Demyelinating Diseases: Myeloperoxidase as an Imaging Biomarker and Therapeutic Target

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Myeloperoxidase (MPO) represents a promising therapeutic target, as well as imaging biomarker, for demyelinating diseases and potentially for other diseases in which MPO is implicated.


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.

Materials and 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.


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.


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.

© RSNA, 2012

Supplemental material:


  • 1 Gray E, Thomas TL, Betmouni S, Scolding N, Love S. Elevated myeloperoxidase activity in white matter in multiple sclerosis. Neurosci Lett 2008;444(2):195–198. Crossref, MedlineGoogle Scholar
  • 2 Gray E, Thomas TL, Betmouni S, Scolding N, Love S. Elevated activity and microglial expression of myeloperoxidase in demyelinated cerebral cortex in multiple sclerosis. Brain Pathol 2008;18(1):86–95. Crossref, MedlineGoogle Scholar
  • 3 Heppner FL, Greter M, Marino D, et al.. Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med 2005;11(2):146–152. Crossref, MedlineGoogle Scholar
  • 4 Bartnik BL, Juurlink BH, Devon RM. Macrophages: their myelinotrophic or neurotoxic actions depend upon tissue oxidative stress. Mult Scler 2000;6(1):37–42. Crossref, MedlineGoogle Scholar
  • 5 Jack C, Ruffini F, Bar-Or A, Antel JP. Microglia and multiple sclerosis. J Neurosci Res 2005;81(3):363–373. Crossref, MedlineGoogle Scholar
  • 6 Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med 2000;343(13):938–952. Crossref, MedlineGoogle Scholar
  • 7 Rasmussen S, Wang Y, Kivisäkk P, et al.. Persistent activation of microglia is associated with neuronal dysfunction of callosal projecting pathways and multiple sclerosis-like lesions in relapsing–remitting experimental autoimmune encephalomyelitis. Brain 2007;130(pt 11):2816–2829. Crossref, MedlineGoogle Scholar
  • 8 Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 2004;55(4):458–468. Crossref, MedlineGoogle Scholar
  • 9 Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al.. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005;128(pt 11):2705–2712. Crossref, MedlineGoogle Scholar
  • 10 Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 1998;352(9139):1498–1504. Crossref, MedlineGoogle Scholar
  • 11 Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. European Study Group on interferon beta-1b in secondary progressive MS. Lancet 1998;352(9139):1491–1497. Crossref, MedlineGoogle Scholar
  • 12 Axtell RC, de Jong BA, Boniface K, et al.. T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med 2010;16(4):406–412. Crossref, MedlineGoogle Scholar
  • 13 Jacobs LD, Beck RW, Simon JH, et al.. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000;343(13):898–904. Crossref, MedlineGoogle Scholar
  • 14 Johnson KP, Brooks BR, Cohen JA, et al.. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995;45(7):1268–1276. Crossref, MedlineGoogle Scholar
  • 15 Polman CH, O’Connor PW, Havrdova E, et al.. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354(9):899–910. Crossref, MedlineGoogle Scholar
  • 16 Bradley PP, Christensen RD, Rothstein G. Cellular and extracellular myeloperoxidase in pyogenic inflammation. Blood 1982;60(3):618–622. Crossref, MedlineGoogle Scholar
