Publications (24) View all
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Article: Extracellular superoxide dismutase is important for hippocampal neurogenesis and preservation of cognitive functions after irradiation.
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ABSTRACT: Cranial irradiation is widely used in cancer therapy, but it often causes cognitive defects in cancer survivors. Oxidative stress is considered a major cause of tissue injury from irradiation. However, in an earlier study mice deficient in the antioxidant enzyme extracellular superoxide dismutase (EC-SOD KO) showed reduced sensitivity to radiation-induced defects in hippocampal functions. To further dissect the role of EC-SOD in neurogenesis and in response to irradiation, we generated a bigenic EC-SOD mouse model (OE mice) that expressed high levels of EC-SOD in mature neurons in an otherwise EC-SOD-deficient environment. EC-SOD deficiency was associated with reduced progenitor cell proliferation in the subgranular zone of dentate gyrus in KO and OE mice. However, high levels of EC-SOD in the granule cell layer supported normal maturation of newborn neurons in OE mice. Following irradiation, wild-type mice showed reduced hippocampal neurogenesis, reduced dendritic spine densities, and defects in cognitive functions. OE and KO mice, on the other hand, were largely unaffected, and the mice performed normally in neurocognitive tests. Although the resulting hippocampal-related functions were similar in OE and KO mice following cranial irradiation, molecular analyses suggested that they may be governed by different mechanisms: whereas neurotrophic factors may influence radiation responses in OE mice, dendritic maintenance may be important in the KO environment. Taken together, our data suggest that EC-SOD plays an important role in all stages of hippocampal neurogenesis and its associated cognitive functions, and that high-level EC-SOD may provide protection against irradiation-related defects in hippocampal functions.Proceedings of the National Academy of Sciences 12/2012; · 9.68 Impact Factor -
Article: Oxidative stress and adult neurogenesis-Effects of radiation and superoxide dismutase deficiency.
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ABSTRACT: Hippocampus plays an important role in learning and memory and in spatial navigation. Production of new neurons that are functionally integrated into the hippocampal neuronal network is important for the maintenance of functional plasticity. In adults, production of new neurons in the hippocampus takes place in the subgranular zone (SGZ) of dentate gyrus. Neural progenitor/stem cells go through processes of proliferation, differentiation, migration, and maturation. This process is exquisitely sensitive to oxidative stress, and perturbation in the redox balance in the neurogenic microenvironment can lead to reduced neurogenesis. Cranial irradiation is an effective treatment for primary and secondary brain tumors. However, even low doses of irradiation can lead to persistent elevation of oxidative stress and sustained suppression of hippocampal neurogenesis. Superoxide dismutases (SODs) are major antioxidant enzymes for the removal of superoxide radicals in different subcellular compartments. To identify the subcellular location where reactive oxygen species (ROS) are continuously generated after cranial irradiation, different SOD deficient mice have been used to determine the effects of irradiation on hippocampal neurogenesis. The study results suggest that, regardless of the subcellular location, SOD deficiency leads to a significant reduction in the production of new neurons in the SGZ of hippocampal dentate gyrus. In exchange, the generation of new glial cells was significantly increased. The SOD deficient condition, however, altered the tissue response to irradiation, and SOD deficient mice were able to maintain a similar level of neurogenesis after irradiation while wild type mice showed a significant reduction in the production of new neurons.Seminars in Cell and Developmental Biology 04/2012; 23(7):738-44. · 6.65 Impact Factor -
Article: Paradoxical Relationship between Mn Superoxide Dismutase Deficiency and Radiation-Induced Cognitive Defects.
