Alterations of Bio-elements, Oxidative, and Inflammatory Status in the Zinc Deficiency Model in Rats
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Our previous study showed that dietary zinc restriction induces depression-like behavior with concomitant up-regulation of the N-methyl-d-aspartate receptor (NMDAR). Because metal ions, oxidative stress, and inflammation are involved in depression/NMDAR function, in the present study, bio-elements (zinc, copper, iron, magnesium, and calcium), oxidative (thiobarbituric acid-reactive substances; protein carbonyl content), and inflammatory (IL-1α, IL-1β) factors were measured in serum, hippocampus (Hp), and prefrontal cortex (PFC) of male Sprague–Dawley rats subjected to a zinc-adequate (ZnA) (50 mg Zn/kg) or a zinc-deficient (ZnD) (3 mg Zn/kg) diet for 4 or 6 weeks. Both periods of dietary zinc restriction reduced serum zinc and increased serum iron levels. At 4 weeks, lowered zinc level in the PFC and Hp as well as lowered iron level in the PFC of the ZnD rats was observed. At 6 weeks, however, iron level was increased in the PFC of these rats. Although at 6 weeks zinc level in the PFC did not differ between the ZnA and ZnD rats, extracellular zinc concentration after 100 mM KCl stimulation was reduced in the PFC of the ZnD rats and was accompanied by increased extracellular iron and glutamate levels (as measured by the in vivo microdialysis). The examined oxidative and inflammatory parameters were generally enhanced in the tissue of the ZnD animals. The obtained data suggest dynamic redistribution of bio-elements and enhancement of oxidative/inflammatory parameters after dietary zinc restriction, which may have a link with depression-like behavior/NMDAR function/neurodegeneration.
KeywordsZinc deficiency Zinc Iron Oxidation Inflammation Glutamate
Zinc is the second (after iron) most prevalent trace element in the human body. Its importance has been demonstrated in many physiological processes. Zinc is crucial for normal development and function of cell-mediated immunity. Zinc deficiency primarily has an impact on T cells function and affects Th1 and (to a lesser extend) Th2 cytokines production (Bonaventura et al. 2015). Zinc deficiency influences also production of interleukin (IL)-1β by macrophages (Bonaventura et al. 2015). IL-1β plays a key role in the damaging inflammatory response in a variety of diseases (Dinarello et al. 2012). Altered production of cytokines during zinc deficiency may lead to inflammation, e.g., zinc depletion from macrophages induces IL-1β secretion and activates NLRP3 inflammasome (Summersgill et al. 2014). Moreover, zinc which is (in contrast to iron) redox inactive metal, serves as an important component of antioxidant defense. It contributes to maintaining redox balance through different mechanisms, e.g., is an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a co-factor of superoxide dismutase (SOD), and induces the generation of cysteine-rich metallothionein, which acts as scavenger of oxidants (Oteiza 2012; Prasad 2014). In contrast, zinc deficiency is associated with increased oxidative stress markers (Prasad 2014).
There is evidence for the involvement of inflammation and oxidative stress in depression (Leonard and Maes 2012; Maes et al. 2012a; Moylan et al. 2014). Depressed patients exhibit increased levels of pro-inflammatory cytokines, e.g., IL-1β, whereas administration of these cytokines (including IL-1β) induces depression-like behavior in experimental animals (Maes et al. 2012a). Both preclinical and clinical data indicate also that depression is accompanied by increased lipid, protein, and DNA peroxidation (Siwek et al. 2013a). Oxidative stress and inflammation may contribute to depression through effects on the glutamatergic system (Marsden 2011). Pro-inflammatory cytokines, such as IL-1β, and reactive oxygen species can enhance the activity of indoleamine 2,3-dioxygenase (IDO), an enzyme which catabolizes tryptophan, the primary precursor of serotonin, into kynurenine, which is further broken down into kynurenic acid and quinolinic acid. While kynurenic acid is the ionotropic glutamate N-methyl-d-aspartate receptor (NMDAR) endogenous antagonist, quinolinic acid is a strong agonist of NMDAR (Leonard and Maes 2012; Maes et al. 2012a; Felger and Lotrich 2013; Myint and Kim 2014). Therefore, inflammation and oxidative stress via activation of IDO pathway may lead to abnormal regulation of glutamate transmission through NMDAR, a phenomenon implicated in the pathophysiology of depression (Sanacora et al. 2012; Ghasemi et al. 2014). Moreover, a mixture of pro-inflammatory cytokines, containing IL-1β, was shown to increase glutamate release (Ida et al. 2008). This observation provides another route by which cytokines may influence the glutamatergic system and conceivably lead to depression.
