Dopamine and Norepinephrine in Discrete Areas of the Copper-Deficient Rat Brain (original) (raw)
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The Journal of Nutritional Biochemistry, 1990
Dietary copper deficiency was produced in Swiss albino mice and Sprague Dawley rats to determine the organ specificity of alterations in norepinephrine (NE) and dopamine (DA) concentrations and the relationship with organ copper levels. A 5-week dietary treatment was used, which started ! week after birth for mice, initially via dams, and 3 weeks after birth for rats. Mice offspring (6 weeks of age) and rats (8 weeks of age) maintained on a copper-deficient (-Cu) treatment were compared with copperadequate (+ Cu) controls. Compared with + Cu animals,-Cu mice and rats were anemic and had low (< 1% of + Cu) ceruloplasmin activities but normal body weights. The-Cu mice had organ copper concentrations ranging between 30% and 65% of + Cu values for eight organs studied, with the thymus being the least depleted. For-Cu rats, the range was 15% to 65%. Significant reductions in NE concentration were observed in the heart, pancreas, and spleen of-Cu mice. Elevated DA levels were observed in all organs except the brain. For-Cu rats, the NE level was lower in the heart and the DA level was higher in both the heart and spleen compared with + Cu rats. Dopamine elevation in the heart and spleen for both-Cu mice and rats was four-and fivefold higher, respectively. Adrenal catecholamine levels were only slightly changed by copper deficiency in mice or rats. Urinary levels of both NE and DA were higher in-Cu rats and mice. Plasma and heart tyrosine levels were not altered in-Cu mice. Elevated DA in-Cu rodents may be due to limiting dopamine-[3-monooxygenase. Higher urinary NE and lower organ NE may be due to a combination of decreased synthesis and enhanced turnover. The magnitude of decreased organ copper was not predictive of altered catecholamine pool size.
Copper Deficiency Alters Rat Dopamine β-Monooxygenase mRNA and Activity
Dopamine -monooxygenase (DBM), a cuproenzyme, converts dopamine to norepinephrine in selected cells. Studies were conducted in albino rats to resolve the known paradox of DBM after copper deficiency in which metabolite analyses of tissues suggest lower activity, whereas direct assay of homogenates suggests enhanced activity. After 4 wk of postweanling copper deficiency, male Holtzman rats exhibited 1.4-fold higher adrenal DBM activity and 1.8-fold higher adrenal DBM mRNA levels than copper-adequate rats. Mixing experiments did not support the existence of endogenous activators or inhibitors. Adrenal catecholamine content indicated lower norepinephrine, higher dopamine and unaffected epinephrine content in copper-deficient compared with copper-adequate rats. Studies in 22-d-old male Sprague-Dawley offspring of dams started on copper deficiency at d 7 of gestation indicated similar results for adrenal DBM mRNA, a 1.75-fold increase compared with copper-adequate pups. Adrenal dopamine content was higher in female copper-deficient offspring compared with controls, but norepinephrine was not lower. Medulla oblongata/pons DBM mRNA concentration was higher in 22-d-old copper-deficient female but not male rats compared with controls. Six weeks of copper repletion to the 22-d-old rats restored adrenal DBM mRNA levels to control values. Enzyme assay and RNA results are consistent with enhanced formation of DBM in adrenal gland and noradrenergic cell bodies of copper-deficient rats. The molecular signal may not be solely lower norepinephrine content because adrenal DBM mRNA changes were evident in both nutritional models, whereas the norepinephrine content was altered only in the postnatal model.
Alterations in Neurotransmitter Receptor Binding in Discrete Areas of the Copper-Deficient Rat Brain
Journal of Neurochemistry, 1982
Neonatal copper deficiency produced alterations in central neurotransmitter receptors that were selective with respect both to brain region and to neurotransmitter receptor type. Both high-and low-affinity dopamine receptor densities in the corpus striatum were significantly lowered, 55% and 29%, respectively, when expressed on a wet weight basis. There was a significant decrease in the level of muscarinic receptors in the striatum whether expressed on the basis of wet weight (50%) or protein (27%). A smaller reduction in muscarinic receptor density was observed in the cortex, whereas there was no effect of copper deficiency in the cerebellum. The treatment did not change P-adrenergic receptor binding in either the cortex or cerebellum. The affinities of the receptors for the ligands was not affected by the low-copper diet. It was previously reported that copper deficiency produces regionally specific decreases in the concentrations of dopamine and norepinephrine. The greatest reduction occurred in the concentration of dopamine in the corpus striatum. The results from both studies suggest that copper deficiency in post-weanling rats may induce a selective morphological lesion.
