders. An adequate supply of nutrients is essential to regulate microbiome health and to improve the efficacy of other psychotherapeutic and psychopharmacological interventions. Lifestyle interventions in the form of dietary coaching could be used as promising, cost-effective, and practical intervention in depressed individuals. Nutritional interventions should be integrated in the multifactorial and treatment-resistant psychiatry patients.
Purpose:
Few studies have examined the role of selenium in anxiety. This study aimed to evaluate the association between serum selenium concentrations and anxiety disorders and symptoms in children.
Design and methods:
This study utilized data from 831 children participating in the China Jintan Child Cohort Study (mean age = 12.67 years; 46.1% female). Serum selenium samples were collected and anxiety was assessed using the Chinese version of the Screen for Child Anxiety Related Disorders. Six types of anxiety scores were calculated, including total anxiety, panic/somatic, generalized anxiety, separation anxiety, social anxiety, and school phobia.
Results:
Controlling for covariates, children with lower serum selenium concentrations were more likely to meet clinical cutoffs for total anxiety (OR = 0.992, p < 0.01), panic/somatic disorder (OR = 0.993, p < 0.05), generalized anxiety disorder (OR = 0.990, p < 0.05), social anxiety disorder (OR = 0.991, p < 0.01), and school phobia (OR = 0.989, p < 0.01), but not separation anxiety (OR = 1.000, p > 0.05). Controlling for covariates, lower serum selenium concentrations were also associated with higher continuous total anxiety, generalized anxiety, and school phobia scores (p < 0.05).
Conclusions:
Lower serum selenium concentrations were associated with higher anxiety. To our knowledge, this was the first study to examine the relationship between serum selenium and anxiety disorders in a sample of children. Results indicate an association between children's micronutrient levels and anxiety disorders.
Practice implications:
Improving child nutrition may be a promising strategy to help reduce childhood anxiety.
Suicide is a multifaceted phenomenon, related to an everlasting interconnection between biological, psychosocial, sociological, philosophical, and cultural aspects of human life. Immune system, which is constantly responding to changing environments and changing in response to them, seems to play a major role in this interaction. Multiple studies have reported increased risk of suicidal behaviours after or during inflammatory conditions. Individuals that engage in suicidal behaviours also have increased concentrations of inflammatory markers, such as interleukins 1β and 6, tumour necrosis factor α, and C-reactive protein, both in blood and the central nervous system (CNS). Stress, which is frequently mentioned among the major risk factors for suicidal behaviours, is also associated with a wide immune system dysregulation, entailing glucocorticoid system disruption and a low-grade inflammation. Mechanisms connecting systemic inflammation and CNS changes include damage to blood-brain barrier and interoceptive alterations, both resulting in changes in the communication between the periphery and the brain. Meanwhile, in CNS, pro-inflammatory cytokines may activate microglia causing a shift in tryptophan metabolism, preferentially generating cellular energy and toxic by-products of kynurenine pathway rather than serotonin. These changes in brain homeostasis lead to anatomical and functional brain alterations, most notably prefrontal cortex and insula, engendering maladaptive behavioural phenotypes, such as anhedonia and impulsivity that may mediate the association between inflammation and suicide. This chapter will provide a condensed overview of this complex association between inflammation and suicidal behaviours, presenting major findings in this area and explaining key pathways linking them.
Given the importance of understanding the role of neuroinflammation in psychiatric illness, including its emergence and progression, it is of practical value to explore the available tools that noninvasively index neuroinflammatory markers in vivo. Various aspects of neuroinflammation can be probed by magnetic resonance imaging (MRI) measures. These aspects include water content accumulation (T2-weighted anatomical MRI, magnetization transfer imaging and diffusion MRI); blood–brain barrier dysfunction and cellular infiltration (contrast-enhanced anatomical MRI); and molecular/metabolic signatures of neuroinflammation (magnetic resonance spectroscopy). This chapter provides a nontechnical overview of these MRI measures, which have been applied to estimate putative neuroinflammatory processes in psychiatric illness.
While the impact of diet on physical health outcomes is well established, the role of dietary and nutritional factors in the onset and outcomes of mental illness is yet to be fully understood. Nonetheless, there is an increasing evidence-base showing that poor diet is associated with adverse mental health outcomes, and that certain nutritional-based therapies may be beneficial in the treatment of mental illness. In this chapter, we firstly describe what is generally considered to constitute a healthy vs. unhealthy diet (and the role these have in physical health outcomes), before going on to discuss the epidemiological and experimental evidence around the impact of diet on mental illness. In particular, the chapter focuses on how ‘dietary inflammation’ could explain the link between adverse diets and poor mental health, along with if and how dietary improvement and nutritional supplements could potentially be used to improve outcomes. Within this, the chapter also explores the emergent evidence around the role of the ‘gut microbiome’ in the link between diet, inflammation, and mental health. The chapter closes with a discussion on the overall implications of the existing evidence for addressing dietary factors in clinical practice.
Purpose of Review
This review tries to provide a comprehension of the relation existing between aging and nutrition.
Recent Findings
Macronutrients and micronutrients obtained from food intake support biological and physiological activities required for optimal health. The past decade has witnessed studies demonstrating a link between malnutrition and accelerated aging or age-related disorders. Aging causes loss of function in tissues and organs and is explained by different theories such as free radical or reactive oxygen species (ROS), nutritional intervention in the name of caloric or dietary restriction (CR/DR), or endocrine theories. These theories confirm the bridge between nutrition and aging, and give the clues on how aging and age-related diseases can be mitigated by macronutrients like proteins and carbohydrates, and by micronutrients, including vitamins and essential minerals.
Summary
This review, besides giving insight into the precedent theories and findings, answers the following questions: Which nutrients are essential or need to be considered in the elderly? Do elderly feed themselves without difficulties? What are the basic causes and consequences of aging that link it to nutrition? Through this insight and those answers, the article lays the path down for further studies on the interaction between the aging process and different types of nutrients.
We established the mouse model of fluoride (68 mg F ion/L deionized water) exposure for 90 days, 120 days and 150 days, and applied diverse methods as behavioral models of anxiety and depression, and analyzed the levels of the anxiety- and depression-like related genes like BDNF1, BDNF4, 5-HT1A, VGLUT, GAD67, and VGAT in the mouse hippocampus. In the mice exposed to NaF for 120 days, compared to the control group, chalky opacity was observed on the enamel of teeth; the results of anxiety-like behavior, like elevated zero maze, light/dark exploration test, novel object recognition test and emergence test were significantly altered, however in the mice exposed for 150 days, only the elevated zero maze and emergence test were significantly altered. Also, the results of depression-like behavior were significantly altered in the 120 days treated mice. Exposure to NaF for 120 days significantly decreased the mRNA expression levels of the BDNF4 with a concomitant increase in the 5-HT1A compared to the control mice. Especially the mRNA expression levels of GAD67 and VGAT were significantly decreased in all the three NaF treated groups. However, no significant changes were observed in the mRNA expression levels of the VGLUT compared to the control mice. In summary, we speculated that fluoride exposure had adverse effects on nervous system, inducing an imbalance between excitation and inhibition, which resulted in abnormal behavior and depression.
