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The lipophilic metal chelators DP‐109 and DP‐460 are neuroprotective in a transgenic mouse model of amyotrophic lateral sclerosis
Author(s) -
Petri Susanne,
Calingasan Noel Y.,
Alsaied Osama A.,
Wille Elizabeth,
Kiaei Mahmoud,
Friedman Jonathan E.,
Baranova Oxana,
Chavez Juan C.,
Beal M. Flint
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04604.x
Subject(s) - neuroprotection , amyotrophic lateral sclerosis , superoxide dismutase , chemistry , oxidative stress , genetically modified mouse , spinal cord , transgene , endocrinology , pharmacology , medicine , biology , biochemistry , neuroscience , disease , gene
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)‐αand α‐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‐1α 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.