title: Myeloperoxidase Nuclear Imaging for Epileptogenesis.
abstract: OBJECTIVE
  To determine if myeloperoxidase (MPO) is involved in epileptogenesis and if molecular nuclear imaging can be used to noninvasively map inflammatory changes in epileptogenesis.
  
  
  METHODS
  The animal and human studies were approved by the institutional review boards. Pilocarpine-induced epileptic mice were treated with 4-aminobenzoic acid hydrazide (n = 46), a specific irreversible MPO inhibitor, or saline (n = 42). Indium-111-bis-5-hydroxytryptamide-diethylenetriaminepentaacetate was used to image brain MPO activity (n = 6 in the 4-aminobenzoic acid hydrazide and saline groups; n = 5 in the sham group) by using single photon emission computed tomography/computed tomography. The role of MPO in the development of spontaneous recurrent seizures was assessed by means of clinical symptoms and biochemical and histopathologic data. Human brain specimens from a patient with epilepsy and a patient without epilepsy were stained for MPO. The Student t test, one-way analysis of variance, and Mann-Whitney and Kruskal-Wallis tests were used. Differences were regarded as significant if P was less than .05.
  
  
  RESULTS
  MPO and leukocytes increased in the brain during epileptogenesis (P < .05). Blocking MPO delayed spontaneous recurrent seizures (99.6 vs 142 hours, P = .016), ameliorated the severity of spontaneous recurrent seizures (P < .05), and inhibited mossy fiber sprouting (Timm index, 0.31 vs 0.03; P = .003). Matrix metalloproteinase activity was upregulated during epileptogenesis in an MPO-dependent manner (1.44 vs 0.94 U/mg, P = .049), suggesting that MPO acts upstream of matrix metalloproteinases. MPO activity was mapped during epileptogenesis in vivo in the hippocampal regions. Resected temporal lobe tissue from a human patient with refractory epilepsy but not the temporal lobe tissue from a patient without seizures demonstrated positive MPO immunostaining, suggesting high translational potential for this imaging technology.
  