Treatment-resistant depression (TRD) remains one of the major psychiatric challenges worldwide. Search for non-monoaminergic agents, possibly effective in treatment of TRD is of prime importance. One of those agents is ketamine – a dissociative, anesthetic drug exhibiting a fast antidepressant action in patients with TRD. Concurrently, anhedonia appears to be significant symptom domain with far-reaching impact on course of treatment. There is data demonstrating that abnormal copper levels might be associated with symptoms of depression. As there is common denominator in ketamine and copper role in neurotransmission this paper is to explore the associations of blood copper levels and psychometric measures in patients with TRD in course of major depressive disorder (MDD) and bipolar disorder (BP), focusing on anhedonia measured with Snaith-Hamilton Pleasure Scale (SHAPS) score.
A comprehensive overview is presented of the nutritional issues faced by people who use drugs or are undergoing treatment for recovery. Chronic substance use affects a person's nutritional status and body composition through decreased intake, nutrient absorption, and dysregulation of hormones that alter the mechanisms of satiety and food intake. Anthropometrics alone is not the best indicator of nutritional status, because this population has hidden deficiencies and disturbed metabolic parameters. Socioeconomic factors (eg, higher education, higher income, presence of a partner, living at home) positively affect nutritional status. Scarce available data on users undergoing treatment indicate improvement in anthropometric and metabolic parameters but with micronutrient intake remaining suboptimal. Weight gain is noted especially among women who use drugs and potentially increases their risk of relapse. Finally, specific amino acids and omega-3 fatty acids are promising in decreasing relapse and improving mental health during treatment; however, additional high-quality studies are needed. Nutrition intervention for people who use drugs or are undergoing treatment for recovery is underused; comprehensive programs addressing this population's unique needs are necessary. Future research will identify which components are needed.
Interactions between the essential dietary metals, iron and copper, have been known for many years. This review highlights recent advances in iron-copper interactions with a focus on tissues and cell types important for regulating whole-body iron and copper homeostasis. Cells that mediate dietary assimilation (enterocytes) and storage and distribution (hepatocytes) of iron and copper are considered, along with the principal users (erythroid cells) and recyclers of red cell iron (reticuloendothelial macrophages). Interactions between iron and copper in the brain are also discussed. Many unanswered questions regarding the role of these metals and their interactions in health and disease emerge from this synopsis, highlighting extensive future research opportunities.
Regulation of hypothalamic-pituitary-adrenocortical (HPA) axis activity by stress is a fundamental survival mechanism and HPA-dysfunction is implicated in psychiatric disorders. Adverse early life experiences, e.g. poor maternal care, negatively influence brain development and programs an abnormal stress response by encoding long-lasting molecular changes, which may extend to the next generation. How HPA-dysfunction leads to the development of affective disorders is complex, but may involve GABAA receptors (GABAARs), as they curtail stress-induced HPA axis activation. Of particular interest are endogenous neurosteroids that potently modulate the function of GABAARs and exhibit stress-protective properties. Importantly, neurosteroid levels rise rapidly during acute stress, are perturbed in chronic stress and are implicated in the behavioral changes associated with early-life adversity. We will appraise how GABAAR-active neurosteroids may impact on HPA axis development and the orchestration of the stress-evoked response. The significance of these actions will be discussed in the context of stress-associated mood disorders.
Vanadium is the 21st most abundant element in the Earth’s crust and the 2nd-to-most abundant transition metal in sea water. The element is ubiquitous also in freshwater and nutrients. The average body load of a human individual amounts to 1 mg. The omnipresence of vanadium hampers checks directed towards its essentiality. However, since vanadate can be considered a close blueprint of phosphate with respect to its built-up, vanadate likely takes over a regulatory function in metabolic processes depending on phosphate. At common concentrations, vanadium is non-toxic. The main source for potentially toxic effects caused by vanadium is exposure to high loads of vanadium oxides in the breathing air of vanadium processing industrial enterprises. Vanadium can enter the body via the lungs or, more commonly, the stomach. Most of the dietary vanadium is excreted. The amount of vanadium resorbed in the gastrointestinal tract is a function of its oxidation state (VV or VIV) and the coordination environment. Vanadium compounds that enter the blood stream are subjected to speciation. The predominant vanadium species in blood are vanadate and vanadyl bound to transferrin. From the blood stream, vanadium becomes distributed to the body tissues and bones. Bones act as storage pool for vanadate. The aqueous chemistry of vanadium(V) at concentration <10 μM is dominated by vanadate. At higher concentrations, oligovanadates come in, decavanadate in particular, which is thermodynamically stable in the pH range 2.3–6.3, and can further be stabilized at higher pH by interaction with proteins.
To explore the potential dose-response relationship between manganese (Mn) exposure and cognitive function and also plasma brain-derived neurotrophic factor (BDNF) levels in occupational Mn exposure workers.
A total 819 workers were identified from our Mn-exposed workers, and 293 control workers were recruited in the same region. All exposed workers were divided into three groups based on Mn cumulative exposure index. The Montreal Cognitive Assessment (MoCA) test was applied to estimate cognitive function for all subjects. Plasma BDNF levels were determined by ELISA in 248 selected exposed workers and 100 controls.
Mn-exposed workers had significantly lower MoCA scores than those in the control group (25.62±0.25): those in high-exposure group had the lowest scores (21.33±0.32), compared with the intermediate-exposure group (23.22±0.30) and low-exposure group (23.57±0.23). Mn exposure levels were inversely associated with MoCA total scores, all p<0.05. A positive correlation was found between plasma BDNF levels and MoCA total scores (r=0.278, p<0.01). Moreover, compared with the control group (288.7±181.7 pg/mL), BDNF levels were lower in the high-exposure group (127.5±99.8 pg/mL), and in the intermediate-exposure (178.2±138.1 pg/mL) and low-exposure groups (223.4±178.3 pg/mL). Additionally, plasma BDNF levels decreased significantly as Mn exposure levels increased (ptrend<0.01).
Mn exposure may be associated with decreased plasma BDNF levels and cognition impairment in this large cross-sectional study.
Despite its very low level in humans, selenium plays an important and unique role among the (semi)metal trace essential elements because it is the only one for which incorporation into proteins is genetically encoded, as the constitutive part of the 21st amino acid, selenocysteine. Twenty-five selenoproteins have been identified so far in the human proteome. The biological functions of some of them are still unknown, whereas for others there is evidence for a role in antioxidant defence, redox state regulation and a wide variety of specific metabolic pathways. In relation to these functions, the selenoproteins emerged in recent years as possible biomarkers of several diseases such as diabetes and several forms of cancer. Comprehension of the selenium biochemical pathways under normal physiological conditions is therefore an important requisite to elucidate its preventing/therapeutic effect for human diseases. This review summarizes the most recent findings on the biochemistry of active selenium species in humans, and addresses the latest evidence on the link between selenium intake, selenoproteins functionality and beneficial health effects. Primary emphasis is given to the interpretation of biochemical mechanisms rather than epidemiological/observational data. In this context, the review includes the following sections: (1) brief introduction; (2) general nutritional aspects of selenium; (3) global view of selenium metabolic routes; (4) detailed characterization of all human selenoproteins; (5) detailed discussion of the relation between selenoproteins and a variety of human diseases.
