An analog computer study of hydraulic servomechanism nonlinearlities

Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Aeronautical Engineering, 1954.Includes bibliographical references (p. 105-106).by Keith A. Erikson, William R. Greenwood, Philip J. Bonomo.M.S

Manganese causes differential regulation of glutamate transporter (GLAST) taurine transporter and metallothionein in cultured rat astrocytes.

, it is likely that in pathological conditions it can reach 100-500 μM. Amino acid (e.g. aspartate, glutamate, taurine), as well as divalent metal (e.g. zinc, manganese) concentrations are regulated by astrocytes in the brain. Recently, it has been reported that cultured rat primary astrocytes exposed to Mn displayed decreased glutamate uptake, thereby, increasing the excitotoxic potential of glutamate. Since the neurotoxic mechanism(s) Mn employs in terms of glutamate metabolism is unknown, a primary goal of this study was to link altered glutamate uptake in Mn exposed astrocytes to alterations in glutamate transporter message. Further, we wanted to examine the gene expression of metallothionein (MT) and taurine transporter (tau-T) as markers of Mn exposure. Glutamate uptake was decreased by nearly 40% in accordance with a 48% decrease in glutamate/aspartate transporter (GLAST) mRNA. Taurine uptake was unaffected by Mn exposure even though tau-T mRNA increased by 123%. MT mRNA decreased in these Mn exposed astrocytes possibly due to altered metal metabolism, although this was not examined. These data show that glutamate and taurine transport in Mn exposed astrocytes are temporally different

Manganese accumulates in iron deficient rat brain regions in a heterogeneous fashion and is associated with neurochemical alterations

Previous studies have shown that iron deficiency (ID) increases brain manganese (Mn), but specific regional changes have not been addressed. Weanling rats were fed one of three semipurified diets: control (CN), iron deficient (ID), or iron deficient/manganese fortified (IDMn+). Seven brain regions were analyzed for Mn concentration and amino acid (glutamate, glutamine, taurine, ?-aminobutyric acid) concentrations. Both ID and IDMn+ diets caused significant (p<0.05) increases in Mn concentration across brain regions compared to CN. The hippocampus was the only brain region in which the IDMn+ group accumulated significantly more Mn than both the CN and ID groups. ID significantly decreased GABA concentration in hippocampus, caudate putamen, and globus pallidus compared to CN rats. Taurine was significantly increased in the substantia nigra of the IDMn+ group compared to both ID and CN. ID also altered glutamate and glutamine concentrations in cortex, caudate putamen, and thalamus compared to CN. In the substantia nigra, Mn concentration positively correlated with increased taurine concentration, whereas in caudate putamen, Mn concentration negatively correlated with decreased GABA. These data show that ID is a significant risk factor for central nervous sys-tem Mn accumulation and that some of the neurochemical alterations associated with ID are specifically attributable to Mn accumulation

Manganese Neurotoxicity

Manganese is an essential trace element and it is required for many ubiquitous enzymatic reactions. While manganese deficiency rarely occurs in humans, manganese toxicity is known to occur in certain occupational settings through inhalation of manganese-containing dust. The brain is particularly susceptible to this excess manganese, and accumulation there can cause a neurodegenerative disorder known as manganism. Characteristics of this disease are described as Parkinson-like symptoms. The similarities between the two disorders can be partially explained by the fact that the basal ganglia accumulate most of the excess manganese compared with other brain regions in manganism, and dysfunction in the basal ganglia is also the etiology of Parkinson's disease. It has been proposed that populations already at heightened risk for neurodegeneration may also be more susceptible to manganese neurotoxicity, which highlights the importance of investigating the human health effects of using the controversial compound, methylcyclopentadienyl manganese tricarbonyl (MMT), in gasoline to increase octane. The mechanisms by which increased manganese levels can cause neuronal dysfunction and death are yet to be elucidated. However, oxidative stress generated through mitochondrial perturbation may be a key event in the demise of the affected central nervous system cells. Our studies with primary astrocyte cultures have revealed that they are a critical component in the battery of defenses against manganese-induced neurotoxicity. Additionally, evidence for the role of oxidative stress in the progression of manganism is reviewed here

Manganese and its Role in Parkinson's disease: from Transport to Neuropathology.

The purpose of this review is to highlight recent advances in the neuropathology associated with Mn exposures. We commence with a discussion on occupational manganism and clinical aspects of the disorder. This is followed by novel considerations on Mn transport (see also chapter by Yokel, this volume), advancing new hypotheses on the involvement of several transporters in Mn entry into the brain. This is followed by a brief description of the effects of Mn on neurotransmitter systems that are putative modulators of dopamine (DA) biology (the primary target of Mn neurotoxicity), as well as its effects on mitochondrial dysfunction and disruption of cellular energy metabolism. Next, we discuss inflammatory activation of glia in neuronal injury and how disruption of synaptic transmission and glial-neuronal communication may serve as underlying mechanisms of Mn-induced neurodegeneration commensurate with the cross-talk between glia and neurons. We conclude with a discussion on therapeutic aspects of Mn exposure. Emphasis is directed at treatment modalities and the utility of chelators in attenuating the neurodegenerative sequelae of exposure to Mn. For additional reading on several topics inherent to this review as well as others, the reader may wish to consult Aschner and Dorman (Toxicological Review 25:147–154, 2007) and Bowman et al. (Metals and neurodegeneration, 2009)

The effects of Dietary Fat and iron interaction on Brain regional iron contents and stereotypical Behaviors in Male c57Bl/6J Mice

Adequate brain iron levels are essential for enzyme activities, myelination, and neurotransmittersynthesis in the brain. Although systemic iron deficiency has been foundin genetically or dietary-induced obese subjects, the effects of obesity-associated irondysregulation in brain regions have not been examined. The objective of this study wasto examine the effect of dietary fat and iron interaction on brain regional iron contents andregional-associated behavior patterns in a mouse model. Thirty C57BL/6J male weanlingmice were randomly assigned to six dietary treatment groups (n = 5) with varyingfat (control/high) and iron (control/high/low) contents. The stereotypical behaviors weremeasured during the 24th week. Blood, liver, and brain tissues were collected at the endof the 24th week. Brains were dissected into the hippocampus, midbrain, striatum, andthalamus regions. Iron contents and ferritin heavy chain (FtH) protein and mRNA expressionsin these regions were measured. Correlations between stereotypical behaviors andbrain regional iron contents were analyzed at the 5% significance level. Results showedthat high-fat diet altered the stereotypical behaviors such as inactivity and total distancetraveled (P < 0.05). The high-fat diet altered brain iron contents and FtH protein andmRNA expressions in a regional-specific manner: (1) high-fat diet significantly decreasedthe brain iron content in the striatum (P < 0.05), but not other regions, and (2) thalamushas a more distinct change in FtH mRNA expression compared with other regions.Furthermore, high-fat diet resulted in a significant decreased total distance traveled anda significant correlation between iron content and sleeping in midbrain (P < 0.05). Dietaryiron also decreased brain iron content and FtH protein expression in a regionally specificmanner. The effect of interaction between dietary fat and iron was observed in brain ironcontent and behaviors. All these findings will lay foundations to further explore the linksamong obesity, behaviors, and brain iron alteration

Ferroportin is a manganese responsive protein that decreases manganese cytotoxicity and accumulation