In addition to oxidative/inflammatory status, NMDAR is a subject to modulation by a number of agents including metal ions (Szewczyk et al. 2012). At resting membrane potential magnesium blocks NMDAR channel, prohibiting calcium influx. Depletion of magnesium block during depolarization allows calcium to enter the postsynaptic neuron. Under certain conditions, magnesium and calcium can block/permeate the channel (Mayer and Westbrook 1987). Zinc is a potent inhibitor of NMDAR (Paoletti et al. 2009). Also copper and iron were found to inhibit this receptor (Vlachova et al. 1996; Nakamichi et al. 2002; Stys et al. 2012). Of note, relationships between altered homeostasis of bio-elements as well as increased oxidative/inflammatory status and NMDAR function were implicated in depressive disorders (Marsden 2011; Leonard and Maes 2012; Serefko et al. 2013; Mlyniec et al. 2014a, 2015).
Recently, a low dietary zinc intake emerged as a risk factor for depression (Vashum et al. 2014). Zinc deficiency is regarded as a public health problem (Jurowski et al. 2014). It induces psychopathological symptoms that correspond to depression symptoms (Szewczyk 2013; Hagmeyer et al. 2015). We have previously shown that depression-like behavior induced by dietary zinc restriction in rats is associated with up-regulation of NMDAR in brain regions (hippocampus, Hp and prefrontal cortex, PFC) (Doboszewska et al. 2015). Because alterations of metals as well as oxidative/inflammatory status may be linked to abnormal NMDAR function and depression, here we measured bio-elements (zinc, copper, calcium, magnesium, and iron) and oxidation/inflammation parameters (thiobarbituric acid-reactive substances (TBARS), protein carbonyl content (PCC), IL-1α and IL-1β) in serum, the Hp and PFC of rats following a zinc-deficient (ZnD) diet administration. Moreover, extracellular zinc, iron, and glutamate levels were measured.
Materials and Methods
Animals and Diet
The amounts of bio-elements: zinc (Zn), copper (Cu), calcium (Ca), magnesium (Mg), and iron (Fe) in the zinc-adequate (ZnA) and zinc-deficient (ZnD) diets
Following 4 or 6 weeks of the ZnA or ZnD diet, the rats were killed by rapid decapitation; their brains were rapidly dissected and immersed in cooled (2–8 °C) 0.9 % sodium chloride (0.9 % NaCl) solution. Complete hippocampus (Hp) (dorsal and ventral) and prefrontal cortex (PFC) were dissected on a cold plate, immediately frozen on dry ice and stored at −80 °C until further analysis. The trunk blood was collected into tubes without anti-coagulant. The blood was allowed to clot for 15–20 min and was centrifuged for 30 min at 1800 rpm at 4 °C. The resulting supernatant (serum) was quickly pipetted into tubes that were stored at −80 °C until analysis.