To assess plasma zinc and copper levels in individuals with anxiety and to test the hypothesis that there is a relationship between copper and zinc concentration and improved symptoms.
Serum from 38 individuals with anxiety and 16 neurotypical age, gender and size similar controls were tested for plasma zinc and copper concentration using inductively-coupled plasma-mass spectrometry. Zinc and copper levels, pre and post therapy, were compared and assessed for perceived anxiety symptoms.
In this preliminary study, individuals with anxiety had significantly higher plasma levels of Cu (P = 0.0348), Cu/Zn (P = 0.0493) and lower Zn (P = 0.0294) compared to controls. Zn levels normalized (increased to the normal range) and Cu/Zn significantly decreased after zinc therapy (P = 0.0004, P = 0.0033, respectively), but Cu did not significantly decrease (0.3577). These same patients improved significantly with respect to perceived overall symptoms after zinc and anti-oxidant therapy (P = 0.013).
These results suggest an association between Zn plasma levels and individuals with anxiety, demonstrate that zinc therapy is effective in increasing zinc plasma levels, and show that zinc supplementation may play a role in improved symptoms.
The purpose of the study was to determine the concentration of serum trace and other essential elements of generalized anxiety disorder patients and to find out the relationship between element levels and nutritional status or socioeconomic factors. The study was conducted among 50 generalized anxiety disorder patients and 51 healthy volunteers. Patients were selected and recruited in the study with the help of a clinical psychologist by random sampling. The concentrations of serum trace elements (Zn, Cu, Mn, and Fe) and other two essential elements (Ca and Mg) were determined by graphite furnace and flame atomic absorption spectroscopy. Data were analyzed by independent t test, Pearson’s correlation analysis, regression analysis, and analysis of variance. The serum concentrations of Zn, Cu, Mn, Fe, Ca, and Mg in generalized anxiety disorder patients were 1.069 ± 0.40, 1.738 ± 0.544, 1.374 ± 0.750, 3.203 ± 2.065, 108.65 ± 54.455, and 21 ± 4.055 mg/L, while those were 1.292 ± 0.621, 0.972 ± 0.427, 0.704 ± 0.527, 1.605 ± 1.1855, 101.849 ± 17.713, and 21.521 ± 3.659 mg/L in control subjects. Significantly decreased (p p p > 0.05). Socioeconomic data revealed that most of the patients were in the lower middle class group and middle-aged. Mean BMI of the control group (23.63 ± 3.91 kg/m2) and the patient group (23.62 ± 3.77 kg/m2) was within the normal range (18.5–25.0 kg/m2). The data obtained from different interelement relations in the generalized anxiety disorder patients and control group strongly suggest that there is a disturbance in the element homeostasis. So changes in the serum trace element level in generalized anxiety disorder patients occur independently and they may provide a prognostic tool for the diagnosis and treatment of this disease.
Background
Prior animal model and human-based studies have linked selenium concentrations to decreased risk for depression; however, this work has not focused on household groundwater levels or specific depressive symptoms. The current study evaluated the link between groundwater selenium levels and depression. We also sought to determine if a functional polymorphism in the glutathione peroxidase 1 (GPX1) gene impacted this link.
Methods
We used a cross-sectional design to analyze data from 585 participants (183 men and 402 women) from Project FRONTIER, a study of rural health in West Texas. Residential selenium concentrations were estimated using Geospatial Information System (GIS) analyses. Linear regression models were created using Geriatric Depression Scale (GDS-30) total and subfactor scores as outcome variables and selenium concentrations as predictor variables. Analyses were re-run after stratification of the sample on GPX1 Pro198Leu genotype (rs1050454).
Results
Selenium levels were significantly and negatively related to all GDS and subfactor scores accounting for up to 17% of the variance beyond covariates. Selenium was most strongly protective against depression among homozygous carriers of the C allele at the Pro198Leu polymorphism of the GPX1 gene. Analyses also point towards a gene-environmental interaction between selenium exposure and GPX1 polymorphism.
Conclusion
Our results support the link between groundwater selenium levels and decreased depression symptoms. These findings also highlight the need to consider the genetics of the glutathione peroxidase system when examining this relationship, as variation in the GPX1 gene is related to depression risk and significantly influences the protective impact of selenium, which is indicative of a gene-environment interaction.
Selenium is considered a protective agent against free radicals through the maintenance of better enzyme activity. The few studies examining the relationship between selenium and depression have yielded inconsistent results and none of these studies considered the role of cognitive function in this context.
A cross-sectional evaluation of 1737 rural Chinese age 65 and over from two provinces in China was conducted. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS). Cognitive function was assessed using various cognitive instruments. Selenium measures were obtained from nail samples. Other information collected included demographic characteristics and medical history. Analysis of covariance models were used to identify factors associated with GDS score.
Higher selenium levels were associated with lower GDS scores adjusting for demographic and medical conditions (p = 0.0321). However, the association between selenium and depressive symptoms was no longer significant when cognitive function score was adjusted in the model (p = 0.2143).
Higher selenium level was associated with lower depressive symptoms without adjusting for cognition in this cohort. However, after cognition was adjusted in the model the association between selenium and depressive symptoms was no longer significant, suggesting that selenium's association with depressive symptoms may be primarily through its association with cognitive function.
This symposium comprised five oral presentations dealing with recent findings on Mn-related cognitive and motor changes from epidemiological studies across the life span. The first contribution highlighted the usefulness of functional neuroimaging of the central nervous system (CNS) to evaluate cognitive as well as motor deficits in Mn-exposed welders. The second dealt with results of two prospective studies in Mn-exposed workers or welders showing that after decrease of Mn exposure the outcome of reversibility in adverse CNS effects may differ for motor and cognitive function and, in addition the issue of plasma Mn as a reliable biomarker for Mn exposure in welders has been addressed. The third presentation showed a brief overview of the results of an ongoing study assessing the relationship between environmental airborne Mn exposure and neurological or neuropsychological effects in adult Ohio residents living near a Mn point source. The fourth paper focused on the association between blood Mn and neurodevelopment in early childhood which seems to be sensitive to both low and high Mn concentrations. The fifth contribution gave an overview of six studies indicating a negative impact of excess environmental Mn exposure from air and drinking water on children's cognitive performance, with special attention to hair Mn as a potential biomarker of exposure. These studies highlight a series of questions about Mn neurotoxicity with respect to cognitive processes, forms and routes of exposure, adequate biomarkers of exposure, gender differences, susceptibility and exposure limits with regard to age.