Copper and the brain noradrenergic system
JBIC Journal of Biological Inorganic Chemistry, 2019
Copper (Cu) plays an essential role in the development and function of the brain. In humans, genetic disorders of Cu metabolism may cause either severe Cu deficiency (Menkes disease) or excessive Cu accumulation (Wilson disease) in the brain tissue. In either case, the loss of Cu homeostasis results in catecholamine misbalance, abnormal myelination of neurons, loss of normal brain architecture, and a spectrum of neurologic and/or psychiatric manifestations. Several metabolic processes have been identified as particularly sensitive to Cu dishomeostasis. This review focuses on the role of Cu in noradrenergic neurons and summarizes the current knowledge of mechanisms that maintain Cu homeostasis in these cells. The impact of Cu misbalance on catecholamine metabolism and functioning of noradrenergic system is discussed.
Copper Neurotoxicity in Rat Substantia Nigra and Striatum Is Dependent on DT-Diaphorase Inhibition
Chemical Research in Toxicology, 2008
The dependence of copper neurotoxicity on DT-diaphorase inhibition was suggested from results obtained from a cell line derived from substantia nigra. Therefore, the aim of this study was to evaluate whether CuSO 4 neurotoxicity in vivo, which was evaluated by determining the contralateral rotation and loss of tyrosine hydroxylase immunostaining, was dependent on DT-diaphorase inhibition by dicoumarol. Animals unilaterally and intranigrally injected with 0.25 nmol of CuSO 4 and 2 nmol of dicoumarol presented a significant and characteristic contralateral rotational behavior (P < 0.01) when they were systemically stimulated with apomorphine (0.5 mg/kg s.c.), similar to that observed in rats injected unilaterally with 6-hydroxydopamine as a positive control. The behavioral effects correlated with the lost of tyrosine hydroxylase-positive staining, since animals unilaterally and intranigrally injected with 0.25 nmol of CuSO 4 together with 2 nmol of dicoumarol exhibited extensive loss of tyrosine hydroxylasepositive fiber density in the striatum (P < 0.01) and cell loss in the substantia nigra (P < 0.01). Our results support the idea that CuSO 4 neurotoxicity is dependent upon DT-diaphorase inhibition.
Effects of a Copper-Deficient Diet on the Biochemistry, Neural Morphology and Behavior of Aged Mice
Aromatase (P450 AROM ), the enzyme responsible for the conversion of testosterone (T) into 17-b estradiol (E 2 ), plays a crucial role in the sexual differentiation of specific hypothalamic nuclei. Moreover, recent findings indicate that local E 2 synthesis has an impact on other brain areas including hippocampus, temporal cortex and cerebellum, and may thus influence also cognitive functions. Numerous studies have described the expression and the distribution of P450 AROM throughout ontogenesis and postnatal development of the central nervous system in several mammals, but data referring to humans are scarce. In the adult human brain, P450 AROM has been detected in the hypothalamus, limbic areas, and in the basal forebrain, and described in glial cells of the cerebral cortex and hippocampus. In this study we report the expression, distribution and cellular localization of P450 AROM in the human fetal and early postnatal cerebral cortex. In our series of fetal brains of the second trimester, P450 AROM expression appeared at gestational week (GW) 17 and resulted limited to groups of cells localized close to the growing neuroepithelium in the ventricular and subventricular zones. At GWs 20-24, scattered P450 AROM immunoreactive (-ir) neural cells were identified in the intermediate plate and subplate, and in the parietal cortical plate. In perinatal and early postnatal individuals the quantity of P450 AROM -ir elements increased, and revealed the morphology typical of glial cells. Double labeling immunostaining with anti-GFAP and anti-P450 AROM antisera, and subsequent confocal analysis, confirmed this observation. Our data show that the expression of P450 AROM in the fetal cortex starts approx at the end of the fourth gestational month, but increases steadily only in the last trimester or in the early postnatal period. This temporal trend may suggest that P450 AROM could act as a differentiation-promoting factor, based on timing of the steroid actions.
Copper-induced alterations in rat brain depends on route of overload and basal copper levels
Nutrition, 2014
Objectives: Copper (Cu) is widely used in industry for the manufacture of a vast range of goods including Cu-intrauterine devices (IUDs), electronic products, agrochemicals, and many others. It is also one of the trace elements essential to human health in the right measure and is used as a parenteral supplement in patients unable to ingest food. Elevated Cu levels have been found in the plasma of women using Cu-IUDs and in farmers working with Cu-based pesticides. However, possible alterations due to Cu overload in the brain have been poorly studied. Therefore, the aim of this study was to investigate the effects of Cu administration on rat brain in Cu-sufficient and Cudeficient animals fed on semi-synthetic diets with different doses of Cu (7 or 35 ppm). Methods: We aimed to investigate the effects of Cu administration using two routes of administration: oral and intraperitoneal (IP). Male Wistar rats were feeding (one month) a complete (7 ppm) or a deficient (traces) Cu diets subdivided into three categories oral-, intraperitoneal-(or both) supplemented with copper carbonate (7 to 35 ppm). Cu content in plasma, brain zones (cortex and hippocampus), antioxidant enzyme activities, and protease systems involved in programmed cell death were determined. Results: The results show that Cu levels and the concentration of Cu in plasma and brain were dosedependent and administration route-dependent and demonstrated a prooxidative effect in plasma and brain homogenates. Oxidative stress biomarkers and antioxidative enzyme activity both increased under Cu overload, these effects being more noticeable when Cu was administered IP. Concomitantly, brain lipids from cortex and hippocampus were strongly modified, reflecting Cuinduced prooxidative damage. A significant increase in the activities of calpain (milli-and micro-) and caspase-3 activity also was observed as a function of dose and administration route. Conclusion: The findings of this study could be important in evaluating the role of Cu in brain metabolism and neuronal survival.
Molecular Neurobiology, 2018
Redox properties enable copper to perform its essential role in many biological processes, but they can also convert it into a potentially hazardous element. Its dyshomeostasis may have serious neurological consequences, and its possible involvement in Parkinson's disease and other neurodegenerative disorders has been suggested. The in vitro and ex vivo ability of copper to increase oxidative stress has already been demonstrated, and the aim of the present study was to assess in vivo the capacity of copper to cause brain oxidative damage and its ability to increase the dopaminergic degeneration induced by 6-hydroxydopamine. We found that chronic copper administration (10 mg Cu 2+ /kg/day, IP) causes its accumulation in different brain areas (cortex, striatum, nigra) and was accompanied by an increase in TBARS levels and a decrease in protein free-thiol content in the cortex. A decrease in catalase activity and an increase in glutathione peroxidase activity were also observed in the cortex. The intrastriatal administration of Cu 2+ caused an increase in some indices of oxidative stress (TBARS and protein free-thiol content) in striatum and nigra, but was unable to induce dopaminergic degeneration. However, when copper was intrastriatally coadministered with 6-hydroxydopamine, it increased dopaminergic degeneration, a fact that was also accompanied by an increase in the assayed indices of oxidative stress, a decrease in catalase activity, and an augmentation in glutathione activity. Evidently, copper cannot cause neurodegeneration per se, but may potentiate the action of other factors involved in the pathogenesis of Parkinson's disease through oxidative stress.
Journal of Neurochemistry, 2007
2 We note that the extent of inhibition observed in this series of experiments is somewhat higher than the data show n in figure 1B with a 5 µM copper concentration, which could probably be due to the small amount of ghost protein used in these experiments. The addition of micromolar concentrations of Aβ peptide to the standard ghost preparations under standard experime ntal conditions produced a turbid mixture resulting in the determination of pH gradient by the acridine orange method unreliable. Therefore, 1/2-1/3 of ghost proteins was used in this series of experiments to avoid the uncertainty. Furthermore, although similar experiments were carried out under conversion conditions, the results were not highly reproducible most likely due to the ill-behavior of Aβ 1-42 in the presence of Cu 2+ and Asc out even in the presence of catalase (for example see ref. (Dikalov et al. 2004)).
Biological Trace Element Research, 2013
Animal models of copper toxicosis rarely exhibit neurological impairments and increased brain copper accumulation impeding the development of novel therapeutic approaches to treat neurodegenerative diseases having high brain Cu content. The aim of this study was to investigate the effects of intraperitoneally injected copper lactate (0.15 mg Cu/100 g body weight) daily for 90 days on copper and zinc levels in the liver and hippocampus, on biochemical parameters, and on neurobehavioral functions (by Morris water maze) of male Wistar rats. Copper-administered animals exhibited significantly decreased serum acetylcholinesterase (AChE) activity and impaired neuromuscular coordination and spatial memory compared to control rats. Copper-intoxicated rats showed significant increase in liver and hippocampus copper content (99.1 and 73 % increase, respectively), 40.7 % reduction in hepatic zinc content, and interestingly, 77.1 % increase in hippocampus zinc content with concomitant increase in copper and zinc levels in serum and urine compared to control rats. Massive grade 4 copper depositions and grade 1 copper-associated protein in hepatocytes of copperintoxicated rats were substantiated by rhodanine and orcein stains, respectively. Copper-intoxicated rats demonstrated swelling and increase in the number of astrocytes and copper deposition in the choroid plexus, with degenerated neurons showing pyknotic nuclei and dense eosinophilic cytoplasm. In conclusion, the present study shows the first evidence in vivo that chronic copper toxicity causes impaired spatial memory and neuromuscular coordination, swelling of astrocytes, decreased serum AChE activity, copper deposition in the choroid plexus, neuronal degeneration, and augmented levels of copper and zinc in the hippocampus of male Wistar rats.