Total Reflection X-Ray Fluorescence
Zinc, copper, and iron concentrations were measured in serum, the Hp, and PFC using total reflection X-ray fluorescence (TXRF) method, as described previously (Opoka et al. 2010). The Hp and PFC were weighted and digested in 100–300 μL (depending on the mass of the sample) of the concentrated nitric acid. As an internal standard, selenium standard was added, so that the final concentration was 5 mg/l for serum and 30–50 mg/kg for brain tissues. From the resulting solutions, 5 μl was pipetted on reflectors made of clean glass used for TXRF analysis. Concentrated nitric acid, suprapur quality, additionally cleaned by subboiling distillation procedure, was purchased from Merck (Darmstadt, Germany). Selenium standard, 1000 mg/l selenium in nitric acid, was purchased from Sigma-Aldrich (Saint Louis, Missouri, United States). NANOHUNTER TXRF Spectrometer from Rigaku (Japan) was used. Mo X-ray tube (50 kV, 0.8 mA) was applied. The results are presented in mg/l (for serum) or mg/kg wet weight of brain tissue.
Flame Atomic Absorption Spectroscopy
Calcium and magnesium concentrations were measured in serum, the Hp, and PFC using flame atomic absorption spectroscopy, as published previously (Kopanski et al. 2000). The Hp and PFC were weighted (0.018–0.198 g) and digested in 1.5 ml of concentrated nitric acid (SupraPur—Merck). Brain tissue samples were mineralized using water bath for 5 h at 80 °C. After cooling the samples, demineralized water was added to the total volume of 5 ml. Magnesium was measured at wavelength of 285.2 nm and calcium at 422.7 nm, both with deuterium (D2) background correction. The results are presented in mg/l (for serum) or mg/kg wet weight of brain tissue.
Endocrine, Oxidative Stress, and Inflammation Assays
Serum corticosterone (CORT), oxidative, and inflammatory parameters were measured using commercially available kits, according to the manufacturer’s protocols. Serum CORT concentration was determined by enzyme-linked immunoassay (ELISA) using Corticosterone Rat/Mouse Elisa Kit (Demeditec Diagnostics GmbH, Kiel, Germany). The levels of lipid and protein peroxidation were measured in serum, the Hp, and PFC using thiobarbituric acid-reactive substances (TBARS) Assay kit or Protein Carbonyl Colorimetric Assay Kit (Cayman Chemical, Ann Arbor, MI, USA), respectively. To determine lipid peroxidation, the malondialdehyde (MDA)-thiobarbituric acid (TBA) adduct was measured fluorometrically at an excitation wavelength of 530 nm and an emission wavelength of 550 nm. The levels of IL-1α and IL-1β were measured in serum, the Hp, and PFC using Rat IL-1α or Il-1β ELISA kit (RayBiotech, Norcross, GA, USA).
In Vivo Microdialysis
Following 6 weeks of the ZnA or ZnD diet, in vivo microdialysis was performed. Five days before the microdialysis, the rats were anesthetized with chloral hydrate (400 mg/kg) and individually placed in a stereotaxic apparatus (David Kopf Instruments, Tujunga, CA, USA). Their skull was exposed, a burr hole was drilled, and a guide cannula (AgnTho’s, Sweden) was implanted in the rat PFC with coordinates: AP = + 2.8; L = + 0.8; V = −2.4, based on the brain atlas (Paxinos and Watson 1998). The guide cannula was secured with dental cement (Dentalon; Heraeus-Kulzer GmbH, Germany) and a screw. After the surgical operation, each rat was housed individually. Five days after implantation of the guide cannula, a microdialysis probe (3 mm, AgnTho’s, Sweden) was inserted into the PFC through the guide cannula. The microdialysis probe was connected with the microdialysis pump, which infused an artificial cerebrospinal fluid (aCSF) containing 147 mM NaCl, 4.0 mM KCl, 1.0 mM MgCl2, 2.2 CaCl2, and pH = 7.4 with a flow of 2 μl/min. After a 2 h washout period, the fractions were collected for 2 h (to determine the basal extracellular concentrations of zinc, iron, and glutamate). Then, the PFC was perfused with 100 mM KCl in Ringer’s solution for 40 min, and the fractions were collected every 20 min (to determine the extracellular concentrations of zinc, iron, and glutamate after depolarization).
