Alterations in serum and brain trace element levels after antidepressant treatment. Part II. Copper

We have studied the effect of chronic treatment with imipramine, citalopram, and electroconvulsive shock (ECS) on serum and brain copper levels in rats. Chronic treatment with citalopram and imipramine (but not ECS) significantly (approx 14%) decreased the serum copper level. Chronic treatment with both drugs did not alter the brain copper level. However, chronic ECS induced a significant increase (by 36%) in the copper level in the hippocampus and also in the cerebellum (by 16%). In contrast to the zinc, where both pharmacologic and ECS treatment increased its hippocampal concentration, these two antidepressant therapy (drugs versus ECS) differ in their effect on brain copper level. These findings suggest that the mechanism by which copper is involved in ECS differs from that of any involvement in the action of the drugs studied.     

Changed serum trace element profile in Down's syndrome

Being cofactors of important antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), which are significantly modified in Down's syndrome (trisomy 21), serum levels of microtrace elements zinc, copper, and selenium and of macroelement magnesium are reported in 16 subjects with Down's syndrome (DS) and their respective well age- and sex-matched controls. Serum zinc and selenium levels were significantly lowered in DS subjects, whereas copper levels were elevated. Consequently, a marked increase (40%) of the copper/zinc ratio in DS persons was observed. There were no differences in serum levels of magnesium between DS and control subjects.     

Effect of long-term therapy with sodium valproate on nail and serum trace element status in epileptic children

Antiepileptic drugs could cause changes in the trace element status of the body. Valproic acid (VPA) is a very effective anticonvulsant agent widely used in the management of various forms of epilepsy. Nail trace element content is a reliable index of trace element nutritional status of the body. To determine whether some of the side effects of antiepileptic drugs could be the result of zinc (Zn) depletion within tissues, Zn concentrations as well as copper (Cu) concentrations in nail and serum in 59 children having various types of epilepsy receiving valproate and 31 controls were assessed. Although serum Zn level in epileptic patients was found to be decreased, there was no difference in nail samples when compared to controls. There was a statistically significant increase in nail Cu level in epileptic patients when compared to controls. On the other hand, serum Cu levels were not different between the groups. Although none of our patients showed any symptoms of Cu elevation and Zn depletion, we should pay attention to potential body trace element changes in patients with epilepsy under VPA treatment. In conclusion, our results indicate that serum trace metal homeostasis might be affected by VPA therapy, but not by the convulsive disorder itself.     

The effect of antidepressant drugs on the ultradian rhythms of the locomotor activity in rats

Abstract

The effect of two antidepressant drugs (+)‐ and (‐)‐oxaprotiline hydrochloride (Ciba‐Geigy, OXA) on the exploration and the basal activity of rats in the light and dark phases of the diurnal cycle was investigated. (+)‐OXA is a selective noradrenaline (NA) uptake inhibitor, while its (‐)‐enantiomer is devoid of such an activity. Male Wistar rats housed individually on a 12:12 h light‐dark schedule (light on: 07.00 h) were treated with (+)‐ or (‐)‐OXA in a dose of 10 mg/kg twice daily, for 14 days. The rats received the last dose at the beginning of the light or dark phase and their movements were registered using Animex actometers for 12 h. The first 30 min of activity was regarded as the exploratory and the further period as the basal activity. In the light phase both (+)‐ and (‐)‐OXA decreased the exploration (80% and 70% of control, resp., p < 0.05) and potentiated it (180% and 190% of control, resp., p < 0.01) in the dark phase. The effect on the ultradian rhythm of the basal activity was phase‐dependent also. (+)‐OXA prolonged the period and did not change mesor, amplitude or acrophase of the rhythm in the light phase, and diminished mesor and amplitude, shifted acrophase and did not change period in the dark phase. (‐)‐OXA did not change parameters of the rhythm in the light phase and shortened period, diminished mesor and shifted acrophase of the rhythm in the dark phase. The results show that both (+)‐ and (‐)‐OXA given in the same dose change the same activity in opposite ways in the light and dark phases of the diurnal cycle. The NA uptake inhibition seems not to be a requisite of the light/dark phase differences.     

