title: Granulocyte colony stimulating factor attenuates inflammation in a mouse model of amyotrophic lateral sclerosis.
abstract: BACKGROUND
  Granulocyte colony stimulating factor (GCSF) is protective in animal models of various neurodegenerative diseases. We investigated whether pegfilgrastim, GCSF with sustained action, is protective in a mouse model of amyotrophic lateral sclerosis (ALS). ALS is a fatal neurodegenerative disease with manifestations of upper and lower motoneuron death and muscle atrophy accompanied by inflammation in the CNS and periphery.
  
  
  METHODS
  Human mutant G93A superoxide dismutase (SOD1) ALS mice were treated with pegfilgrastim starting at the presymptomatic stage and continued until the end stage. After long-term pegfilgrastim treatment, the inflammation status was defined in the spinal cord and peripheral tissues including hematopoietic organs and muscle. The effect of GCSF on spinal cord neuron survival and microglia, bone marrow and spleen monocyte activation was assessed in vitro.
  
  
  RESULTS
  Long-term pegfilgrastim treatment prolonged mutant SOD1 mice survival and attenuated both astro- and microgliosis in the spinal cord. Pegfilgrastim in SOD1 mice modulated the inflammatory cell populations in the bone marrow and spleen and reduced the production of pro-inflammatory cytokine in monocytes and microglia. The mobilization of hematopoietic stem cells into the circulation was restored back to basal level after long-term pegfilgrastim treatment in SOD1 mice while the storage of Ly6C expressing monocytes in the bone marrow and spleen remained elevated. After pegfilgrastim treatment, an increased proportion of these cells in the degenerative muscle was detected at the end stage of ALS.
  
  
  CONCLUSIONS
  GCSF attenuated inflammation in the CNS and the periphery in a mouse model of ALS and thereby delayed the progression of the disease. This mechanism of action targeting inflammation provides a new perspective of the usage of GCSF in the treatment of ALS.
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Eveliina
authors.initials: E
authors.lastname: Pollari
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Savchenko
authors.forename: Merja
authors.initials: M
authors.lastname: Jaronen
authors.forename: Katja
authors.initials: K
authors.lastname: Kanninen
authors.forename: Tarja
authors.initials: T
authors.lastname: Malm
authors.forename: Sara
authors.initials: S
authors.lastname: Wojciechowski
authors.forename: Toni
authors.initials: T
authors.lastname: Ahtoniemi
authors.forename: Gundars
authors.initials: G
authors.lastname: Goldsteins
authors.forename: Raisa
authors.initials: R
authors.lastname: Giniatullina
authors.forename: Rashid
authors.initials: R
authors.lastname: Giniatullin
authors.forename: Jari
authors.initials: J
authors.lastname: Koistinaho
authors.forename: Johanna
authors.initials: J
authors.lastname: Magga
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011092:Polyethylene Glycols; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013116:Spinal Cord / Q000166:cytology; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013482:Superoxide Dismutase / Q000276:immunology; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D000069585:Filgrastim