Taurine improves the spatial learning and memory ability impaired by sub-chronic manganese exposure

Background

Excessive manganese exposure induced cognitive deficit. Several lines of evidence have demonstrated that taurine improves cognitive impairment induced by numerous neurotoxins. However, the role of taurine on manganese-induced damages in learning and memory is still elusive. This goal of this study was to investigate the beneficial effect of taurine on learning and memory capacity impairment by manganese exposure in an animal model.

Results

The escape latency in the Morris Water Maze test was significantly longer in the rats injected with manganese than that in the rats received both taurine and manganese. Similarly, the probe trial showed that the annulus crossings were significantly greater in the taurine plus manganese treated rats than those in the manganese-treated rats. However, the blood level of manganese was not altered by the taurine treatment. Interestingly, the exposure of manganese led to a significant increase in the acetylcholinesterase activity and an evidently decrease in the choline acetyltransferase activity, which were partially restored by the addition of taurine. Additionally, we identified 9 differentially expressed proteins between the rat hippocampus treated by manganese and the control or the manganese plus taurine in the proteomic analysis using the 2-dimensional gel electrophoresis followed by the tandem mass spectrometry (MS/MS). Most of these proteins play a role in energy metabolism, oxidative stress, inflammation, and neuron synapse.

Conclusions

In summary, taurine restores the activity of AChE and ChAT, which are critical for the regulation of acetylcholine. We have identified seven differentially expressed proteins specifically induced by manganese and two proteins induced by taurine from the rat hippocampus. Our results support that taurine improves the impaired learning and memory ability caused by excessive exposure of manganese.     

Superoxide dismutase in senescence-accelerated mouse retina

To examine the relationship between retinal ageing and superoxide dismutase, we studied the dismutase, with immunohistochemistry and immunoquantitative analysis, in the retina of senescence-accelerated mice P8/Ta (SAMP8/Ta) 3 and 12 months after birth. Accelerated senescence-resistant mice R1TA (SAMR1TA), which show no acceleration of senescence, were used as controls. In SAMP8/Ta, copper-zinc superoxide dismutase and manganese superoxide dismutase immunoreactivity in the photoreceptor inner segments, the outer nuclear layer and the inner nuclear layer increased earlier than in the controls. The increase in both superoxide dismutases with age occurred not only in SAMP8/Ta retinas but also in the controls. In conclusion, we propose the possibility that SAMP8/Ta undergo deterioration not only of learning and memory but also acceleration of senescence in the retina. The dismutases also appear to increase with normal ageing in the retina.     

多巴胺信号系统在衰老引起的行为和认知能力退化中的作用

衰老是生物体随时间推移各项生理功能逐渐发生改变的自然现象。动物的衰老伴随着行为和认知能力的降低,因此研究动物行为和认知功能退化的分子神经机制对于提高老年群体的生活质量具有重要意义。近年来,随着正电子发射断层扫描技术和功能性核磁共振脑成像技术在神经生物学上的广泛运用,越来越多证据表明多巴胺系统功能在衰老过程中显著降低,并且这是人类和动物行为和认知功能退化的重要原因。本文将概述自然衰老过程中多巴胺信号系统功能变化及机制和其在动物行为和认知退化中的作用等方面研究进展。     

Manganese-based complexes of radical scavengers as neuroprotective agents

Manganese was incorporated in the structure of the selected antioxidants to mimic the superoxide dismutase (SOD) and to increase radical scavenging ability. Five manganese complexes (1-5) showed potent SOD activity in vitro with IC(50) of 1.18-1.84 microM and action against lipid peroxidation in vitro with IC(50) of 1.97-8.00 microM greater than their ligands and trolox. The manganese complexes were initially tested in vivo at 50 mg/kg for antagonistic activity on methamphetamine (MAP)-induced hypermotility resulting from dopamine release in the mice brain. Only manganese complexes of kojic acid (1) and 7-hydroxyflavone (3) exhibited the significant suppressions on MAP-induced hypermotility and did not significantly decrease the locomotor activity in normal condition. Manganese complex 3 also showed protective effects against learning and memory impairment in transient cerebral ischemic mice. These results supported the brain delivery and the role of manganese in SOD activity as well as in the modulation of brain neurotransmitters in the aberrant condition. Manganese complex 3 from 7-hydroxyflavone was the promising candidate for radical implicated neurodegenerative diseases.     