Analytical Procedures: Microdialysates
The extracellular concentrations of zinc and iron were measured by TXRF method using selenium standard, as described above. The extracellular concentration of glutamate was measured after derivatization with OPA/sulfite reagent. OPA/sulfite glutamate derivative was analyzed using high-performance liquid chromatography (HPLC) method with electrochemical detection. Chromatography was performed using Dionex P580 pump (USA), an LC 4B amperometric detector with a cross-flow detector cell (BAS, IN, USA), and a HR-80 column (4 × 80 mm, 3 µm; ESA, USA). The mobile phase consisted of 0.1 M phosphate buffer with pH 3.6 and 5 % methanol. The flow rate was 0.8 ml/min, and the applied potential of 3-mm glassy carbon electrode was +650 mV at a sensitivity of 5 nA/V. Glutamate derivative concentration was calculated by comparing its peak area with respective standard and was processed by Chromax 2005 (Pol-Lab, Warsaw, Poland) software run on a personal computer.
Data were analyzed using unpaired, two-tailed Student’s t test or Repeated Measures ANOVA followed by a Bonferroni post hoc test. All results are presented as the mean ± SEM. P < 0.05 was considered statistically significant with 95 % confidence (Prism ver. 4, GraphPad Software, San Diego, CA, USA).
The Effects of Dietary Zinc Restriction on Body Weight
The Effects of a 4-week Dietary Zinc Restriction on Zn, Cu, Ca, Mg, Fe, CORT, TBARS, and PCC Levels in Serum
The Effects of a 4-week Dietary Zinc Restriction on Zn, Cu, Ca, Mg, Fe, TBARS, PCC, IL-1α, and IL-1β Levels in the Hp and PFC
The Effects of a 6-week Dietary Zinc Restriction on Zn, Cu, Ca, Mg, Fe, CORT, and TBARS Levels in Serum
The Effects of a 6-week Dietary Zinc Restriction on Zn, Fe, and TBARS Levels in the Hp and PFC
The Effects of a 6-week Dietary Zinc Restriction on Extracellular Zn, Fe, and Glutamate Levels in the PFC
We have previously shown that 4 or 6 weeks of the ZnD diet induces depression-like behavior with concomitant alterations within NMDAR signaling pathway (Doboszewska et al. 2015). In the present study, we measured bio-elements and oxidative/inflammatory parameters, which may be associated with depression/NMDAR function, in the ZnD rats.
Summary of previous findings on the zinc deficiency model in rats
Increased immobility time in the forced swim test (FST)
Reduction of social behavior
Increased immobility time in the FST
Reduction of social behavior
Hp: ↑ GluN2A, ↑GluN2B, ↓p-CREB, ↓BDNF
Hp: ↑ GluN2A, ↑GluN2B, ↓p-CREB, ↓BDNF
PFC: ↔GluN2A, ↔GluN2B, ↔p-CREB, ↔BDNF
PFC: ↑ GluN2A, ↔GluN2B, ↓p-CREB, ↓BDNF
Decreased hippocampal zinc level corresponding to depression-like behavior was found in rats exposed to psychological stress (Dou et al. 2014) and was associated with increased serum CORT concentration (Tao et al. 2013). Increased serum CORT was also demonstrated following zinc restriction (the present data, Watanabe et al. 1992; Chu et al. 2003; Takeda et al. 2007, 2008a, b, Takeda et al. 2012, Mlyniec et al. 2012). Thus, the ZnD diet induces changes in hippocampal zinc and serum CORT similar to those observed after exposure to stress, which is considered as a precipitant of depression.
