Abstract
The toxin beta-methylamino-l-alanine (BMAA) has been proposed to contribute to amyotrophic lateral sclerosis-Parkinsonism Dementia Complex of Guam (ALS/PDC) based on its ability to induce a similar disease phenotype in primates and its presence in cycad seeds, which constituted a dietary item in afflicted populations. Concerns about the apparent low potency of this toxin in relation to estimated levels of human ingestion led to a slowing of BMAA research. However, recent reports identifying potential new routes of exposure compel a re-examination of the BMAA/cycad hypothesis. BMAA was found to induce selective motor neuron (MN) loss in dissociated mixed spinal cord cultures at concentrations ( approximately 30 muM) significantly lower than those previously found to induce widespread neuronal degeneration. The glutamate receptor antagonist NBQX prevented BMAA-induced death, implicating excitotoxic activation of AMPA/kainate receptors. Using microfluorimetric techniques, we further found that BMAA induced preferential [Ca(2+)](i) rises and selective reactive oxygen species (ROS) generation in MNs with minimal effect on other spinal neurons. Cycad seed extracts also triggered preferential AMPA/kainate-receptor-dependent MN injury, consistent with the idea that BMAA is a crucial toxic component in this plant. Present findings support the hypothesis that BMAA may contribute to the selective MN loss in ALS/PDC.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acids, Diamino / administration & dosage
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Amino Acids, Diamino / toxicity*
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Amyotrophic Lateral Sclerosis / etiology
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Amyotrophic Lateral Sclerosis / metabolism
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Amyotrophic Lateral Sclerosis / pathology
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Animals
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Calcium / metabolism
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Cell Survival / drug effects
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Cells, Cultured
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Cyanobacteria Toxins
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Cycas / chemistry
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Dose-Response Relationship, Drug
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Excitatory Amino Acid Agonists / administration & dosage
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Excitatory Amino Acid Agonists / toxicity
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Excitatory Amino Acid Antagonists / pharmacology
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Humans
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Mice
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Motor Neurons / cytology
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Motor Neurons / drug effects*
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Motor Neurons / metabolism
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Neurotoxins / administration & dosage
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Neurotoxins / toxicity
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Plant Extracts / administration & dosage
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Plant Extracts / toxicity
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Plant Poisoning / etiology
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Plant Poisoning / metabolism
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Plant Poisoning / pathology
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Quinoxalines / pharmacology
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Reactive Oxygen Species / metabolism
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Receptors, AMPA / agonists
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Receptors, AMPA / antagonists & inhibitors
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Receptors, AMPA / metabolism*
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Receptors, Kainic Acid / agonists
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Receptors, Kainic Acid / antagonists & inhibitors
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Receptors, Kainic Acid / metabolism*
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Seeds / chemistry
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Spinal Cord / cytology
Substances
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Amino Acids, Diamino
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Cyanobacteria Toxins
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Excitatory Amino Acid Agonists
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Excitatory Amino Acid Antagonists
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Neurotoxins
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Plant Extracts
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Quinoxalines
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Reactive Oxygen Species
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Receptors, AMPA
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Receptors, Kainic Acid
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beta-N-methylamino-L-alanine
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2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
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Calcium