Quantification and Comparison of Soil Elements in the Tibetan Plateau Kaschin-Beck Disease Area

The prevalence rate of Kaschin-Beck disease (KBD) in most parts of China is currently decreasing, but the disease is still active and severe on the Tibetan Plateau. Soil samples including the surface layer (0–20 cm) and the subsurface layer (20–40 cm) in the cultivated and natural soil profiles were collected, and the mechanical composite and total concentration of arsenic, cobalt, copper, iron, mercury, manganese, molybdenum, selenium, and zinc were determined. Concentrations of arsenic, iron, manganese, copper, and selenium in the surface soil were lower than those in the subsurface soil. The same was true of physical clay in the soil profiles. However, there were no significant differences between the different soil layers. The concentrations of selenium, molybdenum, and mercury were somewhat lower compared with the average concentrations of soils in China. Deficiencies of molybdenum and selenium both play a critical role in occurrence of KBD, but whether or not soil mercury at a low level contributes to KBD is still unclear. A correlation analysis of soil elements showed that there is a positive correlation between iron, cobalt, and manganese due to their similar chemical characteristics. Selenium concentrations in soil as well as the physical clay and iron descend with the deterioration of KBD, but mercury concentrations in soil ascend with the aggravation of the disease. The results show that selenium deficiencies greatly influence the disease, and a deficiency of molybdenum is likely another important factor in inducing KBD. Moreover, determining whether low levels of soil mercury contribute to KBD should be investigated in the future.     

On the effect of ferrous sulphate on the available manganese in the soil and the uptake of manganese by the plant

Summary Application of iron as ferrous sulphate or chloride to a loam not deficient in manganese had no effect on the yield but increased the uptake of manganese even in barley which grew vigorously.In an experiment with sugar beet on two soils contrasted with regard to their available manganese supply, applications of manganese, iron and nitrogen were tested in all combinations. On the Købelev soil, not deficient in manganese, no increases in yields were obtained on addition of ferrous sulphate while increases in manganese uptake were found for all combinations of treatments except where iron was added in the presence of manganese.On the manganese deficient Faarevejle soil, significantly higher increases in yields of roots were obtained from ferrous sulphate in the presence of nitrogen than in the presence of manganese. The effect of iron in the presence of nitrogen on the yield of tops was also significant. These treatments also gave the highest increases in manganese uptake.The amounts of manganese extractable from the soils by magnesium nitrate over a range of pH 2–8 could be increased considerably by addition of ferrous sulphate.The results support the suggestion that application of ferrous sulphate to some soils has the same effect as an addition of manganese.     

Battles with iron: manganese in oxidative stress protection

The redox-active metal manganese plays a key role in cellular adaptation to oxidative stress. As a cofactor for manganese superoxide dismutase or through formation of non-proteinaceous manganese antioxidants, this metal can combat oxidative damage without deleterious side effects of Fenton chemistry. In either case, the antioxidant properties of manganese are vulnerable to iron. Cellular pools of iron can outcompete manganese for binding to manganese superoxide dismutase, and through Fenton chemistry, iron may counteract the benefits of non-proteinaceous manganese antioxidants. In this minireview, we highlight ways in which cells maximize the efficacy of manganese as an antioxidant in the midst of pro-oxidant iron.     

