title: Antioxidants halt axonal degeneration in a mouse model of X-adrenoleukodystrophy.
abstract: OBJECTIVE
  Axonal degeneration is a main contributor to disability in progressive neurodegenerative diseases in which oxidative stress is often identified as a pathogenic factor. We aim to demonstrate that antioxidants are able to improve axonal degeneration and locomotor deficits in a mouse model of X-adrenoleukodystrophy (X-ALD).
  
  
  METHODS
  X-ALD is a lethal disease caused by loss of function of the ABCD1 peroxisomal transporter of very long chain fatty acids (VLCFA). The mouse model for X-ALD exhibits a late onset neurological phenotype with locomotor disability and axonal degeneration in spinal cord resembling the most common phenotype of the disease, adrenomyeloneuropathy (X-AMN). Recently, we identified oxidative damage as an early event in life, and the excess of VLCFA as a generator of radical oxygen species (ROS) and oxidative damage to proteins in X-ALD.
  
  
  RESULTS
  Here, we prove the capability of the antioxidants N-acetyl-cysteine, α-lipoic acid, and α-tocopherol to scavenge VLCFA-dependent ROS generation in vitro. Furthermore, in a preclinical setting, the cocktail of the 3 compounds reversed: (1) oxidative stress and lesions to proteins, (2) immunohistological signs of axonal degeneration, and (3) locomotor impairment in bar cross and treadmill tests.
  
  
  CONCLUSIONS
  We have established a direct link between oxidative stress and axonal damage in a mouse model of neurodegenerative disease. This conceptual proof of oxidative stress as a major disease-driving factor in X-AMN warrants translation into clinical trials for X-AMN, and invites assessment of antioxidant strategies in axonopathies in which oxidative damage might be a contributing factor.
authors.affiliation: Neurometabolic Diseases Laboratory, The Bellvitge Institute of Biomedical Research, Hospitalet de Liobregat, Barcelona, Spain.
authors.forename: Jone
authors.initials: J
authors.lastname: López-Erauskin
authors.forename: Stéphane
authors.initials: S
authors.lastname: Fourcade
authors.forename: Jorge
authors.initials: J
authors.lastname: Galino
authors.forename: Montserrat
authors.initials: M
authors.lastname: Ruiz
authors.forename: Agatha
authors.initials: A
authors.lastname: Schlüter
authors.forename: Alba
authors.initials: A
authors.lastname: Naudi
authors.forename: Mariona
authors.initials: M
authors.lastname: Jove
authors.forename: Manuel
authors.initials: M
authors.lastname: Portero-Otin
authors.forename: Reinald
authors.initials: R
authors.lastname: Pamplona
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.forename: Aurora
authors.initials: A
authors.lastname: Pujol
mesh_terms: D000326:Adrenoleukodystrophy / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation
chemical_list: D000975:Antioxidants