title: Neurological deficits caused by tissue hypoxia in neuroinflammatory disease.
abstract: OBJECTIVE
  To explore the presence and consequences of tissue hypoxia in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).
  
  
  METHODS
  EAE was induced in Dark Agouti rats by immunization with recombinant myelin oligodendrocyte glycoprotein and adjuvant. Tissue hypoxia was assessed in vivo using 2 independent methods: an immunohistochemical probe administered intravenously, and insertion of a physical, oxygen-sensitive probe into the spinal cord. Indirect markers of tissue hypoxia (eg, expression of hypoxia-inducible factor-1α [HIF-1α], vessel diameter, and number of vessels) were also assessed. The effects of brief (1 hour) and continued (7 days) normobaric oxygen treatment on function were evaluated in conjunction with other treatments, namely administration of a mitochondrially targeted antioxidant (MitoQ) and inhibition of inducible nitric oxide synthase (1400W).
  
  
  RESULTS
  Observed neurological deficits were quantitatively, temporally, and spatially correlated with spinal white and gray matter hypoxia. The tissue expression of HIF-1α also correlated with loss of function. Spinal microvessels became enlarged during the hypoxic period, and their number increased at relapse. Notably, oxygen administration significantly restored function within 1 hour, with improvement persisting at least 1 week with continuous oxygen treatment. MitoQ and 1400W also caused a small but significant improvement.
  
  
  CONCLUSIONS
  We present chemical, physical, immunohistochemical, and therapeutic evidence that functional deficits caused by neuroinflammation can arise from tissue hypoxia, consistent with an energy crisis in inflamed central nervous system tissue. The neurological deficit was closely correlated with spinal white and gray matter hypoxia. This realization may indicate new avenues for therapy of neuroinflammatory diseases such as MS.
authors.affiliation: Department of Neuroinflammation, University College London Institute of Neurology, London, United Kingdom.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Davies
authors.forename: Roshni A
authors.initials: RA
authors.lastname: Desai
authors.forename: Peter S
authors.initials: PS
authors.lastname: Bloomfield
authors.forename: Peter R
authors.initials: PR
authors.lastname: McIntosh
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Chapple
authors.forename: Christopher
authors.initials: C
authors.lastname: Linington
authors.forename: Richard
authors.initials: R
authors.lastname: Fairless
authors.forename: Ricarda
authors.initials: R
authors.lastname: Diem
authors.forename: Marianne
authors.initials: M
authors.lastname: Kasti
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Smith
mesh_terms: D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000860:Hypoxia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D018977:Micronutrients / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010100:Oxygen / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D020127:Recovery of Function / Q000187:drug effects; D012720:Severity of Illness Index; D016037:Single-Blind Method; D013118:Spinal Cord Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018977:Micronutrients; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009943:Organophosphorus Compounds; D014451:Ubiquinone; C429014:mitoquinone; D010100:Oxygen