The overlapping roles of manganese and Cu/Zn SOD in oxidative stress protection

In various organisms, high intracellular manganese provides protection against oxidative damage through unknown pathways. Herein we use a genetic approach in Saccharomyces cerevisiae to analyze factors that promote manganese as an antioxidant in cells lacking Cu/Zn superoxide dismutase (sod1 Delta). Unlike certain bacterial systems, oxygen resistance in yeast correlates with high intracellular manganese without a lowering of iron. This manganese for antioxidant protection is provided by the Nramp transporters Smf1p and Smf2p, with Smf1p playing a major role. In fact, loss of manganese transport by Smf1p together with loss of the Pmr1p manganese pump is lethal to sod1 Delta cells despite normal manganese SOD2 activity. Manganese-phosphate complexes are excellent superoxide dismutase mimics in vitro, yet through genetic disruption of phosphate transport and storage, we observed no requirement for phosphate in manganese suppression of oxidative damage. If anything, elevated phosphate correlated with profound oxidative stress in sod1 Delta mutants. The efficacy of manganese as an antioxidant was drastically reduced in cells that hyperaccumulate phosphate without effects on Mn SOD activity. Non-SOD manganese can provide a critical backup for Cu/Zn SOD1, but only under appropriate physiologic conditions.     

Differences in the effects of manganese and magnesium on initiation and elongation in the RNA polymerase I reaction

The effects of magnesium and manganese in the initiation and elongation steps of the RNA polymerase I reaction in RNA synthesis were studied. For RNA chain initiation manganese was found to be a better effector than magnesium. For RNA chain elongation either manganese or magnesium acted as an effector, but a high concentration of manganese was inhibitory.     

Manganese complexes of curcumin and its derivatives: evaluation for the radical scavenging ability and neuroprotective activity

In this study, three manganese complexes of curcumin (Cp) and related compounds, diacetylcurcumin (AcylCp) and ethylenediamine derivative (CpED), were synthesized and evaluated in vitro for antilipid peroxidation and superoxide dismutase activity. The manganese complexes exhibited a great capacity to protect brain lipids against peroxidation with IC₅₀ of 6.3–26.3 μM. All manganese complexes showed much greater SOD activity than their corresponding antioxidant ligands as well as trolox with IC₅₀ values of 8.9–29.9 μM. AcylCp and curcumin manganese complexes (AcylCpCpx and CpCpx) also gave the highest inhibitory activity to H₂O₂-induced cell damage (oxidative stress) at 0.1 μg/ml (< 0.2 μM) in NG108-15 cells, which were more potent than curcumin and related compounds. The neuropharmacological tests in mice supported the idea that the SOD mimicking complexes were able to penetrate to the brain as well as their role in the modulation of brain neurotransmitters under the aberrant conditions. The complexes significantly improved the learning and memory impairment induced by transient ischemic/reperfusion. AcylCpCpx, CpCpx, and CpEDCpx showed significant protection at 6.25, 25, and 50 mg/kg (i.p.), respectively, whereas manganese acetate and curcumin had no effect at doses of 50 mg/kg. In addition, treatment of AcylCpCpx and curcumin significantly attenuated MPTP-induced striatal dopamine depletion in mice, which was in accordance with the increase in the density of dopaminergic neurons when compared with MPTP-treated mice. These results support the important role of manganese in importing SOD activity and consequently, the enhancement of radical scavenging activity. AcylCpCpx and CpCpx seem to be the most promising neuroprotective agents for vascular dementia.     

Receptor-Mediated Endocytosis of a Manganese Complex of Transferrin into Neuroblastoma (SHSY5Y) Cells in Culture