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ABSTRACT: Radiation therapy of the CNS, even at low doses, can lead to deficits in neurocognitive functions. Reduction in hippocampal neurogenesis is usually, but not always, associated with cognitive deficits resulting from radiation therapy. Generation of reactive oxygen species is considered the main cause of radiation-induced tissue injuries, and elevated levels of oxidative stress persist long after the initial cranial irradiation. Consequently, mutant mice with reduced levels of the mitochondrial antioxidant enzyme, Mn superoxide dismutase (MnSOD or Sod2), are expected to be more sensitive to radiation-induced changes in hippocampal neurogenesis and the related functions. In this study, we showed that MnSOD deficiency led to reduced generation of immature neurons in Sod2-/+ mice even though progenitor cell proliferation was not affected. Compared to irradiated Sod2+/+ mice, which showed cognitive defects and reduced differentiation of newborn cells towards the neuronal lineage, irradiated Sod2-/+ mice showed normal hippocampal-dependent cognitive functions and normal differentiation pattern for newborn neurons and astroglia. However, we also observed a disproportional decrease in newborn neurons in irradiated Sod2-/+ following behavioral studies, suggesting that MnSOD deficiency may render newborn neurons more sensitive to stress from behavioral trainings following cranial irradiation. A positive correlation between normal cognitive functions and normal dendritic spine densities in dentate granule cells was observed. The data suggest that maintenance of synaptic connections, via maintenance of dendritic spines, may be important for normal cognitive functions following cranial irradiation.PLoS ONE 01/2012; 7(11):e49367. · 4.09 Impact Factor -
Article: Irradiation enhances hippocampus-dependent cognition in mice deficient in extracellular superoxide dismutase.
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ABSTRACT: The effects of ionizing irradiation on the brain are associated with oxidative stress. While oxidative stress following irradiation is generally viewed as detrimental for hippocampal function, it might have beneficial effects as part of an adaptive or preconditioning response to a subsequent challenge. Here we show that in contrast to what is seen in wild-type mice, irradiation enhances hippocampus- dependent cognitive measures in mice lacking extracellular superoxide dismutase. These outcomes were associated with genotype-dependent effects on measures of oxidative stress. When cortices and hippocampi were analyzed for nitrotyrosine formation as an index of oxidative stress, the levels were chronically elevated in mice lacking extracellular superoxide dismutase. However, irradiation caused a greater increase in nitrotyrosine levels in wild-type mice than mice lacking extracellular superoxide dismutase. These paradoxical genotype-dependent effects of irradiation on measures of oxidative stress and cognitive function underscore potential beneficial effects associated with chronic oxidative stress if it exists prior to a secondary insult such as irradiation.Hippocampus 12/2009; 21(1):72-80. · 5.18 Impact Factor -
Article: Radiation-induced reductions in neurogenesis are ameliorated in mice deficient in CuZnSOD or MnSOD.
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ABSTRACT: Ionizing irradiation significantly affects hippocampal neurogenesis and is associated with cognitive impairments; these effects may be influenced by an altered microenvironment. Oxidative stress is a factor that has been shown to affect neurogenesis, and one of the protective pathways that deal with such stress involves the antioxidant enzyme superoxide dismutase (SOD). This study addressed what impact a deficiency in cytoplasmic (SOD1) or mitochondrial (SOD2) SOD has on radiation effects on hippocampal neurogenesis. Wild-type (WT) and SOD1 and SOD2 knockout (KO) mice received a single X-ray dose of 5 Gy, and quantification of the survival and phenotypic fate of newly generated cells in the dentate subgranular zone was performed 2 months later. Radiation exposure reduced neurogenesis in WT mice but had no apparent effect in KO mice, although baseline levels of neurogenesis were reduced in both SOD KO strains before irradiation. Additionally, there were marked and significant differences between WT and both KO strains in how irradiation affected newly generated astrocytes and activated microglia. The mechanism(s) responsible for these effects is not yet known, but a pilot in vitro study suggests a "protective" effect of elevated levels of superoxide. Overall, these data suggest that under conditions of SOD deficiency, there is a common pathway dictating how neurogenesis is affected by ionizing irradiation.Free radical biology & medicine 09/2009; 47(10):1459-67. · 5.42 Impact Factor