Effects of trichophytosis on serum zinc levels in calves

The purpose of this study was to determine the zinc levels in calves with trichophytosis and to research the importance of zinc for fungi. The sera of 20 calves with trichophytosis and 10 healthy calves were used in this study. Zinc levels of the sera were measured by the atomic absorption spectrophotometer method. Serum zinc levels of diseased and healthy animals were found to be 42.0±16.6 μg/dL and 75.8±5.9 μg/dL, respectively. Serum zinc levels of diseased calves were lower than healthy ones and this difference were found to be important statistically (p<0.001), whereas there is no statistical difference on the levels of lymphocyte, monocyte, granulocyte, erythrocyte, hemoglobin, hematocrit, and mean corpuscular volume between groups. These parameters were not influenced by low zinc levels.     

Effects of seasonal and physiological variations on the serum major and trace element levels in sheep

The aim of this study was to investigate the possible effects of the seasonal and physiological variations on the Cu, Zn, Mg, Fe, Se, Ca, K, Na, Cl, and P concentrations and their relationships with the estradiol and progesterone levels in Sakiz-Ivesi sheep. For this purpose 34 healthy Sakiz-Ivesi crossbreed sheep were divided into two groups. The first group (n=22) was mated and the second group (n=12) was not mated. They were raised under pasture conditions and without any dietary supplementation. Their serum samples were collected four times a year at each season and under each physiologic condition. The periods are 1=early pregnancy (October), 2=late pregnancy (January), 3=lactation (April), and 4=dry season (July). The results of this study indicated that (1) Mg concentrations in serum vary with seasonal variations but not physiological variations, (2) Fe and K concentrations in serum vary only with physiological variations, (3) the Cu concentration changes not only pregnancy but also through some other hormonal changes not caused by pregnancy, (4) Ca, P, and Se concentrations could vary with both physiologic and seasonal variations, (5) Zn, Na, and Cl were almost identical for both groups and altered depending on neither season of the year nor the physiologic status, (6) both increased estradiol level and increased progesterone level can raise Cu levels in serum, and (7) increased serum Ca concentrations are related with increased estradiol and decreased P and Mg levels. These observations suggest that seasonal and physiologic variations and sexual cycle have to be taken into consideration for a correct ***DIRECT SUPPORT *** A02Q2015 00006 interpretation of elements status. If sheep are maintained at pasture conditions, the nutritional requirements must be supplemented during certain periods. Otherwise, it is apparent that this will cause a decline in the total performance of sheep and, consequently, economic lost.     

Alterations in monoamine levels in discrete regions of rat brain after chronic administration of carbamazepine

Carbamazepine (25 mg/kg body weight) was administered intraperitoneally to adult male Wistar rats for 45 days and norepinephrine (NE), dopamine (DA) and serotonin (5-HT) levels were simultaneously assayed in discrete brain regions by high performance liquid chromatographic (HPLC) method. Experimental rats displayed no behavioral abnormalities. Body and brain weights were not significantly different from control group of rats. After exposure it was observed that norepinephrine levels were elevated in motor cortex (P<0.01) and cerebellum (P<0.05), while dopamine levels were decreased in these two regions (P<0.001, P<0.05). However, dopamine levels were increased in hippocampus (P<0.01). Serotonin levels were significantly decreased in motor cortex (P<0.001) and hypothalamus (P<0.001) but increased in striatum-accumbens (P<0.001) and brainstem (P<0.001). These results suggest that carbamazepine may mediate its anticonvulsant effect by differential alterations of monoamine levels in discrete brain regions particularly in motor cortex and cerebellum.     

Reference values for trace element levels in the human brain: A systematic review of the literature

Some trace elements (TE) are eminently toxic for humans (e.g., Al, Pb, Hg, Cd) and its presence in the central nervous system has been linked to the etiology of neurodegenerative diseases (ND). More recently, the focus has shifted to the potential role of the imbalances on essential TE levels (e.g., Fe, Cu, Zn, Se) within the brain tissue, and they have also been identified as potentially responsible for the cognitive decline associated with normal ageing and the development of some ND, although their definite role remains unclear.Accurately, well-defined reference values for TE levels in human body fluids and tissues are indispensable to identify possible disturbances in individual cases. Moreover, since the brain is a highly heterogeneous organ, with anatomically and physiologically very different areas, a detailed mapping of TE distribution across the brain tissue of normal individuals, with an in-depth analysis of TE levels in the different brain regions, is a mandatory prior work so that the results obtained from patients suffering from ND and other brain diseases can be interpreted.This review aims to compile and summarize the available data regarding TE levels in the different human brain regions of “normal” (non-diseased) individuals in order to contribute to the establishment of robust reference values. Fifty-four studies, published since 1960, were considered. The results showed a great variability between different studies. The potential sources of this variability are discussed. The need for increased harmonization of experimental strategies is highlighted in order to improve the comparability of the data obtained.     

Elevated corticosterone levels in stomach milk,serum, and brain of male and female offspring after maternal corticosterone treatment in the rat

Early influences such as maternal stress affect the developmental outcome of the offspring. We created an animal model of postpartum depression/stress based on giving high levels of corticosterone (CORT) to the rat dam, which resulted in behavioral and neural changes in the offspring. This study investigated whether highly elevated levels of maternal CORT during pregnancy or the postpartum result in higher levels of CORT in the stomach milk, serum, and brain of offspring. Dams received daily injections of CORT (40 mg/kg) or oil (control) either during pregnancy (gestational days 10–20) or the postpartum (Days 2–21). Pups that were exposed to high gestational maternal CORT had higher CORT levels in serum, but not in stomach milk or brain, on postnatal day (PND) 1. However, on PND7, pups that were exposed to high postpartum maternal CORT had higher CORT levels in stomach milk and brain, but not in serum. Conversely on PND18, pups that were exposed to high postpartum maternal CORT had higher CORT levels in serum, but not in brain (prefrontal cortex, hypothalamus, or hippocampus). Moreover, 24 h after weaning, there were no significant differences in serum CORT levels between the groups. Thus, CORT given to the dam during pregnancy or the postpartum results in elevated levels of CORT in the offspring, but in an age‐ and tissue‐dependent manner. Developmental exposure to high CORT could reprogram the HPA axis and contribute to the behavioral and neural changes seen in adult offspring. © 2010 Wiley Periodicals, Inc. Develop Neurobiol 70: 714–725, 2010     

Application of PIXE analysis to the study of the regional distribution of trace elements in normal human brain

A particle-induced X-ray emission (PIXE) analysis method is presented, which allows measurement of eight elements (i.e., K, Ca, Mn, Fe, Cu, Zn, Se, and Rb) in human brain samples of only a few mg dry weight. The precision and accuracy of the method were investigated by analyzing animal brain matter with both PIXE and instrumental neutron activation analysis (INAA). The method was applied to measure the 8 elements in 46 different regions of 3 human brains. The sections analyzed originated from either the left or the right cerebral hemisphere, brain stem, and cerebellum. For one of the brains, sections were also analyzed from 26 corresponding regions of both hemispheres. For all elements, similar concentrations were found in the corresponding areas of the left and right sides of the brain. The concentrations (in μg/g dry weight) of the elements K, Fe, Cu, Zn, Se, and Rb were consistently higher in cortical structures than in white matter. Deep nuclei and brain stem, which have a mixed composition, showed intermediate values for K, Zn, Se, and Rb. A hierarchical cluster analysis indicated that the various brain regions clustered into two large groups, one comprising gray and mixed matter regions and the other, white and mixed matter brain areas.     

Significance of serum trace element status in patients with rheumatic heart disease

It is known that certain trace elements can affect various heart diseases. In this study, we aimed to evaluate the changes in concentrations of certain serum trace elements in patients with chronic rheumatic heart disease (RHD). Serum analysis of selenium (Se), zinc (Zn), and copper (Cu) trace elements was assayed by atomic absorption spectrophotometry. RHD patients had significantly lower serum concentrations of Se and Zn than control subjects (p<0.05 and p<0.001, respectively). However, the serum Cu concentration was significantly higher in RHD patients than in controls (1.93±0.59 μg/L vs 1.06±0.29 μg/L; p<0.001). Similarly, the Cu/Zn ratio in RHD patients was higher than in control subjects (4.70±0.92 vs 1.68±0.45; p<0.001). Additionally, no significant correlation was found among these trace element concentrations and the functional capacity classes (p>0.05). RHD patients had decreased serum Se and Zn element concentrations and increased serum Cu element concentration. We suggest that Se and Zn deficiency might be contributory factors in the development of rheumatic heart disease, and a high Cu concentration and a high Cu/Zn ratio might reflect an ongoing inflammatory process in this disease.     

Effects of dexamethasone on trace elements and serum protein patterns following brain trauma in rats

The effect of dexamethasone (Dxm) on trace elements and serum protein patterns was investigated in male Sprague-Dawley rats subjected to brain trauma. After 6-or 24 h of the traumatic incident, the level of serum copper was significantly higher in the Dxm-treated rats, compared to controls (p<0.05). The corresponding levels of zinc and iron did not show significant differences. The zinc level returned to normal 24 h after trauma. After 6 and 24 h of trauma, the sodium dodecyl sulfate (SDS)-polyacrylamide gel patterns of serum proteins showed that a 41.6-kDa protein was significantly increased in the Dxm-treated animals. Two proteins weighing 26.6 kDa and 55.1 kDa did not show Dxm-induced changes. These results suggest that increases in the copper-zinc ratio and the changes of the 26.6-kDa, 41.6-kDa, and 55.1-kDa proteins might be a useful prognostic indicator for severe traumatic brain injury.     

Differentiation of serum levels of trace elements in normal and malignant breast patients

The objective of this study was to determine which elements in serum best differentiated breast cancer in a case-control study. Concentrations of 13 elements in serum of 68 breast tumor patients (25 malignant and 43 benign) and 26 healthy controls were measured. Logistic regression with different variable-selection procedures was used to determine a possible configuration of elements. Sensitivity and specificity of the model were calculated to obtain the optimal cutoff point for discriminating malignant breast cancers vs other individuals (including benign breast disease and normal ones). A combination of Cd, Mn, and Fe was found to have a specificity and sensitivity of 100% using forward-type logistic regression, when the cutoff value of the combination score was 52.71. Using stepwise-type logistic regression, a combination of Cr and Mn had a sensitivity of 100% and a specificity of 97.1% when the combination score of 17.4 was chosen as the cutoff. Similar analysis could be implemented to compare the malignant and control groups. Specificity and sensitivity were 100% for Mn (forward and stepwise type) with a cutoff point of 6.40. For the backward regression, specificity was 84.6% and sensitivity was 100% for Zn, with a cutoff point of 869.1. In conclusion, there was a significant difference in concentrations of all 13 elements in serum between breast cancer patients and controls. A combination among Cd, Mn, Fe, Cr, and Zn might be important to determine a differentiating reference for breast cancers if a long-term followed-up study is to be conducted.     

Effects of inflammation and antiinflammatory treatment on serum trace elements concentrations

We investigated the serum concentrations of zinc and copper during the inflammatory process together with the effect of treatment with a nonsteroid anti-inflammatory agent on these trace elements concentrations. In the present study, we used 92 guinea pigs, 12 of which constituted the control group; the remaining 80 were the experimental group. To start with, proquazone (as anti-inflammatory agent) was administered orally to 40 guinea pigs of the experimental group at 20-mg/kg doses 2 h before the surgery. Throughout the experimental period, the above dose was administered to the animals twice a day. We produced inflammation in all animals of the experimental group by using carrageenan (inflammatory agent) dropped into mandibular surgical defects. Serum concentrations of zinc and copper were determined by atomic absorption spectrophotometry in both groups at the 6th, 48th, 120th, 168th, and 240th h. The serum zinc concentrations of the carrageenan-administered group decreased significantly (p<0.01). When comparing the serum zinc concentrations of the carrageenan plus proquazone-administered group with those of control group, the decrease (p<0.05) at the 6th, 48th, and 120th h were statistically significant. When the copper serum concentrations of the carrageenan-administered group were compared with those of the control group, at the 48th, 120th, and 168th h, a statistically significant increase (p<0.01) was observed. However, there was no significant change in the carrageenan plus proquazone-administered group at the 168th and 240th h. As a result during the acute phase of inflammation, serum zinc concentrations decreased, whereas serum copper concentrations increased. The alterations in zinc concentrations were more rapid than those in copper concentrations, but the administration of proquazone slowed the rate of decrease in serum zinc concentrations. This work was presented at the Fourth International Congress of Pathophysiology, June 29–July 5, 2002, Budapest, Hungary.     

Hair zinc and copper: Relationship to hair type and serum concentrations in children and adolescents

The zinc and copper serum and hair concentrations of 691 3-18-y-old girls and boys previously determined as a part of the Multicentre Study of Atherosclerosis Precursors in Finnish Children and Adolescents were further analyzed in order to find a possible association between these two zinc and copper indices. The influence of hair color and the diameter of individual hair strands on hair concentrations were studied by the analysis of covariance. Hair color and serum zinc concentrations were found to be associated with hair zinc concentrations in boys. Such an association was not found for zinc and copper concentrations in girls. Hair vs serum concentrations in different age and hair color groups did not show however, a significant relationship either in copper or in zinc concentrations. The subjects with very low or high serum zinc or copper concentrations did not usually have extreme hair concentrations and vice versa. However, there were some subjects with low or high serum concentrations associated with low or high hair concentrations.     

Efficiency of serum copper/zinc ratio for differential diagnosis of patients with and without lung cancer

We examined serum copper (Cu), serum zinc (Zn), and the serum copper/zinc ratio (Cu/Zn) in 162 patients. All of them were seen to have an abnormal shadow in the chest X-ray films, that is, 109 patients with lung cancer (LC) and 53 patients with no lung cancer (NLC). The mean Cu and Cu/Zn in LC patients were significantly higher than those in NLC patients (p<0.05). In LC patients, Cu and Cu/Zn were higher and Zn was lower in advanced tumors than early ones. There was a significantly clear relation between Cu or Cu/Zn and the tumor (T) stages. When the relative risk (RR) of LC was estimated, it was seen that the higher Cu and Cu/Zn became, the higher RR became. Furthermore, we showed the sensitivity of the receiver operator characteristic of the test (ROC) curve for Cu, Cu/Zn, and carcinoembryonic antigen (CEA) to diagnose LC, as explained in a paragraph of methods.The determinations of Cu, Zn, and Cu/Zn are simple and inexpensive. They also appear to have a great diagnostic value in determining the local invasion of LC and as a screening test in the high-risk patients for LC.     

Change in apparent and true absorption and retention of dietary zinc with age in rats

Two groups of 16 rats each were fed the same diet with 12.9 ppm Zn. Nine days after each animal was injected with⁶⁵Zn for assessing fecal zinc of endogenous origin, zinc intake and excretion were determined for a six-day period at the age of about five (group I) and nine (II) weeks. At mean growth rates of 5.1 and 5.2 g/day, food consumption per gram of gain was 2.01 g in group I vs 2.86 g in II. Overall, zinc retention amounted to 21 vs 25 μg Zn/g of gain. Apparent absorption averaged 92 vs 74% of Zn intake (132 vs 189 μg/day), while true absorption averaged 98 vs 92%. It was concluded that endogenous fecal zinc excretion was limited to the indispensable loss (F _em) in group I (7 μg/day), while it exceeded this minimum loss in group II (33 μg/day). True retention, which reflected total zinc utilization (true absorption times metabolic efficiency), was derived from apparent absorption plusF _em (11 μg/day for group II according to the greater metabolic body size of the rats). It averaged 98% of Zn intake in group I vs 80% in group II. The mean metabolic efficiency was 100% vs 87%. The conclusion was that these marked differences between age groups in utilizing the dietary zinc reflected the efficient homeostatic adjustments in absorption and endogenous excretion of zinc to the respective zinc supply status.     