Abstract: Exposure to manganese compounds often occurs as the result of industrial production or mining. Although manganese appears in traces in animal and human tissue and is essential to certain biological processes, it is also toxic. In humans and animals, toxicity is mainly associated with the nervous system. The mechanism underlying behavioral and biochemical alterations observed after manganese intoxication is not fully understood. We have shown that the manganese present in serum after exposure to manganese oxide is bound to transferrin as trivalent manganic ion. In this study of manganese uptake and storage we used a clone of human neuroblastoma cells (SHSY5Y). These cells differentiate and express catechol-aminergic properties. Saturation binding analysis of the transferrin-manganese complex to the cells revealed a single class of binding sites, with an apparent K _D of 13 ± 1 n M and a density of 11, 000 ± 2, 000 binding sites per cell. The complex was internalized in a temperature-dependent way and reached saturation after 2 h when ∼2% of the added manganese had been internalized. About 80% of the internalized manganese was found in ferritin after 24 h of exposure. The results demonstrate that the transferrin receptor on SHSY5Y cells can bind and internalize a manganese-transferrin complex as efficiently as an iron-transferrin complex, although a saturation of the manganese uptake was achieved.     

Training in the Morris Water Maze of Female and Male Rats Exposed to Hypoxia at Various Periods of Prenatal Development

Capability for learning was studied in the offspring of rats exposed to hyporbaric hypoxia on the days 11–13, 14–16 or 18–20 of pregnancy. Training in the Morris water maze has been shown to lead to consequences of effect of prenatal hypoxia evident in males, but not in females. The most pronounced changes are found at training in the male rats whose mothers were exposed to hypoxia on the days 14–16 of pregnancy. The revealed differences in the character of learning depend on experimental conditions. Under “severe” stress conditions (at the water temperature of 16–17°C), prenatal hypoxia leads to an improvement of learning parameters as compared with control, while under more favorable conditions (at the water temperature of 23–24°C), to their deterioration.     

Sleep deprivation and cognitive testing in internal medicine house staff.

There is increased concern about the effects of sleep deprivation on physician performance. We administered four standard tests of cognitive function to 23 university hospital house staff. Each physician served as his or her own control, and the tests were administered at rest, after a night on call, and after a night of sleep for recovery. The study was designed so that normal learning would minimize any deterioration in the post-on-call test performance. Statistically significant deterioration occurred in 3 of the 4 tests after a night on call. Even physicians acclimated to sleep deprivation on a regular, every-third-or-fourth-night basis showed functional impairment. The results have implications for patient care under conditions where house staff are stressed by sleep deprivation and prolonged fatigue.     

Nerve growth factor, neural stem cells and Alzheimer's disease

The protein family of the neurotrophins (NTs) comprises structurally and functionally related molecules such as nerve growth factor (NGF) which influences the proliferation, differentiation, survival and death of neuronal cells. In addition to their established functions for cell survival, NTs also mediate higher brain activities such as learning and memory. Changes in NT expression levels have thus been implicated in neurological diseases such as Alzheimer's disease (AD), an age-related neurodegenerative disorder that is characterized by progressive loss of memory and deterioration of higher cognitive functions. The present review provides an overview of the functional role of NGF in neural stem cells and AD while pointing to a potential application of this peptide for the treatment of AD.     

Non-heme manganese catalase--the 'other' catalase

Non-heme manganese catalases are widely distributed over microbial life and represent an environmentally important alternative to heme-containing catalases in antioxidant defense. Manganese catalases contain a binuclear manganese complex as their catalytic active site rather than a heme, and cycle between Mn(2)(II,II) and Mn(2)(III,III) states during turnover. X-ray crystallography has revealed the key structural elements of the binuclear manganese active site complex that can serve as the starting point for computational studies on the protein. Four manganese catalase enzymes have been isolated and characterized, and the enzyme appears to have a broad phylogenetic distribution including both bacteria and archae. More than 100 manganese catalase genes have been annotated in genomic databases, although the assignment of many of these putative manganese catalases needs to be experimentally verified. Iron limitation, exposure to low levels of peroxide stress, thermostability and cyanide resistance may provide the biological and environmental context for the occurrence of manganese catalases.     

