The Experts below are selected from a list of 114 Experts worldwide ranked by ideXlab platform
Glen E Kisby - One of the best experts on this subject based on the ideXlab platform.
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Cycad β-N-methylamino-L-alanine (BMAA), methylazoxymethanol, genotoxicity, and neurodegeneration
Toxicon, 2018Co-Authors: Peter S Spencer, Valerie S. Palmer, Glen E KisbyAbstract:Abstract Cycad-associated neurodegenerative disease is more strongly correlated with the gymnosperm's major neurotoxin Cycasin (methylazoxymethanol glucoside) than with the minor neurotoxin β-N-methylamino-L-alanine (L-BMAA).
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Animal models of brain maldevelopment induced by cycad plant genotoxins.
Birth Defects Research Part C-embryo Today-reviews, 2013Co-Authors: Glen E Kisby, Holly Moore, Peter S SpencerAbstract:Cycads are long-lived tropical and subtropical plants that contain azoxyglycosides (e.g., Cycasin, macrozamin) and neurotoxic amino acids (notably β-N-methylamino-L-alanine L-BMAA), toxins that have been implicated in the etiology of a disappearing neurodegenerative disease, amyotrophic lateral sclerosis and parkinsonism-dementia complex that has been present in high incidence among three genetically distinct populations in the western Pacific. The neuropathology of amyotrophic lateral sclerosis/parkinsonism-dementia complex includes features suggestive of brain maldevelopment, an experimentally proven property of Cycasin attributable to the genotoxic action of its aglycone methylazoxymethanol (MAM). This property of MAM has been exploited by neurobiologists as a tool to study perturbations of brain development. Depending on the neurodevelopmental stage, MAM can induce features in laboratory animals that model certain characteristics of epilepsy, schizophrenia, or ataxia. Studies in DNA repair-deficient mice show that MAM perturbs brain development through a DNA damage-mediated mechanism. The brain DNA lesions produced by systemic MAM appear to modulate the expression of genes that regulate neurodevelopment and contribute to neurodegeneration. Epigenetic changes (histone lysine methylation) have also been detected in the underdeveloped brain after MAM administration. The DNA damage and epigenetic changes produced by MAM and, perhaps by chemically related substances (e.g., nitrosamines, nitrosoureas, hydrazines), might be an important mechanism by which early-life exposure to genotoxicants can induce long-term brain dysfunction.
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Does the cycad genotoxin MAM implicated in Guam ALS-PDC induce disease-relevant changes in mouse brain that includes olfaction?
Communicative & Integrative Biology, 2011Co-Authors: Glen E Kisby, Valerie S. Palmer, Michael R. Lasarev, Mihail S. Iordanov, Eli A. Magun, Leona D. Samson, Peter S SpencerAbstract:Western Pacific amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC), a prototypical neurodegenerative disease (tauopathy) affecting distinct genetic groups with common exposure to neurotoxic chemicals in cycad seed, has many features of Parkinson's and Alzheimer's diseases (AD), including early olfactory dysfunction. Guam ALS-PDC incidence correlates with cycad flour content of Cycasin and its aglycone methylazoxymethanol (MAM), which produces persistent DNA damage (O6-methylguanine) in the brains of mice lacking O6-methylguanine methyltransferase (Mgmt-/-). We described in Mgmt-/-mice up to 7 days post-MAM treatment that brain DNA damage was linked to brain gene expression changes found in human neurological disease, cancer, and skin and hair development. This addendum reports 6 months post-MAM treatment- related brain transcriptional changes as well as elevated mitogen activated protein kinases and increased caspase-3 activity, both of which are involved in tau aggregation and neurofibrillary tangle formation typical of ALS-PDC and AD, plus transcriptional changes in olfactory receptors. Does Cycasin act as a "slow (geno)toxin" in ALS-PDC?
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Is Neurodegenerative Disease a Long-Latency Response to Early-Life Genotoxin Exposure?
International Journal of Environmental Research and Public Health, 2011Co-Authors: Glen E Kisby, Peter S SpencerAbstract:Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex, a disappearing neurodegenerative disease linked to use of the neurotoxic cycad plant for food and/or medicine, is intensively studied because the neuropathology (tauopathy) is similar to that of Alzheimer’s disease. Cycads contain neurotoxic and genotoxic principles, notably Cycasin and methylazoxymethanol, the latter sharing chemical relations with nitrosamines, which are derived from nitrates and nitrites in preserved meats and fertilizers, and also used in the rubber and leather industries. This review includes new data that influence understanding of the neurobiological actions of cycad and related genotoxins and the putative mechanisms by which they might trigger neurodegenerative disease.
