title: Cytokine therapy-mediated neuroprotection in a Friedreich's ataxia mouse model.
abstract: OBJECTIVE
  Friedreich's ataxia is a devastating neurological disease currently lacking any proven treatment. We studied the neuroprotective effects of the cytokines, granulocyte-colony stimulating factor (G-CSF) and stem cell factor (SCF) in a humanized murine model of Friedreich's ataxia.
  
  
  METHODS
  Mice received monthly subcutaneous infusions of cytokines while also being assessed at monthly time points using an extensive range of behavioral motor performance tests. After 6 months of treatment, neurophysiological evaluation of both sensory and motor nerve conduction was performed. Subsequently, mice were sacrificed for messenger RNA, protein, and histological analysis of the dorsal root ganglia, spinal cord, and cerebellum.
  
  
  RESULTS
  Cytokine administration resulted in significant reversal of biochemical, neuropathological, neurophysiological, and behavioural deficits associated with Friedreich's ataxia. Both G-CSF and SCF had pronounced effects on frataxin levels (the primary molecular defect in the pathogenesis of the disease) and a regulators of frataxin expression. Sustained improvements in motor coordination and locomotor activity were observed, even after onset of neurological symptoms. Treatment also restored the duration of sensory nerve compound potentials. Improvements in peripheral nerve conduction positively correlated with cytokine-induced increases in frataxin expression, providing a link between increases in frataxin and neurophysiological function. Abrogation of disease-related pathology was also evident, with reductions in inflammation/gliosis and increased neural stem cell numbers in areas of tissue injury.
  
  
  CONCLUSIONS
  These experiments show that cytokines already clinically used in other conditions offer the prospect of a novel, rapidly translatable, disease-modifying, and neuroprotective treatment for Friedreich's ataxia. Ann Neurol 2017;81:212-226.
authors.affiliation: Multiple Sclerosis and Stem Cell Group, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kemp
authors.affiliation: Sensory and Motor Systems Group, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom.
authors.forename: Nadia
authors.initials: N
authors.lastname: Cerminara
authors.affiliation: Multiple Sclerosis and Stem Cell Group, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hares
authors.affiliation: Multiple Sclerosis and Stem Cell Group, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Juliana
authors.initials: J
authors.lastname: Redondo
authors.affiliation: Multiple Sclerosis and Stem Cell Group, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Cook
authors.affiliation: Brain Tumour Research Group, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Harry R
authors.initials: HR
authors.lastname: Haynes
authors.affiliation: Infection and Immunity, School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Bronwen R
authors.initials: BR
authors.lastname: Burton
authors.affiliation: Synthetic Biology Theme, Institute of Environment, Health & Societies, Biosciences, Dept. of Life Sciences, College of Health & Life Sciences, Brunel University London, London, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Pook
authors.affiliation: Sensory and Motor Systems Group, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Apps
authors.affiliation: Multiple Sclerosis and Stem Cell Group, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Scolding
authors.affiliation: Multiple Sclerosis and Stem Cell Group, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Alastair
authors.initials: A
authors.lastname: Wilkins
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D005621:Friedreich Ataxia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D033862:Iron-Binding Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009431:Neural Conduction / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D010525:Peripheral Nerves / Q000187:drug effects*; D019089:Stem Cell Factor / Q000008:administration & dosage / Q000494:pharmacology*; D000096923:Frataxin
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D033862:Iron-Binding Proteins; D018696:Neuroprotective Agents; D019089:Stem Cell Factor; D000096923:Frataxin