  
  CONCLUSIONS
  The findings of this study highlight an important role for MPO in epileptogenesis and show MPO to be a potential therapeutic target and imaging biomarker for epilepsy.
authors.affiliation: From the Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China (Y.Z., Y.P.); Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114 (Y.Z., D.P.S., B.P., G.R.W., L.B., W.A., S.S., Y.I., M.A., E.R., A.M., E.J.K., C.W., F.K.S., J.W.C.); and Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass (W.Z.).
authors.forename: Yinian
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China (Y.Z., Y.P.); Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114 (Y.Z., D.P.S., B.P., G.R.W., L.B., W.A., S.S., Y.I., M.A., E.R., A.M., E.J.K., C.W., F.K.S., J.W.C.); and Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass (W.Z.).
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Seeburg
authors.affiliation: From the Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China (Y.Z., Y.P.); Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114 (Y.Z., D.P.S., B.P., G.R.W., L.B., W.A., S.S., Y.I., M.A., E.R., A.M., E.J.K., C.W., F.K.S., J.W.C.); and Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass (W.Z.).
authors.forename: Benjamin
authors.initials: B
authors.lastname: Pulli
authors.affiliation: From the Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China (Y.Z., Y.P.); Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114 (Y.Z., D.P.S., B.P., G.R.W., L.B., W.A., S.S., Y.I., M.A., E.R., A.M., E.J.K., C.W., F.K.S., J.W.C.); and Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass (W.Z.).
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Wojtkiewicz
authors.affiliation: From the Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China (Y.Z., Y.P.); Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114 (Y.Z., D.P.S., B.P., G.R.W., L.B., W.A., S.S., Y.I., M.A., E.R., A.M., E.J.K., C.W., F.K.S., J.W.C.); and Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass (W.Z.).
authors.forename: Lionel
authors.initials: L
authors.lastname: Bure
authors.affiliation: From the Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China (Y.Z., Y.P.); Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114 (Y.Z., D.P.S., B.P., G.R.W., L.B., W.A., S.S., Y.I., M.A., E.R., A.M., E.J.K., C.W., F.K.S., J.W.C.); and Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass (W.Z.).
authors.forename: Wendy
authors.initials: W
authors.lastname: Atkinson
authors.affiliation: From the Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China (Y.Z., Y.P.); Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114 (Y.Z., D.P.S., B.P., G.R.W., L.B., W.A., S.S., Y.I., M.A., E.R., A.M., E.J.K., C.W., F.K.S., J.W.C.); and Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass (W.Z.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Schob
authors.affiliation: From the Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China (Y.Z., Y.P.); Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114 (Y.Z., D.P.S., B.P., G.R.W., L.B., W.A., S.S., Y.I., M.A., E.R., A.M., E.J.K., C.W., F.K.S., J.W.C.); and Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass (W.Z.).
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: From the Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China (Y.Z., Y.P.); Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114 (Y.Z., D.P.S., B.P., G.R.W., L.B., W.A., S.S., Y.I., M.A., E.R., A.M., E.J.K., C.W., F.K.S., J.W.C.); and Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass (W.Z.).
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ali
authors.affiliation: From the Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China (Y.Z., Y.P.); Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114 (Y.Z., D.P.S., B.P., G.R.W., L.B., W.A., S.S., Y.I., M.A., E.R., A.M., E.J.K., C.W., F.K.S., J.W.C.); and Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass (W.Z.).
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: From the Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China (Y.Z., Y.P.); Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114 (Y.Z., D.P.S., B.P., G.R.W., L.B., W.A., S.S., Y.I., M.A., E.R., A.M., E.J.K., C.W., F.K.S., J.W.C.); and Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass (W.Z.).
authors.forename: Elisenda
authors.initials: E
authors.lastname: Rodriguez
authors.affiliation: From the Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China (Y.Z., Y.P.); Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114 (Y.Z., D.P.S., B.P., G.R.W., L.B., W.A., S.S., Y.I., M.A., E.R., A.M., E.J.K., C.W., F.K.S., J.W.C.); and Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass (W.Z.).
authors.forename: Andrew
authors.initials: A
authors.lastname: Milewski
authors.affiliation: From the Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China (Y.Z., Y.P.); Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114 (Y.Z., D.P.S., B.P., G.R.W., L.B., W.A., S.S., Y.I., M.A., E.R., A.M., E.J.K., C.W., F.K.S., J.W.C.); and Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass (W.Z.).
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Keliher
authors.affiliation: From the Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China (Y.Z., Y.P.); Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114 (Y.Z., D.P.S., B.P., G.R.W., L.B., W.A., S.S., Y.I., M.A., E.R., A.M., E.J.K., C.W., F.K.S., J.W.C.); and Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass (W.Z.).
authors.forename: Cuihua
authors.initials: C
authors.lastname: Wang
authors.affiliation: From the Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China (Y.Z., Y.P.); Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114 (Y.Z., D.P.S., B.P., G.R.W., L.B., W.A., S.S., Y.I., M.A., E.R., A.M., E.J.K., C.W., F.K.S., J.W.C.); and Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass (W.Z.).
authors.forename: Yawen
authors.initials: Y
authors.lastname: Pan
authors.affiliation: From the Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China (Y.Z., Y.P.); Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114 (Y.Z., D.P.S., B.P., G.R.W., L.B., W.A., S.S., Y.I., M.A., E.R., A.M., E.J.K., C.W., F.K.S., J.W.C.); and Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass (W.Z.).
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
authors.affiliation: From the Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China (Y.Z., Y.P.); Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114 (Y.Z., D.P.S., B.P., G.R.W., L.B., W.A., S.S., Y.I., M.A., E.R., A.M., E.J.K., C.W., F.K.S., J.W.C.); and Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass (W.Z.).
authors.forename: John W
authors.initials: JW
authors.lastname: Chen
mesh_terms: D010129:4-Aminobenzoic Acid; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004827:Epilepsy / Q000000981:diagnostic imaging* / Q000201:enzymology*; D005434:Flow Cytometry; D051379:Mice; D064847:Multimodal Imaging; D009195:Peroxidase / Q000378:metabolism*; D010862:Pilocarpine; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: D010862:Pilocarpine; D009195:Peroxidase; D010129:4-Aminobenzoic Acid