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The Cycad Genotoxin MAM Modulates Brain Cellular Pathways Involved in Neurodegenerative Disease and Cancer in a DNA Damage-Linked Manner
PLOS ONE, 2011Co-Authors: Glen E Kisby, Valerie S. Palmer, Michael R. Lasarev, Theodor K. Bammler, Richard P. Beyer, Mona I. Churchwell, Daniel R. Doerge, Lisiane B. Meira, Ana Luiza Ramos-crawfordAbstract:Methylazoxymethanol (MAM), the genotoxic metabolite of the cycad azoxyglucoside Cycasin, induces genetic alterations in bacteria, yeast, plants, insects and mammalian cells, but adult nerve cells are thought to be unaffected. We show that the brains of adult C57BL6 wild-type mice treated with a single systemic dose of MAM acetate display DNA damage (O6-methyldeoxyguanosine lesions, O6-mG) that remains constant up to 7 days post-treatment. By contrast, MAM-treated mice lacking a functional gene encoding the DNA repair enzyme O6-mG DNA methyltransferase (MGMT) showed elevated O6-mG DNA damage starting at 48 hours post-treatment. The DNA damage was linked to changes in the expression of genes in cell-signaling pathways associated with cancer, human neurodegenerative disease, and neurodevelopmental disorders. These data are consistent with the established developmental neurotoxic and carcinogenic properties of MAM in rodents. They also support the hypothesis that early-life exposure to MAM-glucoside (Cycasin) has an etiological association with a declining, prototypical neurodegenerative disease seen in Guam, Japan, and New Guinea populations that formerly used the neurotoxic cycad plant for food or medicine, or both. These findings suggest environmental genotoxins, specifically MAM, target common pathways involved in neurodegeneration and cancer, the outcome depending on whether the cell can divide (cancer) or not (neurodegeneration). Exposure to MAM-related environmental genotoxins may have relevance to the etiology of related tauopathies, notably, Alzheimer's disease.
Peter S Spencer - One of the best experts on this subject based on the ideXlab platform.
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Cycad β-N-methylamino-L-alanine (BMAA), methylazoxymethanol, genotoxicity, and neurodegeneration
Toxicon, 2018Co-Authors: Peter S Spencer, Valerie S. Palmer, Glen E KisbyAbstract:Abstract Cycad-associated neurodegenerative disease is more strongly correlated with the gymnosperm's major neurotoxin Cycasin (methylazoxymethanol glucoside) than with the minor neurotoxin β-N-methylamino-L-alanine (L-BMAA).
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Animal models of brain maldevelopment induced by cycad plant genotoxins.
Birth Defects Research Part C-embryo Today-reviews, 2013Co-Authors: Glen E Kisby, Holly Moore, Peter S SpencerAbstract:Cycads are long-lived tropical and subtropical plants that contain azoxyglycosides (e.g., Cycasin, macrozamin) and neurotoxic amino acids (notably β-N-methylamino-L-alanine L-BMAA), toxins that have been implicated in the etiology of a disappearing neurodegenerative disease, amyotrophic lateral sclerosis and parkinsonism-dementia complex that has been present in high incidence among three genetically distinct populations in the western Pacific. The neuropathology of amyotrophic lateral sclerosis/parkinsonism-dementia complex includes features suggestive of brain maldevelopment, an experimentally proven property of Cycasin attributable to the genotoxic action of its aglycone methylazoxymethanol (MAM). This property of MAM has been exploited by neurobiologists as a tool to study perturbations of brain development. Depending on the neurodevelopmental stage, MAM can induce features in laboratory animals that model certain characteristics of epilepsy, schizophrenia, or ataxia. Studies in DNA repair-deficient mice show that MAM perturbs brain development through a DNA damage-mediated mechanism. The brain DNA lesions produced by systemic MAM appear to modulate the expression of genes that regulate neurodevelopment and contribute to neurodegeneration. Epigenetic changes (histone lysine methylation) have also been detected in the underdeveloped brain after MAM administration. The DNA damage and epigenetic changes produced by MAM and, perhaps by chemically related substances (e.g., nitrosamines, nitrosoureas, hydrazines), might be an important mechanism by which early-life exposure to genotoxicants can induce long-term brain dysfunction.
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Does the cycad genotoxin MAM implicated in Guam ALS-PDC induce disease-relevant changes in mouse brain that includes olfaction?