Although manganese (Mn) is an essential trace element for human development and growth, chronic exposure to excessive Mn levels can result in psychiatric and motor disturbances, referred to as manganism. However, there are no known mechanism(s) for efflux of excess Mn from mammalian cells. Here, we test the hypothesis that the cytoplasmic iron (Fe) exporter ferroportin (Fpn) may also function as a Mn exporter to attenuate Mn toxicity. Using an inducible human embryonic kidney (HEK293T) cell model, we examined the influence of Fpn expression on Mn-induced cytotoxicity and intracellular Mn concentrations. We found that induction of an Fpn-green fluorescent protein fusion protein in HEK293T cells was cytoprotective against several measures of Mn toxicity, including Mn-induced cell membrane leakage and Mn-induced reductions in glutamate uptake. Fpn-green fluorescent protein mediated cytoprotection correlated with decreased Mn accumulation following Mn exposure. Thus, Fpn expression reduces Mn toxicity concomitant with reduced Mn accumulation. To determine if mammalian cells may utilize Fpn in response to increased intracellular Mn concentrations and toxicity, we assessed endogenous Fpn levels in Mn-exposed HEK293T cells and in mouse brain in vivo. We find that 6 h of Mn exposure in HEK293T cells is associated with a significant increase in Fpn levels. Furthermore, mice exposed to Mn showed an increase in Fpn levels in both the cerebellum and cortex. Collectively, these results indicate that (i) Mn exposure promotes Fpn protein expression, (ii) Fpn expression reduces net Mn accumulation, and (iii) reduces cytotoxicity associated with exposure to this metal

Genetic risk for Parkinson's disease correlates with alterations in neuronal manganese sensitivity between two human subjects.

Manganese (Mn) is an environmental risk factor for Parkinson's disease (PD). Recessive inheritance of PARK2 mutations is strongly associated with early onset PD (EOPD). It is widely assumed that the influence of PD environmental risk factors may be enhanced by the presence of PD genetic risk factors in the genetic background of individuals. However, such interactions may be difficult to predict owing to the complexities of genetic and environmental interactions. Here we examine the potential of human induced pluripotent stem (iPS) cell-derived early neural progenitor cells (NPCs) to model differences in Mn neurotoxicity between a control subject (CA) with no known PD genetic risk factors and a subject (SM) with biallelic loss-of-function mutations in PARK2 and family history of PD but no evidence of PD by neurological exam. Human iPS cells were generated from primary dermal fibroblasts of both subjects. We assessed several outcome measures associated with Mn toxicity and PD. No difference in sensitivity to Mn cytotoxicity or mitochondrial fragmentation was observed between SM and CA NPCs. However, we found that Mn exposure was associated with significantly higher reactive oxygen species (ROS) generation in SM compared to CA NPCs despite significantly less intracellular Mn accumulation. Thus, this report offers the first example of human subject-specific differences in PD-relevant environmental health related phenotypes that are consistent with pathogenic interactions between known genetic and environmental risk factors for PD

Organotellurium and Organoselenium compounds attenuate Mn-induced toxicity in C. elegans by preventing oxidative stress.

Organochalcogens have been widely studied given their antioxidant activity, which confers neuroprotection, antiulcer, and antidiabetic properties. Given the complexity of mammalian models, understanding the cellular and molecular effects of organochalcogens has been hampered. The nematode worm Caenorhabditis elegans is an alternative experimental model that affords easy genetic manipulations, green fluorescent protein tagging, and in vivo live analysis of toxicity. We previously showed that manganese (Mn)-exposed worms exhibit oxidative-stress-induced neurodegeneration and life-span reduction. Here we use Mn-exposed worms as a model for an oxidatively challenged organism to investigate the underlying mechanisms of organochalcogen antioxidant properties. First, we recapitulate in C. elegans the effects of organochalcogens formerly observed in mice, including their antioxidant activity. This is followed by studies on the ability of these compounds to afford protection against Mn-induced toxicity. Diethyl-2-phenyl-2-tellurophenyl vinyl phosphonate (DPTVP) was the most efficacious compound, fully reversing the Mn-induced reduction in survival and life span. Ebselen was also effective, reversing the Mn-induced reduction in survival and life span, but to a lesser extent compared with DPTVP. DPTVP also lowered Mn-induced increases in oxidant levels, indicating that the increased survival associated with exposure to this compound is secondary to a decrease in oxidative stress. Furthermore, DPTVP induced nuclear translocation of the transcriptional factor DAF-16/FOXO, which regulates stress responsiveness and aging in worms. Our findings establish that the organochalcogens DPTVP and ebselen act as antiaging agents in a model of Mn-induced toxicity and aging by regulating DAF-16/FOXO signaling and attenuating oxidative stress