1.1. This paper reviews recent findings on cellular and humoral immunity and inflammatory markers in depression.2.2. It is shown that major depression may be accompanied by systemic immune activation or an inflammatory response with involvement of phagocytic (monocytes, neutrophils) cells, T cell activation, B cell proliferation, an “acute” phase response with increased plasma levels of positive and decreased levels of negative acute phase proteins, higher autoantibody (antinuclear, antiphospholipid) titers, increased prostaglandin secretion, disorders in exopeptidase enzymes, such as dipeptidyl peptidase IV, and increased production of interleukin (IL)-1β and IL-6 by peripheral blood mononuclear cells.3.3. It is hypothesized that increased monocytic production of interleukins (Il-1β and Il-6) in severe depression may constitute key phenomena underlying the various aspects of the immune and “acute” phase response, while contributing to hypothalamic-pituitary-adrenalaxis hyperactivity, disorders in serotonin metabolism, and to the vegetative symptoms (i.e. the sickness behavior) of severe depression.
To assess plasma zinc and copper concentration in individuals with Asperger's Syndrome, Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) and autistic disorder, and to analyze the efficacy of zinc therapy on the normalization of zinc and copper levels and symptom severity in these disorders.
Plasma from 79 autistic individuals, 52 individuals with PDD-NOS, 21 individuals with Asperger's Syndrome (all meeting DSM-IV diagnostic criteria), and 18 age and gender similar neurotypical controls, were tested for plasma zinc and copper using inductively-coupled plasma-mass spectrometry.
Autistic and PDD-NOS individuals had significantly elevated plasma levels of copper. None of the groups (autism, Asperger's or PDD-NOS) had significantly lower plasma zinc concentrations. Post zinc and B-6 therapy, individuals with autism and PDD-NOS had significantly lower levels of copper, but individuals with Asperger's did not have significantly lower copper. Individuals with autism, PDD-NOS and Asperger's all had significantly higher zinc levels. Severity of symptoms decreased in autistic individuals following zinc and B-6 therapy with respect to awareness, receptive language, focus and attention, hyperactivity, tip toeing, eye contact, sound sensitivity, tactile sensitivity and seizures. None of the measured symptoms worsened after therapy. None of the symptoms in the Asperger's patients improved after therapy.
These results suggest an association between copper and zinc plasma levels and individuals with autism, PDD-NOS and Asperger's Syndrome. The data also indicates that copper levels normalize (decrease to levels of controls) in individuals with autism and PDD-NOS, but not in individuals with Asperger's. These same Asperger's patients do not improve with respect to symptoms after therapy, whereas many symptoms improved in the autism group. This may indicate an association between copper levels and symptom severity.
Copper misregulation has been implicated in the pathological processes underlying deterioration of learning and memory in Alzheimer's disease and other neurodegenerative disorders. Supporting this, inhibition of long-term potentiation (LTP) by copper (II) has been well established, but the exact mechanism is poorly characterized. It is thought that an interaction between copper and postsynaptic NMDA receptors is a major part of the mechanism; however, in this study, we found that copper (II) inhibited NMDA receptor-independent LTP in the CA3 region of hippocampal slices. In addition, in the CA3 and CA1 regions, copper modulated the paired-pulse ratio (PPR) in an LTP-dependent manner. Combined, this suggests the involvement of a presynaptic mechanism in the modulation of synaptic plasticity by copper. Inhibition of the copper-dependent changes in the PPR with cyclothiazide suggested that this may involve an interaction with the presynaptic AMPA receptors that regulate neurotransmitter release.
Thyroid hormone plays a crucial role in the development and function of the nervous system. In order to bind to its nuclear receptor and regulate gene transcription thyroxine needs to be activated in the brain. This activation occurs via conversion of thyroxine to T3, which is catalyzed by the type 2 iodothyronine deiodinase (D2) in glial cells, in astrocytes, and tanycytes in the mediobasal hypothalamus. We discuss how thyroid hormone affects glial cell function followed by an overview on the fine-tuned regulation of T3 generation by D2 in different glial subtypes. Recent evidence on the direct paracrine impact of glial D2 on neuronal gene expression underlines the importance of glial-neuronal interaction in thyroid hormone regulation as a major regulatory pathway in the brain in health and disease.
Copper is an essential trace element required by all living organisms. Excess amounts of copper, however, results in cellular damage. Disruptions to normal copper homeostasis are hallmarks of three genetic disorders: Menkes disease, occipital horn syndrome, and Wilson’s disease.
Menkes disease and occipital horn syndrome are characterized by copper deficiency. Typical features of Menkes disease result from low copper-dependent enzyme activity. Standard treatment involves parenteral administration of copper-histidine. If treatment is initiated before 2 months of age, neurodegeneration can be prevented, while delayed treatment is utterly ineffective. Thus, neonatal mass screening should be implemented. Meanwhile, connective tissue disorders cannot be improved by copper-histidine treatment. Combination therapy with copper-histidine injections and oral administration of disulfiram is being investigated. Occipital horn syndrome characterized by connective tissue abnormalities is the mildest form of Menkes disease. Treatment has not been conducted for this syndrome.
Wilson’s disease is characterized by copper toxicity that typically affects the hepatic and nervous systems severely. Various other symptoms are observed as well, yet its early diagnosis is sometimes difficult. Chelating agents and zinc are effective treatments, but are inefficient in most patients with fulminant hepatic failure. In addition, some patients with neurological Wilson’s disease worsen or show poor response to chelating agents. Since early treatment is critical, a screening system for Wilson’s disease should be implemented in infants. Patients with Wilson’s disease may be at risk of developing hepatocellular carcinoma. Understanding the link between Wilson’s disease and hepatocellular carcinoma will be beneficial for disease treatment and prevention.
Vanadium is a trace element present in practically all cells in plants and animals. While the essentiality of vanadium for human beings remains to be well established, vanadium has become an increasingly important environmental metal. Vanadium compounds exert a variety of biological activities and responses. At pharmacological doses, vanadium compounds display relevant biological actions such as insulin and growth factor mimetic or enhancing effects, as well as osteogenic and cardioprotective activity. On the other hand, depending on the nature of compounds and their concentrations, toxicological actions and adverse side effects may also be shown. Nevertheless, the toxic effects may be useful to develop new antitumoral drugs. In this review, the authors summarize current knowledge and new advances on in vitro and in vivo effects of inorganic and organically-chelated vanadium compounds. The effects of vanadium derivatives on some cellular signaling pathways related to different diseases are compiled. In particular, the pathways relevant to the insulin mimetic, osteogenic, cadioprotective and antitumoral actions of vanadium compounds have been comprehensively reviewed. The knowledge of these intracellular signaling pathways may facilitate the rational design of new vanadium compounds with promising therapeutic applications as well as the understanding of secondary side effects derived from the use of vanadium as a therapeutic agent.
