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Correction of humoral derangements from mutant superoxide dismutase 1 spinal cord
Author(s) -
Kim YunSook,
Martinez Tara,
Deshpande Deepa M.,
Drummond Jennifer,
ProvostJavier Katie,
Williams Ariel,
McGurk Julie,
Maragakis Nicholas,
Song Hongjun,
Ming GuoLi,
Kerr Douglas A.
Publication year - 2006
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21034
Subject(s) - amyotrophic lateral sclerosis , spinal cord , motor neuron , axon , embryonic stem cell , biology , superoxide dismutase , neuroscience , spinal cord injury , microbiology and biotechnology , immunology , anatomy , pathology , medicine , oxidative stress , endocrinology , biochemistry , gene , disease
Objective We sought to define molecular and cellular participants that mediate motor neuron injury in amyotrophic lateral sclerosis using a coculture system. Methods We cocultured embryonic stem cell–derived motor neurons with organotypic slice cultures from wild‐type or SOD1G93A (MT) mice. We examined axon lengths and cell survival of embryonic stem cell–derived motor neurons. We defined and quantified the humoral factors that differed between wild‐type and MT organotypic cultures, and then corrected these differences in cell culture. Results MT spinal cord organotypic slices were selectively toxic to motor neurons as defined by axonal lengths and cell survival. MT spinal cord organotypic slices secreted higher levels of nitric oxide, interleukin (IL)‐1β, IL‐6, and IL‐12p70 and lower levels of vascular endothelial growth factor. The toxicity of MT spinal cord organotypic cultures was reduced and axonal lengths were restored to near normal by coculturing in the presence of reactive oxygen species scavenger, vascular endothelial growth factor, and neutralizing antibodies to IL‐1β, IL‐6, and IL‐12. Interpretation MT spinal cord organotypic cultures overexpress certain factors and underexpress others, creating a nonpermissive environment for cocultured motor neurons. Correction of these abnormalities as a group, but not individually, restores axonal length to near normal. Such a “cocktail” approach to the treatment of amyotrophic lateral sclerosis should be investigated further. Ann Neurol 2006;60:716–728