The lack of differences between zinc level in the Hp or PFC of the ZnD and control rats after prolonged (a 6-week) deprivation suggests dynamic redistribution of the bio-element during its dietary regimen. It should be noted, however, that at 6 weeks of the ZnD diet, a concomitant decrease in evoked zinc release in the PFC was observed, which was accompanied by increased glutamate release (as measured by the in vivo microdialysis). Because we have previously found significantly increased level of NMDAR GluN2A protein in the PFC of rats at 6 weeks of zinc restriction (Doboszewska et al. 2015) (Table 2) (which indicates that a 6-week ZnD diet may alter the function of NMDAR in the PFC), our previous and present observations suggest that zinc deficiency may enhance glutamate signaling through NMDAR.
Reductions in protein expression of zinc transporter 3 (ZnT3) in Brodmann area 9 (which is a part of the frontal cortex) were shown to be significantly associated with elevated depression scores in patients with dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), and Alzheimer disease (AD) (Whitfield et al. 2015). Because in ZnT3 knockouts, synaptic zinc is undetectable (Cole et al. 1999), these data provide evidence for the role of decreased synaptic zinc in depression. Therefore, decreased evoked zinc release in the PFC of the ZnD rats, suggesting decreased level of synaptic zinc, may be linked to depression-like behavior in the zinc deficiency paradigm.
In the present study, the 4-week ZnD diet reduced iron content of the PFC, whereas an increase in iron content of the PFC was observed after the 6-week ZnD diet. Iron deficiency may lead to abnormal mood and behavior (Kim and Wessling-Resnick. 2014). On the other hand, iron progressively accumulates in the brain with aging (Bilgic et al. 2012; Ramos et al. 2014) and its accumulation in the brain has been implicated in the etiology of numerous neurodegenerative disorders (Schipper 2012; Zheng and Monnot 2012). There is evidence that depression is accompanied by a progressive process of neurodegeneration (Szewczyk et al. 2011; Maes et al. 2012b; Smaga et al. 2014). Magnetic resonance imaging studies in elderly depressed patients have shown that an older age of onset and a greater severity of depression are associated with increased iron deposition in specific brain regions (Steffens et al. 1998). Moreover, exposure to psychological stress was found to increase iron level in the cortex and Hp (Wang et al. 2008; Yu et al. 2011), whereas zinc supplementation was found to decrease iron deposition in the cortex and Hp induced by psychological stress (Li et al. 2012). Thus, the increase in iron level in the brain may be a common effect of prolonged zinc deficiency, psychological stress, and depression.
As mentioned above, we have previously found significantly increased level of NMDAR GluN2A protein in the PFC of rats after the 6-week ZnD diet; however, no differences in the levels of NMDAR GluN2A or GluN2B proteins were observed in the PFC between the ZnD and control animals after the 4-week ZnD diet (Doboszewska et al. 2015) (Table 2). These data, together with the present data concerning increased glutamate release after 6 weeks of the ZnD diet administration, indicate that prolonged (6 weeks) zinc restriction may lead to activation of NMDAR in the PFC. It has been demonstrated that the stimulation of NMDAR induces iron uptake (Cheah et al. 2006). This mechanism may explain iron accumulation in the PFC of rats after 6 weeks, but not after 4 weeks of zinc deprivation. Moreover, at 6 weeks, but not at 4 weeks, we found decreased brain-derived neurotrophic factor (BDNF) protein expression in the PFC of the ZnD rats (Doboszewska et al. 2015) (Table 2). BDNF can ameliorate iron accumulation in neurons (Zhang et al. 2014). Thus, increased iron level in the PFC of rats at 6 weeks might result from decreased level of BDNF.
In addition to decreased zinc release, increased evoked iron release was observed in the PFC of the ZnD rats. Iron transporter ferroportin was found to be expressed in synaptic vesicles (Wu et al. 2004); however, iron homeostasis in the brain has not been clearly defined (Ward et al. 2014). Presumably, the presence of iron in extracellular space may induce oxidative stress.