  • 17 Nagra RM, Becher B, Tourtellotte WW, et al.. Immunohistochemical and genetic evidence of myeloperoxidase involvement in multiple sclerosis. J Neuroimmunol 1997;78(1-2):97–107. Crossref, MedlineGoogle Scholar
  • 18 Heinecke JW. Tyrosyl radical production by myeloperoxidase: a phagocyte pathway for lipid peroxidation and dityrosine cross-linking of proteins. Toxicology 2002;177(1):11–22. Crossref, MedlineGoogle Scholar
  • 19 Zhang R, Brennan ML, Shen Z, et al.. Myeloperoxidase functions as a major enzymatic catalyst for initiation of lipid peroxidation at sites of inflammation. J Biol Chem 2002;277(48):46116–46122. Crossref, MedlineGoogle Scholar
  • 20 Eiserich JP, Baldus S, Brennan ML, et al.. Myeloperoxidase, a leukocyte-derived vascular NO oxidase. Science 2002;296(5577):2391–2394. Crossref, MedlineGoogle Scholar
  • 21 Galijasevic S, Saed GM, Diamond MP, Abu-Soud HM. Myeloperoxidase up-regulates the catalytic activity of inducible nitric oxide synthase by preventing nitric oxide feedback inhibition. Proc Natl Acad Sci U S A 2003;100(25):14766–14771. Crossref, MedlineGoogle Scholar
  • 22 Wang Z, Nicholls SJ, Rodriguez ER, et al.. Protein carbamylation links inflammation, smoking, uremia and atherogenesis. Nat Med 2007;13(10):1176–1184. Crossref, MedlineGoogle Scholar
  • 23 Brennan M, Gaur A, Pahuja A, Lusis AJ, Reynolds WF. Mice lacking myeloperoxidase are more susceptible to experimental autoimmune encephalomyelitis. J Neuroimmunol 2001;112(1-2):97–105. Crossref, MedlineGoogle Scholar
  • 24 Chataway J, Sawcer S, Feakes R, et al.. A screen of candidates from peaks of linkage: evidence for the involvement of myeloperoxidase in multiple sclerosis. J Neuroimmunol 1999;98(2):208–213. Crossref, MedlineGoogle Scholar
  • 25 Nelissen I, Fiten P, Vandenbroeck K, et al.. PECAM1, MPO and PRKAR1A at chromosome 17q21-q24 and susceptibility for multiple sclerosis in Sweden and Sardinia. J Neuroimmunol 2000;108(1-2):153–159. Crossref, MedlineGoogle Scholar
  • 26 Zakrzewska-Pniewska B, Styczynska M, Podlecka A, et al.. Association of apolipoprotein E and myeloperoxidase genotypes to clinical course of familial and sporadic multiple sclerosis. Mult Scler 2004;10(3):266–271. Crossref, MedlineGoogle Scholar
  • 27 Ramsaransing G, Teelken A, Prokopenko VM, Arutjunyan AV, De Keyser J. Low leucocyte myeloperoxidase activity in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2003;74(7):953–955. Crossref, MedlineGoogle Scholar
  • 28 Chen JW, Breckwoldt MO, Aikawa E, Chiang G, Weissleder R. Myeloperoxidase-targeted imaging of active inflammatory lesions in murine experimental autoimmune encephalomyelitis. Brain 2008;131(pt 4):1123–1133. Crossref, MedlineGoogle Scholar
  • 29 Chen JW, Querol Sans M, Bogdanov A, Weissleder R. Imaging of myeloperoxidase in mice by using novel amplifiable paramagnetic substrates. Radiology 2006;240(2):473–481. LinkGoogle Scholar
  • 30 Kettle AJ, Gedye CA, Hampton MB, Winterbourn CC. Inhibition of myeloperoxidase by benzoic acid hydrazides. Biochem J 1995;308(pt 2):559–563. Crossref, MedlineGoogle Scholar
  • 31 Kettle AJ, Gedye CA, Winterbourn CC. Mechanism of inactivation of myeloperoxidase by 4-aminobenzoic acid hydrazide. Biochem J 1997;321(pt 2):503–508. Crossref, MedlineGoogle Scholar
  • 32 Malle E, Furtmüller PG, Sattler W, Obinger C. Myeloperoxidase: a target for new drug development? Br J Pharmacol 2007;152(6):838–854. Crossref, MedlineGoogle Scholar
  • 33 de Haas AH, Boddeke HW, Brouwer N, Biber K. Optimized isolation enables ex vivo analysis of microglia from various central nervous system regions. Glia 2007;55(13):1374–1384. Crossref, MedlineGoogle Scholar