Postpartum depression is a common complication of childbirth, and its prevention is an important public-health issue because of its negative effects on mother, infant, and family. The present randomized, double-blind, placebo-controlled trial was conducted to examine the effect of prenatal selenium supplementation on the postpartum depression level in Iranian women.
A total of 166 primigravid pregnant women in the first trimester of pregnancy, were randomized to receive 100 μg of selenium (n = 83) or a placebo (n = 83) per day until delivery. The symptoms of postpartum depression were evaluated during the eight weeks following delivery by means of the Edinburgh Postnatal Depression Scale (EPDS). Serum selenium concentrations were measured at baseline and at the end of study.
There was no significant difference in demographic characteristics and perceived social support between the selenium and control groups at baseline (p > 0.05). There were 22 drop-outs in the selenium-supplemented group and 19 in the placebo group. Forty-four women in the selenium group and 41 women in the placebo group completed the trial and the EPDS questionnaire. Selenium supplementation was associated with a significant increase in mean serum selenium concentration at term (p < 0.001) but remained unchanged in the control group. The mean EPDS score in the selenium group was significantly lower than that of the control group (p < 0.05).
These findings suggest that supplementation with selenium during pregnancy might be an effective approach for the prevention of postpartum depression.
Diabetes mellitus is accompanied by hormonal and neurochemical changes that can be associated with anxiety and depression. Both diabetes and depression negatively interact, in that depression leads to poor metabolic control and hyperglycemia exacerbates depression. We hypothesize one novel vanadium complex of vanadium-enriched Cordyceps sinensis (VECS), which is beneficial in preventing depression in diabetes, and influences the long-term course of glycemic control. Vanadium compounds have the ability to imitate the action of insulin, and this mimicry may have further favorable effects on the level of treatment satisfaction and mood. C. sinensis has an antidepressant-like activity, and attenuates the diabetes-induced increase in blood glucose concentrations. We suggest that the VECS may be a potential strategy for contemporary treatment of depression and diabetes through the co-effect of C. sinensis and vanadium. The validity of the hypothesis can most simply be tested by examining blood glucose levels, and swimming and climbing behavior in streptozotocin-induced hyperglycemic rats.
Manganese is an essential mineral that is found at low levels in virtually all diets. Manganese ingestion represents the principal route of human exposure, although inhalation also occurs, predominantly in occupational cohorts. Regardless of intake, animals generally maintain stable tissue manganese levels as a result of homeostatic mechanisms that tightly regulate the absorption and excretion of this metal. However, high-dose exposures are associated with increased tissue manganese levels, causing adverse neurological, reproductive and respiratory effects. In humans, manganese-induced neurotoxicity is associated with a motor dysfunction syndrome, commonly referred to as manganism or Parkinsonism, which is of paramount concern and is considered to be one of the most sensitive endpoints. This article focuses on the dosimetry of manganese with special focus on transport mechanisms of manganese into the CNS. It is not intended to be an exhaustive review of the manganese literature; rather it aims to provide a useful synopsis of contemporary studies from which the reader may progress to other research citations as desired. Specific emphasis is directed towards recent published literature on manganese transporters’ systemic distribution of manganese upon inhalation exposure as well as the utility of magnetic resonance imaging in quantifying brain manganese distribution.
Essential elements are very important for the proper functioning of the human body. They are required for fundamental life processes such as cell division and differentiation and protein synthesis. Thus a deficiency of these essential elements is associated with an enormous health risk that can ultimately lead to death. In recent years, studies have provided valuable information on the involvement of essential elements in psychiatric disorders, in particular depression and anxiety.
There is strong evidence indicating that deficiency of essential elements can lead to the development of depressive and/or anxiogenic behaviour and supplementation can enhance therapeutic effect of antidepressants and anxiolytics. This review presents the most important results from preclinical and clinical studies showing involvement of essential elements such as zinc, magnesium, lithium, iron, calcium and chromium in depression and anxiety. From these studies it is evident that different types of depression and anxiety respond to treatment at different receptors indicating that the underlying mechanisms are slightly different. Furthermore, administration of low dose antidepressants supplemented with an element is effective and can reduce unwanted side effects in different types of depression/anxiety.
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.
Glutamate and γ-aminobutyric acid (GABA) are the major excitatory and inhibitory neurotransmitter systems, respectively in the central nervous system (CNS). Dysregulation, in any of these or both, has been implicated in various CNS disorders. GABA acts via ionotropic (GABAA and GABAC receptor) and metabotropic (GABAB) receptor. Dysregulation of GABAergic signaling and alteration in GABAB receptor expression has been implicated in various CNS disorders. Clinically, baclofen-a GABAB receptor agonist, is available for the treatment of spasticity, dystonia etc. associated with various neurological disorders. Moreover, GABAB receptor ligands has also been suggested to be beneficial in various neuropsychiatric and neurodegenerative disorders. The present review is aimed to discuss the role of GABAB receptors and the possible outcomes of GABAB receptor modulation in CNS disorders.
The purpose of this study was to investigate the depression-like behavior performances of subclinical hypothyroidism (SCH) rat. SCH rat model was induced by hemi-thyroid electrocauterization, and the behavior performances were measured by sucrose preference test, force swimming test (FST), and tail suspension test (TST). SCH rat model was established successfully by hemi-thyroid electrocauterization. In the behavior tasks, SCH rats displayed depression-like behavior were indicated as a significant elevation of immobility time in both the TST and FST, though the sucrose preference was not significantly decreased. The index of left adrenal cortex in both SCH and clinical hypothyroidism (CH) group significantly increased, and many large lipid vacuoles were observed in the zona fasciculata cells. The serum corticosterone concentration and hypothalamic corticotropin-releasing hormone mRNA expression 2 h after behavior test was markedly up-regulated in CH rats, but not SCH rats, indicated that SCH induced a less impairment of HPA axis than CH did. The important finding of this study was that the concentration of hippocampal T3 was lower in SCH group than that of the sham group. Furthermore, the results of Pearson correlation test showed that the immobility behaviors in TST and FST were both negatively correlated with hippocampal T3 concentration. Taking together, our results indicated that SCH could result in depression-like behavior, accompanied with subtle hyperactivity of HPA axis. The reduced hippocampal T3 prior to the reduction of thyroid hormone in serum might be taken as an early sign of hippocampus impairment in the progression from SCH to CH.
In the present study we report the results of investigations into the serum copper levels in a clinical study of 19 patients with unipolar depression; 16 normal controls and three animal models of depression: chronic severe stress (CSS), chronic mild stress (CMS) and olfactory bulbectomy (OB) in rats. Unipolar depressed patients exhibit significantly higher serum copper levels than the appropriate controls (depression 1·15±0·17 mg/l; control 0·95±0·09 mg/l). There was no alteration in that value in rat models of depression. The data indicate that the increased serum copper level in the depressed patients might potentially be a marker of that illness. Moreover, animal models of human depression do not show changes in this marker. Copyright © 1999 John Wiley & Sons, Ltd.
