Regulation of the Manganese Superoxide Dismutase and Inducible Nitric Oxide Synthase Gene in Rat Neuronal and Glial Cells

Kifle, Y.; Monnier, Joan M.; Chesrown, SE; Raizada, Mohan K.; Nick, Harry S.

doi:10.1046/j.1471-4159.1996.66052128.x

Cited by 75 publications

(32 citation statements)

References 40 publications

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“…Astrocytes have efficient self-protective systems, such as active glycolytic (52,60) and de novo glutathione-synthesizing (13,33,53,61) pathways or higher superoxide dismutase expression (62), which account for the resistance shown by glial cells to a wide range of insults, including ⅐ NO exposure (this work). In contrast to astrocytes, neurons are vulnerable cells that, upon exposure to either endogenous (9,63) or exogenous (52) excess ⅐ NO, rapidly (within 1 h) undergo apoptotic death (this study).…”

Section: Discussionmentioning

confidence: 99%

Peroxynitrite Protects Neurons against Nitric Oxide-mediated Apoptosis

Garcı́a-Nogales¹,

Almeida²,

Bolaños³

2003

Journal of Biological Chemistry

150

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Peroxynitrite is thought to be a nitric oxide-derived neurotoxic effector molecule involved in the disruption of key energy-related metabolic targets. To assess the consequences of such interference in cellular glucose metabolism and viability, we studied the possible modulatory role played by peroxynitrite in glucose oxidation in neurons and astrocytes in primary culture. Here, we report that peroxynitrite triggered rapid stimulation of pentose phosphate pathway (PPP) activity and the accumulation of NADPH, an essential cofactor for glutathione regeneration. In contrast to peroxynitrite, nitric oxide elicited NADPH depletion, glutathione oxidation, and apoptotic cell death in neurons, but not in astrocytes. These events were noticeably counteracted by pretreatment of neurons with peroxynitrite. In an attempt to elucidate the mechanism responsible for this PPP stimulation and neuroprotection, we found evidence consistent with both exogenous and endogenous peroxynitrite-mediated activation of glucose-6-phosphate dehydrogenase (G6PD), an enzyme that catalyzes the first rate-limiting step in the PPP. Moreover, functional overexpression of the G6PD gene in stably transformed PC12 cells induced NADPH accumulation and offered remarkable resistance against nitric oxide-mediated apoptosis, whereas G6PD gene-targeted antisense inhibition depleted NADPH levels and exacerbated cellular vulnerability. In light of these results, we suggest that G6PD activation represents a novel role for peroxynitrite in neuroprotection against nitric oxidemediated apoptosis.

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Section: Discussionmentioning

confidence: 99%

Peroxynitrite Protects Neurons against Nitric Oxide-mediated Apoptosis

Garcı́a-Nogales¹,

Almeida²,

Bolaños³

2003

Journal of Biological Chemistry

150

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“…This protein is located in the mitochondria and allows an adaptation of the oxidative metabolism. 83 Its expression is highly regulated by various cytokines, 84,85 e.g., in response to oxidant injury. 82 Accordingly, focal ischemia induces delayed hyperintensity on T 1 W MR imaging of the human brain, [86][87][88][89] in agreement with intense MnSOD immunoreactivities 83 in reactive astrocytosis.…”

Section: Astrocytesmentioning

confidence: 99%

<i>In Vivo</i> Brain MR Imaging at Subnanoliter Resolution: Contrast and Histology

2016

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This article provides an overview of in vivo magnetic resonance (MR) imaging contrasts obtained for mammalian brain in relation to histological knowledge. Emphasis is paid to the (1) significance of high spatial resolution for the optimization of T 1 , T 2 , and magnetization transfer contrast, (2) use of exogenous extra-and intracellular contrast agents for validating endogenous contrast sources, and (3) histological structures and biochemical compounds underlying these contrasts and (4) their relevance to neuroradiology. Comparisons between MR imaging at subnanoliter resolution and histological data indicate that (a) myelin sheaths, (b) nerve cells, and (c) the neuropil are most responsible for observed MR imaging contrasts, while (a) diamagnetic macromolecules, (b) intracellular paramagnetic ions, and (c) extracellular free water, respectively, emerge as the dominant factors. Enhanced relaxation rates due to paramagnetic ions, such as iron and manganese, have been observed for oligodendrocytes, astrocytes, microglia, and blood cells in the brain as well as for nerve cells. Taken together, a plethora of observations suggests that the delineation of specific structures in high-resolution MR imaging of mammalian brain and the absence of corresponding contrasts in MR imaging of the human brain do not necessarily indicate differences between species but may be explained by partial volume effects. Second, paramagnetic ions are required in active cells in vivo which may reduce the magnetization transfer ratio in the brain through accelerated T 1 recovery. Third, reductions of the magnetization transfer ratio may be more sensitive to a particular pathological condition, such as astrocytosis, microglial activation, inflammation, and demyelination, than changes in relaxation. This is because the simultaneous occurrence of increased paramagnetic ions (i.e., shorter relaxation times) and increased free water (i.e., longer relaxation times) may cancel T 1 or T 2 effects, whereas both processes reduce the magnetization transfer ratio.

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“…The resultant increase in LMWI level leads to oxidative stress exacerbation, activation of ferritin synthesis [25] and, hence, to iron sequestration. This correlates with the up-regulation of manganese superoxide dismutase in human glioblastomas [26] . The immunosuppressive effect of ferritin [27] can, in turn, promote tumor growth.…”

Section: Discussionmentioning

confidence: 57%

Dysregulation of Non-Heme Iron Metabolism in Glial Brain Tumors

Mykhaylyk¹,

Dudchenko²,

Cherchenko

et al. 2005

Med Princ Pract

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Objective: To study iron exchange irregularities in experimental animals and patients with glial brain tumors to ascertain the role of the ‘iron component’ in glial brain tumor pathogenesis. Subject and Methods: A suspension of A.101.08 tumor cells was implanted in the cortex of the left-brain hemisphere of rats to model experimentally induced glial brain tumor. At 7 or 14 days after implantation, blood and tissue samples from the tumor, peritumoral tissue, and brain regions were taken for analysis. Blood and plasma samples were obtained from 23 patients as well as biopsy samples taken during tumor removal surgery. Electron resonance spectroscopy was used to determine the concentrations of transferrin iron, transferrin in whole blood and in blood cells, and chelatable and stored iron in the tissues of experimental animals and patients. Results: Hypoferremia was found in rats with both small and large glial brain tumors, whereas hyperferremia was found to be a characteristic of malignant glial brain tumors in humans. We identified statistically significant increases in stored and chelatable iron concentrations in the tumor and peritumoral brain tissue compared to the blood and the adjacent brain tissue (probably normal) in both human malignant glial brain tumors and in rat experimental glial brain tumors. Conclusions: These findings suggest that iron misregulation plays a part in glial brain tumor pathogenesis and this may provide a basis for understanding the association between glial brain tumors and epilepsy.

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Regulation of the Manganese Superoxide Dismutase and Inducible Nitric Oxide Synthase Gene in Rat Neuronal and Glial Cells

Cited by 75 publications

References 40 publications

Peroxynitrite Protects Neurons against Nitric Oxide-mediated Apoptosis

Peroxynitrite Protects Neurons against Nitric Oxide-mediated Apoptosis

<i>In Vivo</i> Brain MR Imaging at Subnanoliter Resolution: Contrast and Histology

Dysregulation of Non-Heme Iron Metabolism in Glial Brain Tumors

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