Changes in free amino acid concentrations in serum,brain, and CSF throughout embryogenesis

Using the developing chick embryo as a model and a very sensitive micromethod for amino acid analysis, a complete analysis is presented of the developmental changes in free amino acid concentration in the blood, in the CSF, and in two different brain regions (optic lobe and frontal lobe) of the chick embryo (from day 4 of incubation, until day 5 post hatching). The developmental profile of Lys is the only one that is almost identical in all three compartments. The developmental profiles of the serum and of the brain are very similar for Arg and Phe, less so for Leu and Gly, and towards the end of the embryonic period, similar also for Val, Ile, Trp, and Met. The amino acid concentrations in the CSF are either much lower than in serum and brain already at the earliest stages, or they progressively decline to levels lower than those in brain and serum, most rapidly between day 6 and 8 of embryonic life. The concentrations of neuroactive amino acids (Gln, Glu, Asp, GABA, Tau, and Gly) in both brain regions begin to increase very early, and continue to rise, except Tau, which goes through a maximum at day 8. Comparative analysis of the developmental profiles of each amino acid in serum, brain, and CSF reveals that the blood supply and the cellular uptake, retention, and metabolism by neural cells are the major determinants of the free amino acid pool of the developing brain.     

苯污染对大鼠脑组织环核苷酸与相关蛋白水平的影响

为了探索苯污染对人类健康损伤作用的因素,选用SPF级Wistar大鼠为实验对象,分为4组:低剂量组灌胃苯0.19 g·kg-1,中剂量组灌胃苯0.38 g·kg-1,高剂量组灌胃苯0.76 g·kg-1,对照组灌胃菜籽油2 mL·kg-1;用酶联免疫吸附法(ELISA)检测脑组织中环核苷酸和相关蛋白的水平.结果发现,连...     

干预措施对噪声污染大鼠脑组织基因表达及去甲肾上腺素水平的影响

为了探索干预措施对噪声污染大鼠脑组织基因表达水平的影响, 将50只SPF级Wistar大鼠随机分为空白对照组、噪声污染组(分为30、60、80 dB三个组)、干预组(利血平+80 dB), 每组10只动物。每天刺激1次, 每次刺激30 min, 连续刺激15 d。第16天解剖出脑组织用酶联免疫吸附法(ELISA)检测基因表达水平。结果发现, 噪声污染组大脑前额叶皮质(PFC)和海马(Hipp)组织中去甲肾上腺素(noradrenaline,NA)水平比对照组分别升高了22.87%、50.35%、94.65%和 12.00%、31.76%、61.83%; 干预组NA水平比对照组分别降低了33.66%和52.06%; 去甲肾上腺素转运蛋白(noradrenaline transporter, NAt)水平比对照组分别升高了22.87%、50.35%、94.65%和12.00%、31.76%、61.83%, 干预组NAt水平比对照组分别降低了33.66%和52.06%; 脑源性神经营养因子(brain derived neurotrophic factor, BDNF)水平比对照组分别升高了24.87%、39.27%、67.41%和44.97%、80.81%、95.84%, 干预组BDNF水平比对照组分别升高了16.36%和14.34%, 升高程度明显低于噪声污染组; 酪氨酸激酶受体B(Tyrosine kinase B, TrkB)水平比对照组分别升高了32.64%、59.95%、82.64%和31.02%、57.31%、80.23%, 干预组TrkB水平比对照组分别升高了4.75%和10.52%, 升高程度明显低于噪声污染组。结果显示, 噪声污染使动物体内去甲肾上腺素等水平升高, 去甲肾上腺素是噪声污染引起组织器官损伤的主要因素, 脑源性神经营养因子和酪氨酸激酶受体B防止神经元受损死亡, 改善神经元的病理状态, 利血平使去甲肾上腺素耗竭, 保护组织器官免受噪声污染的损伤。