Communicative & Integrative Biology, 2011Co-Authors: Glen E Kisby, Valerie S. Palmer, Michael R. Lasarev, Mihail S. Iordanov, Eli A. Magun, Leona D. Samson, Peter S SpencerAbstract:Western Pacific amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC), a prototypical neurodegenerative disease (tauopathy) affecting distinct genetic groups with common exposure to neurotoxic chemicals in cycad seed, has many features of Parkinson's and Alzheimer's diseases (AD), including early olfactory dysfunction. Guam ALS-PDC incidence correlates with cycad flour content of Cycasin and its aglycone methylazoxymethanol (MAM), which produces persistent DNA damage (O6-methylguanine) in the brains of mice lacking O6-methylguanine methyltransferase (Mgmt-/-). We described in Mgmt-/-mice up to 7 days post-MAM treatment that brain DNA damage was linked to brain gene expression changes found in human neurological disease, cancer, and skin and hair development. This addendum reports 6 months post-MAM treatment- related brain transcriptional changes as well as elevated mitogen activated protein kinases and increased caspase-3 activity, both of which are involved in tau aggregation and neurofibrillary tangle formation typical of ALS-PDC and AD, plus transcriptional changes in olfactory receptors. Does Cycasin act as a "slow (geno)toxin" in ALS-PDC?
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Is Neurodegenerative Disease a Long-Latency Response to Early-Life Genotoxin Exposure?
International Journal of Environmental Research and Public Health, 2011Co-Authors: Glen E Kisby, Peter S SpencerAbstract:Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex, a disappearing neurodegenerative disease linked to use of the neurotoxic cycad plant for food and/or medicine, is intensively studied because the neuropathology (tauopathy) is similar to that of Alzheimer’s disease. Cycads contain neurotoxic and genotoxic principles, notably Cycasin and methylazoxymethanol, the latter sharing chemical relations with nitrosamines, which are derived from nitrates and nitrites in preserved meats and fertilizers, and also used in the rubber and leather industries. This review includes new data that influence understanding of the neurobiological actions of cycad and related genotoxins and the putative mechanisms by which they might trigger neurodegenerative disease.
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The Guam Cycad Toxin Methylazoxymethanol Damages Neuronal DNA and Modulates Tau mRNA Expression and Excitotoxicity
Experimental Neurology, 1999Co-Authors: Françoise Esclaire, Glen E Kisby, Peter S Spencer, John Milne, Mathieu Lesort, Jacques HugonAbstract:Abstract As in Alzheimer's disease, brains of Guam Chamorros with amyotrophic lateral sclerosis (ALS) and Parkinsonism–dementia complex (PDC) contain intraneuronal-paired helical filaments composed of accumulated phosphorylated tau protein. Tau mRNA expression in rat neuronal cultures—normally modulated by glutamate—increases after treatment with the aglycone of Cycasin, a cycad-derived toxin whose concentration in Chamorro food varies with disease incidence. ElevatedTaugene expressionin vitrois coincident with increased Cycasin-related DNA adducts and reduced DNA repair. Cycasin and endogenous glutamate may together promote the accumulation of tau protein and neuronal degeneration in Western Pacific ALS/PDC.
Toshiyuki Matsuoka - One of the best experts on this subject based on the ideXlab platform.
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na dependent and phlorizin inhibitable transport of glucose and Cycasin in brain endothelial cells
Journal of Neurochemistry, 2002Co-Authors: Toshiyuki Matsuoka, Tomoyuki Nishizaki, Glen E KisbyAbstract:Abstract: Although Cycasin (methylazoxymethanol β-d-glucoside) is proposed to be a significant etiological factor for the prototypical neurodegenerative disorder Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex, the mechanism underlying transport of Cycasin across the blood-brain barrier (BBB) is unknown. We examined Cycasin transport in cultured bovine brain endothelial cells, a major element of the BBB. Cycasin was taken up into endothelial cells in a dose-dependent manner with maximal uptake observed at a concentration of 10 µM. Cycasin uptake was significantly inhibited by α-methyl-d-glucoside, a specific analogue for the Na+-dependent glucose transporter (SGLT), by the SGLT inhibitor phlorizin, by replacement of extracellular NaCl with LiCl, and by dinitrophenol (DNP), an inhibitor of energy metabolism. In addition, Cycasin produced inward currents in a whole-cell voltage clamp configuration. Peak currents were observed at 10 µM with a trend toward reduction at higher concentrations, and currents were clearly blocked by α-methyl-d-glucoside, phlorizin, and DNP. In addition, Cycasin never evoked currents in Na+-free extracellular solution. These results suggest that Cycasin is selectively transported across brain endothelial cells, possibly across the BBB by a Na+/energy-dependent glucose transporter.