The essential trace element selenium, as selenocysteine, is incorporated into antioxidant selenoproteins such as glutathione peroxidases (GPx), thioredoxin reductases (TrxR) and selenoprotein P (Sepp1). Although comparatively low in selenium content, the brain exhibits high priority for selenium supply and retention under conditions of dietary selenium deficiency. Liver-derived Sepp1 is the major transport protein in plasma to supply the brain with selenium, serving as a "survival factor" for neurons in culture. Sepp1 expression has also been detected within the brain. Presumably, astrocytes secrete Sepp1, which is subsequently taken up by neurons via the apolipoprotein E receptor 2 (ApoER2). Knock-out of Sepp1 or ApoER2 as well as neuron-specific ablation of selenoprotein biosynthesis results in neurological dysfunction in mice. Astrocytes, generally less vulnerable to oxidative stress than neurons, are capable of up-regulating the expression of antioxidant selenoproteins upon brain injury. Occurrence of neurological disorders has been reported occasionally in patients with inadequate nutritional selenium supply or a mutation in the gene encoding selenocysteine synthase, one of the enzymes involved in selenoprotein biosynthesis. In three large trials carried out among elderly persons, a low selenium status was associated with faster decline in cognitive functions and poor performance in tests assessing coordination and motor speed. Future research is required to better understand the role of selenium and selenoproteins in brain diseases including hepatic encephalopathy.
Background:
With increasing evidence that hydroperoxides are not only toxic but rather exert essential physiological functions, also hydroperoxide removing enzymes have to be re-viewed. In mammals, the peroxidases inter alia comprise the 8 glutathione peroxidases (GPx1-GPx8) so far identified.
Scope of the review:
Since GPxs have recently been reviewed under various aspects, we here focus on novel findings considering their diverse physiological roles exceeding an antioxidant activity.
Major conclusions:
GPxs are involved in balancing the H2O2 homeostasis in signalling cascades, e.g. in the insulin signalling pathway by GPx1; GPx2 plays a dual role in carcinogenesis depending on the mode of initiation and cancer stage; GPx3 is membrane associated possibly explaining a peroxidatic function despite low plasma concentrations of GSH; GPx4 has novel roles in the regulation of apoptosis and, together with GPx5, in male fertility. Functions of GPx6 are still unknown, and the proposed involvement of GPx7 and GPx8 in protein folding awaits elucidation.
General significance:
Collectively, selenium-containing GPxs (GPx1-4 and 6) as well as their non-selenium congeners (GPx5, 7 and 8) became key players in important biological contexts far beyond the detoxification of hydroperoxides. This article is part of a Special Issue entitled Cellular functions of glutathione.
The brain is an organ predisposed to oxidative/nitrosative stress. This is especially true in the case of aging as well as several neurodegenerative diseases. Under such circumstances, a decline in the normal antioxidant defense mechanisms leads to an increase in the vulnerability of the brain to the deleterious effects of oxidative damage. Highly reactive oxygen/nitrogen species damage lipids, proteins, and mitochondrial and neuronal genes. Unless antioxidant defenses react appropriately to damage inflicted by radicals, neurons may experience microalteration, microdysfunction, and degeneration. We reviewed how oxidative and nitrosative stresses contribute to the pathogenesis of depressive disorders and reviewed the clinical implications of various antioxidants as future targets for antidepressant treatment.
Vanadium is an ultratrace element, widely distributed in nature, yet with no presently known specific physiological function in mammals. The apparent role of vanadium in regulation of intracellular signaling, as a cofactor of enzymes essential in energy metabolism, and as a possible therapeutic agent in diabetes is of increasing interest as more and more research reports present evidence of vanadium's potentially unique biological function. In this mini-review, the author summarizes current knowledge of the bioinorganic chemistry of vanadium, the basic features of diabetes mellitus and its metabolic sequelae, and the in vitro and in vivo effects of both inorganic and organically-chelated vanadium compounds. Results of clinical trials to date, as well as kinetic studies of tissue uptake are covered. Examples of ways to enhance the positive effects of vanadium as an oral therapeutic adjunct in diabetic control, while minimizing potential toxicity, are compared with regard to desirable features and possible drawbacks.
Selenium-containing molecules show promising pharmacological properties. The antidepressant-like action of CH(3)SePh in the mouse forced swimming test (FST) and the tail suspension test (TST), models predictive of depressant activity, were investigated in this study. Moreover, the involvement of dopaminergic system in the antidepressant-like action of CH(3)SePh was studied. The behavioral results showed that CH(3)SePh significantly reduced the immobility time in the FST (25 and 50 mg/kg, intragastrically; i.g.) and the TST (50 mg/kg, i.g.), without accompanying changes in ambulation when assessed in the open-field test (OFT). The anti-immobility effect of CH(3)SePh (50 mg/kg, intragastrically; i.g.) in the FST was prevented by pretreatment of mice with haloperidol (0.2 mg/kg, i.p., a dopamine D(2) receptor antagonist), SCH 23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopamine D(2) and D(3) antagonist). These results suggest that CH(3)SePh produced an antidepressant-like action in the mouse FST and TST. The antidepressant-like action of CH(3)SePh, a simple selenium-containing molecule, seems most likely to be mediated through an interaction with the dopaminergic system.
N-Methyl-D-aspartate (NMDA) receptors mediate a wide range of important nervous system functions. Conversely, excessive NMDA receptor activity leads to cytotoxic calcium overload and neuronal damage in a wide variety of CNS disorders. It is well established that NMDA receptors are tightly regulated by a number of cell signalling pathways. Recently, it has been shown that NMDA receptor activity is modulated by cellular prion protein (PrP(C)) in a copper-dependent manner. Here we give an overview of the current state of knowledge concerning the novel concept of potent modulation of this receptor's kinetics by copper ions, and the interplay between NMDA receptors and PrP(C) in the context of neurological diseases such as Alzheimer's disease, epilepsy, pain and depression.
This paper reviews that cell-mediated-immune (CMI) activation and inflammation contribute to depressive symptoms, including anhedonia; anxiety-like behaviors; fatigue and somatic symptoms, e.g. illness behavior or malaise; and mild cognitive impairment (MCI). These effects are in part mediated by increased levels of pro-inflammatory cytokines (PICs), e.g. interleukin-1 (IL-1), IL-6 and tumor necrosis factor (TNF)α, and Th-1-derived cytokines, such as IL-2 and interferon (IFN)γ. Moreover, new pathways, i.e. concomitants and sequels of CMI activation and inflammation, were detected in depression: (1) Induction of indoleamine 2,3-dioxygenase (IDO) by IFNγ and some PICs is associated with depleted plasma tryptophan, which may interfere with brain 5-HT synthesis, and increased production of anxiogenic and depressogenic tryptophan catabolites. (2) Increased bacterial translocation may cause depression-like behaviors by activating the cytokine network, oxidative and nitrosative stress (O&NS) pathways and IDO. (3) Induction of O&NS causes damage to membrane ω3 PUFAs, functional proteins, DNA and mitochondria, and autoimmune responses directed against intracellular molecules that may cause dysfunctions in intracellular signaling. (4) Decreased levels of ω3 PUFAs and antioxidants, such as coenzyme Q10, glutathione peroxidase or zinc, are associated with an increased inflammatory potential; more oxidative damage; the onset of specific symptoms; and changes in the expression or functions of brain 5-HT and N-methyl-d-aspartate receptors. (5) All abovementioned factors cause neuroprogression, that is a combination of neurodegeneration, neuronal apoptosis, and lowered neurogenesis and neuroplasticity. It is concluded that depression may be the consequence of a complex interplay between CMI activation and inflammation and their sequels/concomitants which all together cause neuroprogression that further shapes the depression phenotype. Future research should employ high throughput technologies to collect genetic and gene expression and protein data from patients with depression and analyze these data by means of systems biology methods to define the dynamic interactions between the different cell signaling networks and O&NS pathways that cause depression.