  • 34 Klebanoff SJ, Waltersdorph AM, Rosen H. Antimicrobial activity of myeloperoxidase. Methods Enzymol 1984;105:399–403. Crossref, MedlineGoogle Scholar
  • 35 Shashoua VE. Extracellular fluid proteins of goldfish brain: studies of concentration and labeling patterns. Neurochem Res 1981;6(10):1129–1147. Crossref, MedlineGoogle Scholar
  • 36 Breckwoldt MO, Chen JW, Stangenberg L, et al.. Tracking the inflammatory response in stroke in vivo by sensing the enzyme myeloperoxidase. Proc Natl Acad Sci U S A 2008;105(47):18584–18589. Crossref, MedlineGoogle Scholar
  • 37 Rodríguez E, Nilges M, Weissleder R, Chen JW. Activatable magnetic resonance imaging agents for myeloperoxidase sensing: mechanism of activation, stability, and toxicity. J Am Chem Soc 2010;132(1):168–177. Crossref, MedlineGoogle Scholar
  • 38 Nahrendorf M, Sosnovik D, Chen JW, et al.. Activatable magnetic resonance imaging agent reports myeloperoxidase activity in healing infarcts and noninvasively detects the antiinflammatory effects of atorvastatin on ischemia-reperfusion injury. Circulation 2008;117(9):1153–1160. Crossref, MedlineGoogle Scholar
  • 39 Swirski FK, Wildgruber M, Ueno T, et al.. Myeloperoxidase-rich Ly-6C+ myeloid cells infiltrate allografts and contribute to an imaging signature of organ rejection in mice. J Clin Invest 2010;120(7):2627–2634. Crossref, MedlineGoogle Scholar
  • 40 Ronald JA, Chen JW, Chen Y, et al.. Enzyme-sensitive magnetic resonance imaging targeting myeloperoxidase identifies active inflammation in experimental rabbit atherosclerotic plaques. Circulation 2009;120(7):592–599. Crossref, MedlineGoogle Scholar
  • 41 Rivest S. Regulation of innate immune responses in the brain. Nat Rev Immunol 2009;9(6):429–439. Crossref, MedlineGoogle Scholar
  • 42 Bauer J, Sminia T, Wouterlood FG, Dijkstra CD. Phagocytic activity of macrophages and microglial cells during the course of acute and chronic relapsing experimental autoimmune encephalomyelitis. J Neurosci Res 1994;38(4):365–375. Crossref, MedlineGoogle Scholar
  • 43 Gelderman MP, Stuart R, Vigerust D, et al.. Perpetuation of inflammation associated with experimental arthritis: the role of macrophage activation by neutrophilic myeloperoxidase. Mediators Inflamm 1998;7(6):381–389. Crossref, MedlineGoogle Scholar
  • 44 Klinke A, Nussbaum C, Kubala L, et al.. Myeloperoxidase attracts neutrophils by physical forces. Blood 2011;117(4):1350–1358. Crossref, MedlineGoogle Scholar
  • 45 Lau D, Mollnau H, Eiserich JP, et al.. Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins. Proc Natl Acad Sci U S A 2005;102(2):431–436. Crossref, MedlineGoogle Scholar
  • 46 Lefkowitz DL, Mills K, Morgan D, Lefkowitz SS. Macrophage activation and immunomodulation by myeloperoxidase. Proc Soc Exp Biol Med 1992;199(2):204–210. Crossref, MedlineGoogle Scholar
  • 47 Shepherd VL, Hoidal JR. Clearance of neutrophil-derived myeloperoxidase by the macrophage mannose receptor. Am J Respir Cell Mol Biol 1990;2(4):335–340. Crossref, MedlineGoogle Scholar
  • 48 Lanza F. Clinical manifestation of myeloperoxidase deficiency. J Mol Med (Berl) 1998;76(10):676–681. Crossref, MedlineGoogle Scholar

Article History

Received July 28, 2011; revision requested September 12; final revision received October 4; accepted October 18; final version accepted November 14.
Published online: May 2012
Published in print: May 2012