title: Correction of humoral derangements from mutant superoxide dismutase 1 spinal cord.
abstract: 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)-1beta, 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-1beta, IL-6, and IL-12.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Yun-Sook
authors.initials: YS
authors.lastname: Kim
authors.forename: Tara
authors.initials: T
authors.lastname: Martinez
authors.forename: Deepa M
authors.initials: DM
authors.lastname: Deshpande
authors.forename: Jennifer
authors.initials: J
authors.lastname: Drummond
authors.forename: Katie
authors.initials: K
authors.lastname: Provost-Javier
authors.forename: Ariel
authors.initials: A
authors.lastname: Williams
authors.forename: Julie
authors.initials: J
authors.lastname: McGurk
authors.forename: Nicholas
authors.initials: N
authors.lastname: Maragakis
authors.forename: Hongjun
authors.initials: H
authors.lastname: Song
authors.forename: Guo-Li
authors.initials: GL
authors.lastname: Ming
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Kerr
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D000818:Animals; D000906:Antibodies / Q000494:pharmacology* / Q000627:therapeutic use; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007378:Interleukins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D009924:Organ Culture Techniques; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000906:Antibodies; D017077:Culture Media, Conditioned; D016166:Free Radical Scavengers; D007378:Interleukins; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase