Abstract
One of the hypotheses for the development of familial amyotrophic lateral sclerosis (ALS) is that mutations in the superoxide dismutase 1 enzyme lead to aberrant properties of the copper within the active site of the enzyme which then causes increased oxidative damage. The lipophilic metal chelators DP-109 and DP-460 which chelate calcium, copper, and zinc were tested in the G93A-transgenic ALS mouse model. Both compounds significantly extended survival, DP-109 (5 mg/kg/day) by 10%, DP-460 (10 mg/kg/day) by 9%. While the effect on survival was relatively small, chelator treatment also improved motor performance, dramatically reduced cell loss in the lumbar spinal cord and decreased reactive astrocytosis and microgliosis. Markers of oxidative damage, tumor necrosis factor (TNF)-alpha and alpha-synuclein were reduced in the lumbar spinal cord of G93A mice treated with DP-109 or DP-460 as compared with vehicle-treated animals. Furthermore, the treatment induced protein expression of the transcription factor hypoxia inducible factor-1alpha and mRNA levels of vascular endothelial growth factor as a corresponding target gene. In line with previous studies using metal chelators in the G93A animal model, our results suggest that these compounds have neuroprotective capacities in ALS.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyotrophic Lateral Sclerosis / drug therapy*
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Amyotrophic Lateral Sclerosis / metabolism
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Amyotrophic Lateral Sclerosis / physiopathology
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Animals
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Biomarkers / metabolism
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Cell Survival / drug effects
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Cell Survival / physiology
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Central Nervous System / drug effects*
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Central Nervous System / metabolism
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Central Nervous System / physiopathology
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Chelating Agents / pharmacology*
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Chelating Agents / therapeutic use
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Disease Models, Animal
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Egtazic Acid / analogs & derivatives*
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Egtazic Acid / pharmacology
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Egtazic Acid / therapeutic use
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Female
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Hypoxia-Inducible Factor 1, alpha Subunit / drug effects
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Male
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Membrane Lipids / metabolism
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Metals / antagonists & inhibitors*
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Metals / metabolism
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Mice
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Mice, Transgenic
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Nerve Degeneration / drug therapy
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Nerve Degeneration / physiopathology
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Nerve Degeneration / prevention & control
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Neuroprotective Agents / pharmacology*
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Neuroprotective Agents / therapeutic use
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Oxidative Stress / drug effects*
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Oxidative Stress / physiology
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RNA, Messenger / drug effects
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RNA, Messenger / metabolism
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism
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Superoxide Dismutase-1
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Treatment Outcome
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Vascular Endothelial Growth Factor A / genetics
Substances
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Biomarkers
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Chelating Agents
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DP 460
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DP-109
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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Membrane Lipids
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Metals
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Neuroprotective Agents
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RNA, Messenger
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, mouse
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Egtazic Acid
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Sod1 protein, mouse
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Superoxide Dismutase
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Superoxide Dismutase-1