title: Demyelinating diseases: myeloperoxidase as an imaging biomarker and therapeutic target.
abstract: OBJECTIVE
  To evaluate myeloperoxidase (MPO) as a newer therapeutic target and bis-5-hydroxytryptamide-diethylenetriaminepentaacetate-gadolinium (Gd) (MPO-Gd) as an imaging biomarker for demyelinating diseases such as multiple sclerosis (MS) by using experimental autoimmune encephalomyelitis (EAE), a murine model of MS.
  
  
  METHODS
  Animal experiments were approved by the institutional animal care committee. EAE was induced in SJL mice by using proteolipid protein (PLP), and mice were treated with either 4-aminobenzoic acid hydrazide (ABAH), 40 mg/kg injected intraperitoneally, an irreversible inhibitor of MPO, or saline as control, and followed up to day 40 after induction. In another group of SJL mice, induction was performed without PLP as shams. The mice were imaged by using MPO-Gd to track changes in MPO activity noninvasively. Imaging results were corroborated by enzymatic assays, flow cytometry, and histopathologic analyses. Significance was computed by using the t test or Mann-Whitney U test.
  
  
  RESULTS
  There was a 2.5-fold increase in myeloid cell infiltration in the brain (P = .026), with a concomitant increase in brain MPO level (P = .0087). Inhibiting MPO activity with ABAH resulted in decrease in MPO-Gd-positive lesion volume (P = .012), number (P = .009), and enhancement intensity (P = .03) at MR imaging, reflecting lower local MPO activity (P = .03), compared with controls. MPO inhibition was accompanied by decreased demyelination (P = .01) and lower inflammatory cell recruitment in the brain (P < .0001), suggesting a central MPO role in inflammatory demyelination. Clinically, MPO inhibition significantly reduced the severity of clinical symptoms (P = .0001) and improved survival (P = .0051) in mice with EAE.
  
  
  CONCLUSIONS
  MPO may be a key mediator of myeloid inflammation and tissue damage in EAE. Therefore, MPO could represent a promising therapeutic target, as well as an imaging biomarker, for demyelinating diseases and potentially for other diseases in which MPO is implicated.
authors.affiliation: Center for Systems Biology, Harvard Medical School, Richard B. Simches Research Center, Boston, MA 02114, USA.
authors.forename: Reza
authors.initials: R
authors.lastname: Forghani
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Wojtkiewicz
authors.forename: Yinian
authors.initials: Y
authors.lastname: Zhang
authors.forename: Daniel
authors.initials: D
authors.lastname: Seeburg
authors.forename: Benjamin R M
authors.initials: BR
authors.lastname: Bautz
authors.forename: Benjamin
authors.initials: B
authors.lastname: Pulli
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Milewski
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Atkinson
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Zhang
authors.forename: Martin
authors.initials: M
authors.lastname: Etzrodt
authors.forename: Elisenda
authors.initials: E
authors.lastname: Rodriguez
authors.forename: Clinton S
authors.initials: CS
authors.lastname: Robbins
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: John W
authors.initials: JW
authors.lastname: Chen
mesh_terms: D010129:4-Aminobenzoic Acid; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D003287:Contrast Media; D003711:Demyelinating Diseases / Q000175:diagnosis* / Q000201:enzymology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000175:diagnosis* / Q000201:enzymology*; D005260:Female; D005434:Flow Cytometry; D005682:Gadolinium; D007124:Immunoenzyme Techniques; D051379:Mice; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D009195:Peroxidase / Q000378:metabolism*; D018709:Statistics, Nonparametric
chemical_list: D015415:Biomarkers; D003287:Contrast Media; D005682:Gadolinium; D009195:Peroxidase; D010129:4-Aminobenzoic Acid