Moreover, both the 4- and the 6-week ZnD diets lowered serum zinc and increased serum iron concentrations. Data concerning the relationship between depression and serum iron concentration are inconsistent (Maes et al. 1996; Rybka et al. 2013). In contrast, decreased serum zinc level associated with depression has been repeatedly observed (Siwek et al. 2013b) and has been demonstrated through a meta-analysis of clinical studies (Swardfager et al. 2013). The altered levels of magnesium and calcium in serum following zinc depletion suggest redistribution of these elements after dietary zinc regimen, although peripheral alterations were in the present study not accompanied by central alterations. In this study, the 4-week ZnD diet increased serum magnesium concentration. In animal models of depression based on stress exposure and in olfactory bulbectomy model, no differences in serum magnesium levels were demonstrated (Zieba et al. 2000); however, higher serum magnesium concentrations have been reported in depressed patients, compared to healthy controls, yet the data are not consistent (Serefko et al. 2013). Lowered level of magnesium in the Hp was recently shown in post-mortem study of suicide subjects (Sowa-Kucma et al. 2013).
Also, data regarding the relationship between serum copper concentration and depression are not consistent, but higher serum copper levels in patients suffering from depression have been reported (Manser et al. 1989; Schlegel-Zawadzka et al. 1999). In the present study, we did not observe differences in copper levels either in serum or brain tissues. Likewise, the study of zinc deficiency in mice, which demonstrated depression-like behavior and decreased serum zinc level, did not show differences in serum copper levels (Mlyniec et al. 2014b).
Associations between the increase in the lipid (TBARS) and protein (PCC) oxidation, pro-inflammatory cytokine (IL-1α and β) levels, decrease of zinc, and increase of iron levels have been noted previously in in vivo (Arruda et al. 2013; Mehrpouya et al. 2015) and in vitro/cell culture (Tate et al. 1999; Wessels et al. 2013) experiments. Moreover, a link of depression-like behavior with the enhancement of oxidative stress/pro-inflammatory status and with iron content in other experimental models and in clinical studies (Wayhs et al. 2010; Lopresti et al. 2014; Spanemberg et al. 2014; Mehrpouya et al. 2015; Tsai and Huang. 2015) was demonstrated. Increased oxidative stress as well as pro-inflammatory cytokines may lead to NMDAR activation (Leonard and Maes. 2012; Maes et al. 2012a; Felger and Lotrich 2013; Myint and Kim 2014). Furthermore, a mixture of pro-inflammatory cytokines, containing IL-1β, was shown to increase glutamate release (Ida et al. 2008), whereas administration of IL-1β induced depression-like behavior (Maes et al. 2012a). Thus, increased levels of pro-inflammatory cytokines and enhancement of oxidation in the Hp and PFC of the ZnD rats may contribute to increased release of glutamate, NMDAR activation, and depression-like behavior.
Dietary zinc restriction induces peripheral and central alterations of bio-elements (namely zinc and iron) and enhances oxidative damage and pro-inflammatory status. These alterations share some similarities to those observed after exposure to stress and in depression, which further highlights that zinc deficiency [recently proposed as a model of depression (Whittle et al. 2009; Mlyniec et al. 2013; Doboszewska et al. 2015)] and depression may share a common pathophysiology. The changes observed in the present study may have a link to depression-like behavior in the zinc deficiency paradigm and may lead to/result from enhanced glutamate transmission through NMDAR.
The study was partially supported by the project Interdisciplinary PhD Studies “Molecular sciences for medicine” (co-financed by the European Social Fund within the Human Capital Operational Programme), Grant POIG.01.01.02-12-004/09-00, and Statutory Activity of the Institute of Pharmacology PAS and Jagiellonian University Medical College in Kraków.
Compliance with Ethical Standards
The study was funded by the project Interdisciplinary PhD Studies “Molecular sciences for medicine” (co-financed by the European Social Fund within the Human Capital Operational Programme), Grant POIG.01.01.02-12-004/09-00, and Statutory Activity of the Institute of Pharmacology PAS and Jagiellonian University Medical College in Kraków.
Conflict of Interest
The authors declare that they have no conflict of interest.
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