The objective of the present study was to evaluate motor function in order to assess the effects of long-term, low-level environmental manganese (Mn) exposure in residents of an Ohio community where a large ferro- and silico-Mn smelter has been active for more than 50 years.
One hundred residents from the Mn-exposed Ohio community were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS), a postural sway test, and a comprehensive questionnaire exploring demographics and general health. The results were compared to those of 90 residents from a demographically similar comparison town in Ohio. Mn exposure was assessed using modeled airborne Mn and blood Mn (Mn-B). The UPDRS was employed to evaluate parkinsonian motor features. Postural sway was measured using a CATSYS 2000 (Danish Product Development).
No significant difference between the exposed and comparison groups was evident as to Mn-B, demographics or major health outcomes. The risk of abnormal UPDRS performance using "Motor and Bradykinesia" criteria was increased in the Mn-exposed group after adjustment for potential confounders such as the presence of other neurotoxic metals, factors affecting susceptibility to Mn, potential factors influencing motor performance, and other possible demographic confounders. No participant was diagnosed with clinical manganism by neurological examination. After adjustment for various potential confounders, the Mn-exposed group showed significantly higher postural sway scores under eyes-open conditions than the comparison group.
Subclinical findings on the UPDRS and postural sway in the Mn-exposed group may possibly reflect early subtle effects of chronic low-level Mn exposure. However, the cross-sectional study design, the small to medium effect sizes, and the little biological plausibility are limiting the possibility of a causal relationship between the environmental Mn-air exposure and the early subclinical neurotoxic effects observed.
Half a century after the first formulation of the monoamine hypothesis, compelling evidence implies that long-term changes in an array of brain areas and circuits mediating complex cognitive-emotional behaviors represent the biological underpinnings of mood/anxiety disorders. A large number of clinical studies suggest that pathophysiology is associated with dysfunction of the predominant glutamatergic system, malfunction in the mechanisms regulating clearance and metabolism of glutamate, and cytoarchitectural/morphological maladaptive changes in a number of brain areas mediating cognitive-emotional behaviors. Concurrently, a wealth of data from animal models have shown that different types of environmental stress enhance glutamate release/transmission in limbic/cortical areas and exert powerful structural effects, inducing dendritic remodeling, reduction of synapses and possibly volumetric reductions resembling those observed in depressed patients. Because a vast majority of neurons and synapses in these areas and circuits use glutamate as neurotransmitter, it would be limiting to maintain that glutamate is in some way 'involved' in mood/anxiety disorders; rather it should be recognized that the glutamatergic system is a primary mediator of psychiatric pathology and, potentially, also a final common pathway for the therapeutic action of antidepressant agents. A paradigm shift from a monoamine hypothesis of depression to a neuroplasticity hypothesis focused on glutamate may represent a substantial advancement in the working hypothesis that drives research for new drugs and therapies. Importantly, despite the availability of multiple classes of drugs with monoamine-based mechanisms of action, there remains a large percentage of patients who fail to achieve a sustained remission of depressive symptoms. The unmet need for improved pharmacotherapies for treatment-resistant depression means there is a large space for the development of new compounds with novel mechanisms of action such as glutamate transmission and related pathways. This article is part of a Special Issue entitled 'Anxiety and Depression'.
We examined the association between non-occupational exposure to Mn and cognitive functions. The study was carried out in a mining district located in Hidalgo State, Mexico, with 288 adults. Air and blood Mn concentrations were determined, and neuropsychological tests were administered to explore cognitive functions and depression. Blood Mn mean was 9.5 ± 4.14 μg/L. A total of 73% of the study group were in contact with air Mn levels that surpassed the EPA recommended guideline level for non-occupational environments (0.05 μg/m(3)). Air Mn concentration was associated as a risk factor for attention impairment (OR=1.75, 95% CI: 1.01-3.06). Blood Mn levels were not associated to any of the measured outcomes. The main finding of this study is the presence of attention impairments associated to high levels of air Mn exposure. These results confirm previous studies, in which cognitive impairment is reported for exposed population.
In order to find multifunction anticancer complexes, three Mn(II) complexes of N-substituted di(2-pyridylmethyl)amine were characterized and used as agents to interfere with the functions of mitochondria and the metabolite of O(2) in cancer cells. It was found that carboxylate-bridged dimanganese(II) systems are good models of catalase and exhibit good inhibition of the proliferation of U251 and HeLa cells. The inhibiting activity of these manganese(II) complexes on the tumor cells in vitro was related to their disproportionating H(2)O(2) activity. The reaction of carboxylate-bridged dimanganese Mn(II) complex with H(2)O(2) forms a stable Mn(III)-(μ-O)(2)-Mn(IV) complex. Extensive experimental results show that chloride-bridged dimanganese(II) complexes could inhibit the swelling of calcium(II) overloaded mitochondria, and carboxylate-bridged manganese(II) complexes enhance the swelling of calcium(II) overloaded mitochondria. These results indicate that the interactions between Mn(II) complexes of N-substituted di(picolyl)amine and mitochondria are influenced by the structure and conformation of the complexes. Mn(II) complexes of N-substituted di(picolyl)amine could be developed as multifunctional anticancer complexes to interfere with the absorption of calcium(II) in mitochondria and the metabolite of O(2) through the H(2)O(2) or ROS involved signaling induced apoptosis of cancer cells.
Serotonergic and opioid systems have been implicated in major depression and in the action mechanism of antidepressants. The organoselenium compound m-trifluoromethyl-diphenyl diselenide (m-CF(3)-PhSe)(2) shows antioxidant and anxiolytic activities and is a selective inhibitor of monoamine oxidase A activity. The present study was designed to investigate the antidepressant-like effect of (m-CF(3)-PhSe)(2) in female mice, employing the forced swimming test. The involvement of the serotonergic and opioid systems in the antidepressant-like effect of (m-CF(3)-PhSe)(2) was appraised. (m-CF(3)-PhSe)(2) at doses of 50 and 100mg/kg (p.o.) exhibited antidepressant-like action in the forced swimming test. The effect of (m-CF(3)-PhSe)(2) (50mg/kg p.o.) was prevented by pretreatment of mice with WAY100635 (0.1mg/kg, s.c. a selective 5-HT(1A) receptor antagonist), ritanserin (4 mg/kg, i.p., a non-selective 5HT(2A/2C) receptor antagonist), ondansetron (1mg/kg, i.p., a selective 5-HT(3) receptor antagonist) and naloxone (1mg/kg, i.p., a non-selective antagonist of opioid receptors). These results suggest that (m-CF(3)-PhSe)(2) produced an antidepressant-like effect in the mouse forced swimming test and this effect seems most likely to be mediated through an interaction with serotonergic and opioid systems.