Bioaccumulation of manganese in selected tissues of the freshwater crab,Potamonautes warreni (Calman), from industrial and mine-polluted freshwater ecosystems

Manganese concentrations in water and sediments of the Bronkhorstspruit River, Nooitgedacht Dam and especially in the Natalspruit River, did not fall within stated limits for the protection of aquatic life. Tissue manganese concentrations in Potamonautes warreni from the Natalspruit River were generally higher than those in the tissues of crabs from the other two aquatic ecosystems. The highest mean manganese tissue concentration in crabs from the three systems was detected in the carapace (587± 445 µg g^-1 wet weight). It appears that the carapace in these animals acts as a sink in which manganese can be deposited, thus also playing an important role in the detoxification of manganese in these crustaceans. No seasonal or sex-related variation was detected. Body size of the crabs, however, seems to be an important influencing factor in manganese bioaccumulation. A significant increase in carapace manganese concentrations was detected with an increase in body size. However, muscle manganese concentrations were higher in the smaller groups.The concentration factors (BF) calculated for the different tissues with respect to the water were highest in the carapace and ranged from 280.9 to 742.8. The BF with respect to the sediment was comparatively low for all the tissues (0.1 to 0.7). As the manganese concentration in the tissues reflects to some extent the degree of manganese contamination of the surrounding aquatic environment, it appears that P. warreni may be useful as a potential biomonitor of manganese pollution.     

Manganese superoxide dismutase in Saccharomyces cerevisiae acquires its metal co-factor through a pathway involving the Nramp metal transporter, Smf2p

Eukaryotes express both copper/zinc (SOD1)- and manganese (SOD2)-requiring superoxide dismutase enzymes that guard against oxidative damage. Although SOD1 acquires its copper through a specific copper trafficking pathway, nothing is known regarding the intracellular manganese trafficking pathway for SOD2. We demonstrate here that in Saccharomyces cerevisiae cells delivery of manganese to SOD2 in the mitochondria requires the Nramp metal transporter, Smf2p. SOD2 activity is greatly diminished in smf2Delta mutants, even though the mature SOD2 polypeptide accumulates to normal levels in mitochondria. Treating smf2Delta cells with manganese supplements corrected the SOD2 defect, as did elevating intracellular manganese through mutations in PMR1. Hence, manganese appears to be inaccessible to mitochondrial SOD2 in smf2 mutants. Cells lacking SMF2 also exhibited defects in manganese-dependent steps in protein glycosylation and showed an overall decrease in steady-state levels of accumulated manganese. By comparison, mutations in the cell surface Nramp transporter, Smf1p, had very little impact on manganese accumulation and trafficking. Smf2p resides in intracellular vesicles and shows no evidence of plasma membrane localization, even in an end4 mutant blocked for endocytosis. We propose a model in which Smf2p-containing vesicles play a central role in manganese trafficking to the mitochondria and other cellular sites as well.     

Learning of animals during adaptation to altitude and its relations with serotonin metabolism in the brain

The influence of high altitude (3 200 m) on learning was studied on 104 non-linear male rats weighing 120 to 140 g, along with biochemical analysis of serotonin content (5-HT) and noradrenaline (NA) in brain structures. A drastic deterioration in the animals' learning has been established in conditions of high altitude, both with alimentary and pain reinforcement attended with a considerable suppression of the 5-HT and NA brain systems activity. Systematic administration of 5-HTP resulting in an enhanced serotonin level in the cortex and the caudal part of the brainstem, improved the learning process, regardless of the emotional sign of the reinforcing stimulus. The prospect, is being substantiated, of evolving methods preventing pathological implications of external influences of high altitudes on the organism by means of pharmacological actions on monoamines' metabolism.     

Effect of intracerebroventricular injection of histamine on the behavior of the white rat

Previous references showed that the histamine injected peripherically produced a deterioration of the learning in experimental animals. The effects of 100 and 200 micrograms of histamine administered in the cerebral lateral ventricle, have been tested using an experimental paradigm which isolated attentional, motivational, and motor factor from the complex learned behavior. The obtained results showed to be similar to those produced by peripheric injection, and demonstrated a worsening in attentional, motivational, and motor parameters.