title: The lipophilic metal chelators DP-109 and DP-460 are neuroprotective in a transgenic mouse model of amyotrophic lateral sclerosis.
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.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, New York, USA. petri.susanne@mh-hannover.de
authors.forename: Susanne
authors.initials: S
authors.lastname: Petri
authors.forename: Noel Y
authors.initials: NY
authors.lastname: Calingasan
authors.forename: Osama A
authors.initials: OA
authors.lastname: Alsaied
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wille
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Kiaei
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Friedman
authors.forename: Oxana
authors.initials: O
authors.lastname: Baranova
authors.forename: Juan C
authors.initials: JC
authors.lastname: Chavez
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002614:Chelating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D008670:Metals / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D015415:Biomarkers; D002614:Chelating Agents; C523466:DP 460; C428063:DP-109; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008563:Membrane Lipids; D008670:Metals; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D004533:Egtazic Acid; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1