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Na+‐Dependent and Phlorizin‐Inhibitable Transport of Glucose and Cycasin in Brain Endothelial Cells
Journal of Neurochemistry, 2002Co-Authors: Toshiyuki Matsuoka, Tomoyuki Nishizaki, Glen E KisbyAbstract:Abstract: Although Cycasin (methylazoxymethanol β-d-glucoside) is proposed to be a significant etiological factor for the prototypical neurodegenerative disorder Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex, the mechanism underlying transport of Cycasin across the blood-brain barrier (BBB) is unknown. We examined Cycasin transport in cultured bovine brain endothelial cells, a major element of the BBB. Cycasin was taken up into endothelial cells in a dose-dependent manner with maximal uptake observed at a concentration of 10 µM. Cycasin uptake was significantly inhibited by α-methyl-d-glucoside, a specific analogue for the Na+-dependent glucose transporter (SGLT), by the SGLT inhibitor phlorizin, by replacement of extracellular NaCl with LiCl, and by dinitrophenol (DNP), an inhibitor of energy metabolism. In addition, Cycasin produced inward currents in a whole-cell voltage clamp configuration. Peak currents were observed at 10 µM with a trend toward reduction at higher concentrations, and currents were clearly blocked by α-methyl-d-glucoside, phlorizin, and DNP. In addition, Cycasin never evoked currents in Na+-free extracellular solution. These results suggest that Cycasin is selectively transported across brain endothelial cells, possibly across the BBB by a Na+/energy-dependent glucose transporter.
Tomoyuki Nishizaki - One of the best experts on this subject based on the ideXlab platform.
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na dependent and phlorizin inhibitable transport of glucose and Cycasin in brain endothelial cells
Journal of Neurochemistry, 2002Co-Authors: Toshiyuki Matsuoka, Tomoyuki Nishizaki, Glen E KisbyAbstract:Abstract: Although Cycasin (methylazoxymethanol β-d-glucoside) is proposed to be a significant etiological factor for the prototypical neurodegenerative disorder Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex, the mechanism underlying transport of Cycasin across the blood-brain barrier (BBB) is unknown. We examined Cycasin transport in cultured bovine brain endothelial cells, a major element of the BBB. Cycasin was taken up into endothelial cells in a dose-dependent manner with maximal uptake observed at a concentration of 10 µM. Cycasin uptake was significantly inhibited by α-methyl-d-glucoside, a specific analogue for the Na+-dependent glucose transporter (SGLT), by the SGLT inhibitor phlorizin, by replacement of extracellular NaCl with LiCl, and by dinitrophenol (DNP), an inhibitor of energy metabolism. In addition, Cycasin produced inward currents in a whole-cell voltage clamp configuration. Peak currents were observed at 10 µM with a trend toward reduction at higher concentrations, and currents were clearly blocked by α-methyl-d-glucoside, phlorizin, and DNP. In addition, Cycasin never evoked currents in Na+-free extracellular solution. These results suggest that Cycasin is selectively transported across brain endothelial cells, possibly across the BBB by a Na+/energy-dependent glucose transporter.
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Na+‐Dependent and Phlorizin‐Inhibitable Transport of Glucose and Cycasin in Brain Endothelial Cells
Journal of Neurochemistry, 2002Co-Authors: Toshiyuki Matsuoka, Tomoyuki Nishizaki, Glen E KisbyAbstract:Abstract: Although Cycasin (methylazoxymethanol β-d-glucoside) is proposed to be a significant etiological factor for the prototypical neurodegenerative disorder Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex, the mechanism underlying transport of Cycasin across the blood-brain barrier (BBB) is unknown. We examined Cycasin transport in cultured bovine brain endothelial cells, a major element of the BBB. Cycasin was taken up into endothelial cells in a dose-dependent manner with maximal uptake observed at a concentration of 10 µM. Cycasin uptake was significantly inhibited by α-methyl-d-glucoside, a specific analogue for the Na+-dependent glucose transporter (SGLT), by the SGLT inhibitor phlorizin, by replacement of extracellular NaCl with LiCl, and by dinitrophenol (DNP), an inhibitor of energy metabolism. In addition, Cycasin produced inward currents in a whole-cell voltage clamp configuration. Peak currents were observed at 10 µM with a trend toward reduction at higher concentrations, and currents were clearly blocked by α-methyl-d-glucoside, phlorizin, and DNP. In addition, Cycasin never evoked currents in Na+-free extracellular solution. These results suggest that Cycasin is selectively transported across brain endothelial cells, possibly across the BBB by a Na+/energy-dependent glucose transporter.
Phillip R Ackery - One of the best experts on this subject based on the ideXlab platform.
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the protective role of Cycasin in cycad feeding lepidoptera
Phytochemistry, 1992Co-Authors: Robert J Nash, Arthur E Bell, Phillip R AckeryAbstract:Abstract Cycasin was detected in dried museum specimens of the cycad-feeding butterflies Taenaris butleri , T. catops , T. onolaus and Luthrodes cleotas , but was absent from the more cryptic species Theclinesthes onycha . It is suggested that in New Guinea the toxic Taenaris species are models for a mimicry complex that involves various butterfly species, including other Taenaris .