Anxiety disorders, depression, and alcohol use disorder are common neuropsychiatric diseases that often occur together. Oxidative stress has been suggested to contribute to their etiology. Oxidative stress is a consequence of either increased generation of reactive oxygen species or impaired enzymatic or non-enzymatic defense against it. When excessive it leads to damage of all major classes of macromolecules, and therefore affects several fundamentally important cellular functions. Consequences that are especially detrimental to the proper functioning of the brain include mitochondrial dysfunction, altered neuronal signaling, and inhibition of neurogenesis. Each of these can further contribute to increased oxidative stress, leading to additional burden to the brain. In this review, we will provide an overview of recent work on oxidative stress markers in human patients with anxiety, depressive, or alcohol use disorders, and in relevant animal models. In addition, putative oxidative stress-related mechanisms important for neuropsychiatric diseases are discussed. Despite the considerable interest this field has obtained, the detailed mechanisms that link oxidative stress to the pathogenesis of neuropsychiatric diseases remain largely unknown. Since this pathway may be amenable to pharmacological intervention, further studies are warranted.
Chronic manganese (Mn) exposure often leads to impairments in fine motor and cognitive functions, particularly memory. However, the neural correlates of Mn-induced alterations in memory remain unclear. In the present study, we performed functional MRI (fMRI) with 2-back memory tests to assess the neural correlates of Mn-induced memory impairment in response to subclinical dysfunction in the working memory networks in welders exposed to Mn for extended periods of time. Within-group and between-group analyses revealed that brain activity in working memory networks was increased in welders with chronic Mn exposure during the 2-back verbal working memory task compared to healthy control individuals. Therefore, our fMRI findings indicate that welders might require more neural resources in working memory networks to compensate for subtle deficits in working memory and altered working memory processes, even if they performed the tasks at the same level as healthy control individuals.
This paper reviews the body of evidence that major depression is accompanied by a decreased antioxidant status and by induction of oxidative and nitrosative (IO&NS) pathways. Major depression is characterized by significantly lower plasma concentrations of a number of key antioxidants, such as vitamin E, zinc and coenzyme Q10, and a lowered total antioxidant status. Lowered antioxidant enzyme activity, e.g. glutathione peroxidase (GPX), is another hallmark of depression. The abovementioned lowered antioxidant capacity may impair protection against reactive oxygen species (ROS), causing damage to fatty acids, proteins and DNA by oxidative and nitrosative stress (O&NS). Increased ROS in depression is demonstrated by increased levels of plasma peroxides and xanthine oxidase. Damage caused by O&NS is shown by increased levels of malondialdehyde (MDA), a by-product of polyunsaturated fatty acid peroxidation and arachidonic acid; and increased 8-hydroxy-2-deoxyguanosine, indicating oxidative DNA damage. There is also evidence in major depression, that O&NS may have changed inactive autoepitopes to neoantigens, which have acquired immunogenicity and serve as triggers to bypass immunological tolerance, causing (auto)immune responses. Thus, depression is accompanied by increased levels of plasma IgG antibodies against oxidized LDL; and increased IgM-mediated immune responses against membrane fatty acids, like phosphatidyl inositol (Pi); oleic, palmitic, and myristic acid; and NO modified amino-acids, e.g. NO-tyrosine, NO-tryptophan and NO-arginine; and NO-albumin. There is a significant association between depression and polymorphisms in O&NS genes, like manganese superoxide dismutase, catalase, and myeloperoxidase. Animal models of depression very consistently show lowered antioxidant defences and activated O&NS pathways in the peripheral blood and the brain. In animal models of depression, antidepressants consistently increase lowered antioxidant levels and normalize the damage caused by O&NS processes. Antioxidants, such as N-acetyl-cysteine, compounds that mimic GPX activity, and zinc exhibit antidepressive effects. This paper reviews the pathways by which lowered antioxidants and O&NS may contribute to depression, and the (neuro)degenerative processes that accompany that illness. It is concluded that aberrations in O&NS pathways are--together with the inflammatory processes--key components of depression. All in all, the results suggest that depression belongs to the spectrum of (neuro)degenerative disorders.
According to new hypothesis, depression is characterized by decreased neurogenesis and enhanced neurodegeneration which, in part, may be caused by inflammatory processes. There is much evidence indicating that depression, age-related changes often associated with impaired brain function and cognitive performances or neurodegenerative processes could be related to dysfunctions affecting the zinc ion availability. Clinical studies revealed that depression is accompanied by serum hypozincemia, which can be normalized by successful antidepressant treatment. In patients with major depression, a low zinc serum level was correlated with an increase in the activation of markers of the immune system, suggesting that this effect may result in part from a depression-related alteration in the immune-inflammatory system. Moreover, a preliminary clinical study demonstrated the benefit of zinc supplementation in antidepressant therapy in both treatment non-resistant and resistant patients. In the preclinical study, the antidepressant activity of zinc was observed in the majority of rodent tests and models of depression and revealed a causative role for zinc deficiency in the induction of depressive-like symptoms, the reduction of neurogenesis and neuronal survival or impaired learning and memory ability. This paper provides an overview of the clinical and experimental evidence that implicates the role of zinc in the pathophysiology and therapy of depression within the context of the inflammatory and neurodegenerative hypothesis of this disease.
The present study investigated a possible antidepressant-like activity of bis selenide using two predictive tests for antidepressant effect on rodents: the forced swimming test (FST) and the tail suspension test (TST). Bis selenide (0.5-5 mg/kg, p.o.) decreased the immobility time in the mouse FST and TST. The anti-immobility effect of bis selenide (1 mg/kg, p.o.) in the TST was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis), ketanserin (1 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), and ondasentron (1 mg/kg, i.p., a 5-HT(3) receptor antagonist). Pretreatment of mice with prazosin (1 mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a beta-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D(2) receptor antagonist), or WAY 100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) did not block the antidepressant-like effect of bis selenide (1 mg/kg, p.o.) in the TST. Administration of bis selenide (0.1 mg/kg, p.o.) and fluoxetine (1 mg/kg), at subeffective doses, produced an antidepressant-like effect in the TST. Bis selenide did not alter Na(+) K(+) ATPase, MAO-A and MAO-B activities in whole brains of mice. Bis selenide produced an antidepressant-like effect in the mouse TST and FST, which may be related to the serotonergic system (5-HT(2A/2C) and 5-HT(3) receptors).